FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Cypel, YS Kress, AM Eber, SM Schneiderman, AI Davey, VJ AF Cypel, Yasmin S. Kress, Amii M. Eber, Stephanie M. Schneiderman, Aaron I. Davey, Victoria J. TI Herbicide Exposure, Vietnam Service, and Hypertension Risk in Army Chemical Corps Veterans SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID AIR-FORCE VETERANS; AGENT-ORANGE EXPOSURE; POSTTRAUMATIC-STRESS-DISORDER; PERSISTENT ORGANIC POLLUTANTS; NUTRITION EXAMINATION SURVEY; OPERATION RANCH HAND; AMERICAN-HEART-ASSOCIATION; HEALTH-STATUS; SERUM CONCENTRATIONS; MILITARY SERVICE AB Objective:We examined hypertension risk in Army Chemical Corps (ACC) veterans who sprayed defoliant in Vietnam.Methods:We analyzed data from the 2013 health survey of 3086 ACC veterans and investigated the association between self-reported physician-diagnosed-hypertension (SRH) and herbicide-spray-history adjusting for Vietnam-service-status, rank, age, tobacco/alcohol use, race, and body mass index (BMI). Spray-history was verified against serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (n=636). SRH was confirmed by blood pressure (BP) measurement by trained medical technicians and medical record reviews.Results:Herbicide-spray-history (ORadjusted[95%confidence interval {CI}]=1.74[1.44,2.11]) and Vietnam-service-status (ORadjusted=1.26[1.05,1.53]) were significantly associated with SRH. The association was highest when comparing Vietnam-service-sprayers to non-Vietnam-service-nonsprayers (ORadjusted=2.21[1.76,2.77]). Serum TCDD was highest for Vietnam-service-sprayers. Mean systolic BPs were significantly higher among veterans with SRH than those without (P0.001). Medical records and SRH overall agreement was 89%.Conclusion:Occupational herbicide exposure history and Vietnam-service-status were significantly associated with hypertension risk. C1 [Cypel, Yasmin S.; Kress, Amii M.; Eber, Stephanie M.; Schneiderman, Aaron I.] US Dept Vet Affairs, Program Epidemiol, Postdeployment Hlth Serv 10P4Q, Off Patient Care Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. [Davey, Victoria J.] Vet Hlth Adm, Off Res & Dev, Washington, DC USA. RP Cypel, YS (reprint author), US Dept Vet Affairs, Program Epidemiol, Postdeployment Hlth Serv 10P4Q, Off Patient Care Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. EM yasmin.cypel@va.gov FU Epidemiology Program, Post-Deployment Health Services, Office of Patient Care Services, Department ofVeterans Affairs (VA) FX This study was funded by the Epidemiology Program, Post-Deployment Health Services, Office of Patient Care Services, Department ofVeterans Affairs (VA). No conflicts of interest for any co-authors are declared. NR 85 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD NOV PY 2016 VL 58 IS 11 BP 1127 EP 1136 DI 10.1097/JOM.0000000000000876 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EB3OD UT WOS:000387273800017 PM 27820763 ER PT J AU Mack, JW Cannavale, K Sattayapiwat, O Cheung, B Chen, LH Cooper, RM Chao, CR AF Mack, Jennifer W. Cannavale, Kimberly Sattayapiwat, Olivia Cheung, Bianca Chen, Lie H. Cooper, Robert M. Chao, Chun R. TI Care in the Final Month of Life among Adolescent and Young Adult Cancer Patients in Kaiser Permanente Southern California SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID END-OF-LIFE; PALLIATIVE CARE; INDICATORS; ONCOLOGY AB Background: Little is known about the care that adolescent and young adult (AYA) patients with cancer receive at the end of life (EOL). Objective: To examine care in the last month of life among AYA patients with cancer. Design: Medical record review of the last 30 days of life. Setting/Subjects: One hundred eleven AYA patients aged 15-39 years at death with either stage I-III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. Patients received care in Kaiser Permanente Southern California, an integrated healthcare delivery system, and died from 2007 to 2010. Measurements: Use of intensive measures, including chemotherapy in the last 14 days of life and emergency room visits, hospitalizations, and intensive care unit admissions in the last 30 days; documented care preferences; symptom prevalence and treatment; advance care planning; hospice use; and location of death. Results: One hundred seven patients (96%) had documented care preferences in the last month of life. At first documentation, 72% of patients wished for life-prolonging care, 20% wished for care focused on comfort, and 8% were undecided. Forty-seven percent of patients had documented changes in preferences in the last month, with 40% wishing for life-prolonging care when preferences were last noted before death, 56% preferring comfort, and 4% undecided. Seventy-eight percent of patients received at least one form of intensive EOL care, including 75% of those who preferred comfort measures at last documentation. Conclusions: Many AYA patients enter the last month of life wishing for life-prolonging care. While most ultimately wish for comfort, intensive care is prevalent even among such patients. C1 [Mack, Jennifer W.] Dana Farber Canc Inst, Div Populat Sci, Dept Pediat Oncol, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Cannavale, Kimberly; Sattayapiwat, Olivia; Cheung, Bianca; Chen, Lie H.; Chao, Chun R.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA USA. [Cooper, Robert M.] Kaiser Permanente Southern Calif, Dept Pediat Oncol, Pasadena, CA USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, Div Populat Sci, Dept Pediat Oncol, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. EM jennifer_mack@dfci.harvard.edu FU Cancer Research Network/National Cancer Institute [U24CA171524] FX This study was funded by the Cancer Research Network/National Cancer Institute (U24CA171524.) NR 21 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV PY 2016 VL 19 IS 11 BP 1136 EP 1141 DI 10.1089/jpm.2015.0527 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB2XF UT WOS:000387225200006 PM 27482745 ER PT J AU Lee, KA Ganta, N Horton, JR Chai, E AF Lee, Kathleen A. Ganta, Niharika Horton, Jay R. Chai, Emily TI Evidence for Neurotoxicity Due to Morphine or Hydromorphone Use in Renal Impairment: A Systematic Review SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Review ID CHRONIC KIDNEY-DISEASE; CANCER-PATIENTS; PALLIATIVE CARE; INDUCED NEUROEXCITATION; INTRAVENOUS MORPHINE; MYOCLONIC SPASMS; HOSPICE PATIENTS; PLASMA MORPHINE; PAIN; METABOLITE AB Background: Opioids are the mainstay of pain control for patients with chronic pain. Often, opioids with reported active metabolites, such as morphine and hydromorphone, are thought to increase the risk of neurotoxicity in renal impairment. Objectives: To identify and assess the quality of evidence for neurotoxic effects in patients with renal impairment receiving morphine or hydromorphone. Methods: Systematic searches were conducted of the following databases from inception to December 2015: MEDLINE, CINAHL, EMBASE, in addition to hand-searching relevant review articles' citations. Studies were included if they reported neurotoxic effects of either morphine or hydromorphone for chronic or malignant pain in patients with renal impairment. Review articles and case reports were excluded. Narrative review was undertaken. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess study quality. Results: Six original articles, three prospective and three retrospective studies were identified and assessed. No relevant randomized clinical trials were identified. Conclusions: Although morphine and hydromorphone use may be associated with neurotoxic effects in patients with renal impairment, current evidence consists of very low-quality studies with conflicting findings. Clinicians may consider using either morphine or hydromorphone in mild-to-moderate renal impairment, while closely monitoring for neurotoxic effects, particularly when used in high doses and for extended duration. C1 [Lee, Kathleen A.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. [Ganta, Niharika] Univ Penn, Dept Med, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Horton, Jay R.; Chai, Emily] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. RP Lee, KA (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. EM kathleena_lee@dfci.harvard.edu NR 41 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV PY 2016 VL 19 IS 11 BP 1179 EP 1187 DI 10.1089/jpm.2016.0101 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB2XF UT WOS:000387225200012 PM 27399959 ER PT J AU Ganguli, I Chittenden, E Jackson, V Kimball, AB AF Ganguli, Ishani Chittenden, Eva Jackson, Vicki Kimball, Alexa B. TI Survey on Clinician Perceptions and Practices Regarding Goals of Care Conversations SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article AB Background: Early conversations between clinicians and patients about goals of care may improve patients' quality of life and prevent nonbeneficial care near the end of life, but these conversations are limited in frequency and scope. To address this issue, clinicians are increasingly asked to use standardized medical order forms, like the Medical Orders for Life-Sustaining Treatment (MOLST), to document end-of-life conversations and to help ensure that patients' wishes are realized. In kind, the Centers for Medicare and Medicaid Services recently decided to reimburse physicians as well as nurse practitioners and physician assistants for these conversations. Objective: To explore physicians' and advanced practitioners' (APs') attitudes and behaviors around initiating and documenting goals of care conversations and to identify targets for improvement. Design: Online survey administered between October 1, 2014 and February 20, 2015. Setting/Subjects: Physicians (n = 2492) and APs (n = 336) at an urban academic medical center. Measurements: Clinicians' perceptions and self-reported behaviors regarding goals of care conversations and the Massachusetts MOLST form. Results: We found that 44.0% of physicians and 33.0% of APs reported that they discussed goals of care with all patients with serious, life-limiting illness (p < 0.001). APs were more likely than physicians to report awareness of MOLST forms (55.1% vs. 45.1%, p < 0.001) but less likely to feel comfortable making recommendations on end-of-life care (25.3% vs. 41.0% recommending against resuscitation, p < 0.001; 35.1% vs. 55.7% recommending for resuscitation, p < 0.001). Conclusions: These findings suggest the need to educate physicians and empower APs to facilitate goals of care conversations and use standardized forms, as well as an opportunity for interdisciplinary collaboration. C1 [Ganguli, Ishani; Kimball, Alexa B.] Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02114 USA. [Chittenden, Eva; Jackson, Vicki] Massachusetts Gen Hosp, Palliat Care Serv, Boston, MA 02114 USA. RP Ganguli, I (reprint author), Massachusetts Gen Phys Org, 55 Fruit St,Bulfinch 205, Boston, MA 02114 USA. EM ishani.ganguli@gmail.com NR 6 TC 0 Z9 0 U1 5 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV PY 2016 VL 19 IS 11 BP 1215 EP 1217 DI 10.1089/jpm.2015.0424 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB2XF UT WOS:000387225200017 PM 27303805 ER PT J AU Boehm, I Geisler, D Tam, F King, JA Ritschel, F Seidel, M Bernardoni, F Murr, J Goschke, T Calhoun, VD Roessner, V Ehrlich, S AF Boehm, Ilka Geisler, Daniel Tam, Friederike King, Joseph A. Ritschel, Franziska Seidel, Maria Bernardoni, Fabio Murr, Julia Goschke, Thomas Calhoun, Vince D. Roessner, Veit Ehrlich, Stefan TI Partially restored resting-state functional connectivity in women recovered from anorexia nervosa SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Article ID DEFAULT MODE NETWORK; COGNITIVE CONTROL; COMPONENT ANALYSIS; EATING-DISORDERS; BULIMIA-NERVOSA; CORTEX; BRAIN; PSYCHOPATHOLOGY; HYPOACTIVATION; SCHIZOPHRENIA AB Background We have previously shown increased resting-state functional connectivity (rsFC) in the frontoparietal network (FPN) and the default mode network (DMN) in patients with acute anorexia nervosa. Based on these findings we investigated within-network rsFC in patients recovered from anorexia nervosa to examine whether these abnormalities are a state or trait marker of the disease. To extend the understanding of functional connectivity in patients with anorexia nervosa, we also estimated rsFC between large-scale networks. Methods Girls and women recovered from anorexia nervosa and pair-wise, age- and sex-matched healthy controls underwent a resting-state fMRI scan. Using independent component analyses (ICA), we isolated the FPN, DMN and salience network. We used standard comparisons as well as a hypothesis-based approach to test the findings of our previous rsFC study in this recovered cohort. Temporal correlations between network time-course pairs were computed to investigate functional network connectivity (FNC). Results Thirty-one patients recovered from anorexia nervosa and 31 controls participated in our study. Standard group comparisons revealed reduced rsFC between the dorsolateral prefrontal cortex (dlPFC) and the FPN in the recovered group. Using a hypothesis-based approach we extended the previous finding of increased rsFC between the angular gyrus and the FPN in patients recovered from anorexia nervosa. No group differences in FNC were revealed. Limitations The study design did not allow us to conclude that the difference found in rsFC constitutes a scar effect of the disease. Conclusion This study suggests that some abnormal rsFC patterns found in patients recovered from anorexia nervosa normalize after long-term weight restoration, while distorted rsFC in the FPN, a network that has been associated with cognitive control, may constitute a trait marker of the disorder. C1 [Boehm, Ilka; Geisler, Daniel; Tam, Friederike; King, Joseph A.; Ritschel, Franziska; Seidel, Maria; Bernardoni, Fabio; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Eating Disorder Serv & Res Ctr, Dept Child & Adolescent Psychiat, Fac Med, Dresden, Germany. [Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ehrlich, Stefan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Murr, Julia] Tech Univ Dresden, Fac Med, Dept Psychotherapy & Psychosomat Med, Dresden, Germany. [Goschke, Thomas] Tech Univ Dresden, Dept Psychol, Dresden, Germany. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. RP Ehrlich, S (reprint author), Tech Univ Dresden, Univ Hosp CG Carus, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect,Fac Med, Fetscherstr 74, Dresden, Germany. EM stefan.ehrlich@uniklinikum-dresden.de FU Deutsche Forschungsgemeinschaft [367/5-1, SFB 940]; Swiss Anorexia Nervosa Foundation FX This work was supported by Deutsche Forschungsgemeinschaft (367/5-1 & SFB 940) and Swiss Anorexia Nervosa Foundation grants to S. Ehrlich. The authors thank all members of the research team for their assistance and thank all participants for their cooperation. NR 62 TC 1 Z9 1 U1 2 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 1180-4882 EI 1488-2434 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD NOV PY 2016 VL 41 IS 6 BP 377 EP 385 DI 10.1503/jpn.150259 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EB1OD UT WOS:000387121400006 PM 27045551 ER PT J AU Zhao, WB Yang, W Zhang, HL Yang, J Luo, X Zhu, YQ Yang, M Luo, CM AF Zhao, Wenbing Yang, William Zhang, Honglei Yang, Jack Luo, Xiong Zhu, Yueqin Yang, Mary Luo, Chaomin TI High-throughput state-machine replication using software transactional memory SO JOURNAL OF SUPERCOMPUTING LA English DT Article DE State-machine replication; Software transactional memory; Ordered strong strict two-phase locking; Multiversion concurrency control; One-copy serializability ID BYZANTINE FAULT-TOLERANCE; TRUSTWORTHY COORDINATION AB State-machine replication is a common way of constructing general purpose fault tolerance systems. To ensure replica consistency, requests must be executed sequentially according to some total order at all non-faulty replicas. Unfortunately, this could severely limit the system throughput. This issue has been partially addressed by identifying non-conflicting requests based on application semantics and executing these requests concurrently. However, identifying and tracking non-conflicting requests require intimate knowledge of application design and implementation, and a custom fault tolerance solution developed for one application cannot be easily adopted by other applications. Software transactional memory offers a new way of constructing concurrent programs. In this article, we present the mechanisms needed to retrofit existing concurrency control algorithms designed for software transactional memory for state-machine replication. The main benefit for using software transactional memory in state-machine replication is that general purpose concurrency control mechanisms can be designed without deep knowledge of application semantics. As such, new fault tolerance systems based on state-machine replications with excellent throughput can be easily designed and maintained. In this article, we introduce three different concurrency control mechanisms for state-machine replication using software transactional memory, namely, ordered strong strict two-phase locking, conventional timestamp-based multiversion concurrency control, and speculative timestamp-based multiversion concurrency control. Our experiments show that speculative timestamp-based multiversion concurrency control mechanism has the best performance in all types of workload, the conventional timestamp-based multiversion concurrency control offers the worst performance due to high abort rate in the presence of even moderate contention between transactions. The ordered strong strict two-phase locking mechanism offers the simplest solution with excellent performance in low contention workload, and fairly good performance in high contention workload. C1 [Zhao, Wenbing] Cleveland State Univ, Dept Elect Engn & Comp Sci, Cleveland, OH 44115 USA. [Yang, William] Univ Texas Austin, Texas Adv Comp Ctr, 10100 Burnet Rd, Austin, TX 78758 USA. [Zhang, Honglei] Agilysys Inc, Bellevue, WA USA. [Yang, Jack] Massachusetts Gen Hosp, Div Biostat & Biomath, Boston, MA 02114 USA. [Yang, Jack] Harvard Med Sch, Boston, MA 02114 USA. [Luo, Xiong] Univ Sci & Technol Beijing, Sch Comp & Commun Engn, Beijing 100083, Peoples R China. [Zhu, Yueqin] Minist Land & Resources, Res Dev Ctr, China Geol Survey, Key Lab Geol Informat Technol, Beijing 100037, Peoples R China. [Yang, Mary] Univ Arkansas, Joint Bioinformat Program, George Washington Donaghey Coll Engn & Informat T, Dept Informat Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Yang, Mary] Univ Arkansas Med Sci, 2801 S Univ Ave, Little Rock, AR 72204 USA. [Luo, Chaomin] Univ Detroit Mercy, Dept Elect & Comp Engn, Detroit, MI 48221 USA. RP Zhao, WB (reprint author), Cleveland State Univ, Dept Elect Engn & Comp Sci, Cleveland, OH 44115 USA. EM wenbing@ieee.org OI Zhao, Wenbing/0000-0002-3202-1127 FU Graduate Faculty Travel Award from Cleveland State University; National Key Technologies R&D Program of China [2015BAK38B01]; special funds project for scientific research of public welfare industry from the Ministry of Land and Resources of the Peoples Republic of China [201511079] FX We sincerely thank the anonymous reviewers for their invaluable comments and suggestions. An earlier version of this paper was presented at the 8th International Conference on Advanced Software Engineering & Its Applications [31]. This work was supported in part by a Graduate Faculty Travel Award from Cleveland State University, by the National Key Technologies R&D Program of China under Grant 2015BAK38B01, and by a grant from the special funds project for scientific research of public welfare industry from the Ministry of Land and Resources of the Peoples Republic of China No. 201511079. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8542 EI 1573-0484 J9 J SUPERCOMPUT JI J. Supercomput. PD NOV PY 2016 VL 72 IS 11 BP 4379 EP 4398 DI 10.1007/s11227-016-1747-2 PG 20 WC Computer Science, Hardware & Architecture; Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA EB3AR UT WOS:000387234200019 ER PT J AU Janssen, SJ Pereira, NRP Raskin, KA Ferrone, ML Hornicek, FJ Van Dijk, CN Lozano-Calderon, SA Schwab, JH AF Janssen, Stein J. Pereira, Nuno Rui Paulino Raskin, Kevin A. Ferrone, Marco L. Hornicek, Francis J. Van Dijk, C. Niek Lozano-Calderon, Santiago A. Schwab, Joseph H. TI A Comparison of Questionnaires for Assessing Physical Function in Patients With Lower Extremity Bone Metastases SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE bone; metastasis; function ID REPORTED OUTCOMES ASSESSMENT; SURGICAL-TREATMENT; HEALTH-STATUS; ITEM BANK; SARCOMA; QUALITY; SYSTEM; PROMIS; DISEASE; SCALE AB Objectives: To assess, (i) the degree to which the: PROMIS Physical Function Cancer, PROMIS Neuro-QoL Mobility, Toronto Extremity Salvage Score (TESS), Lower Extremity Function Score (LEFS), and Musculoskeletal Tumor Society score (MSTS), measure physical function; (ii) differences in coverage and reliability; and (iii) difference in completion time. Methods: One hundred of 115 (87%) patients with lower extremity metastases participated in this prospective study. We used exploratory factor analysis-correlating questionnaires with an underlying trait-to assess if questionnaires measure the same. Coverage was assessed by floor and ceiling effect and reliability by the standard error of measurement (SEM). Completion time was compared using the Friedman test. Results: All questionnaires measured the same concept; demonstrated by high correlations (>0.7). Floor effect was absent, while ceiling effect was present in all, but highest for the PROMIS Neuro-QoL Mobility (7%). The SEM was below the threshold-indicating reliability-over a wide range of ability levels for the PROMIS-Physical Function, TESS, and LEFS. Completion time differed between questionnaires (P<0.001) and was shortest for the PROMIS questionnaires. Conclusions: The PROMIS Physical Function is the most useful questionnaire. This is due to its reliability over a wide range of ability levels, validity, brevity, and good coverage. (C) 2016 Wiley Periodicals, Inc. C1 [Janssen, Stein J.; Pereira, Nuno Rui Paulino; Raskin, Kevin A.; Hornicek, Francis J.; Lozano-Calderon, Santiago A.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Boston, MA USA. [Ferrone, Marco L.] Harvard Med Sch, Brigham & Womens Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Boston, MA USA. [Van Dijk, C. Niek] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Amsterdam, Netherlands. RP Janssen, SJ (reprint author), Massachusetts Gen Hosp, Orthopaed Surg, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM steinjanssen@gmail.com FU Anna Foundation (Oegstgeest, the Netherlands); De Drie Lichten Foundation (Hilversum, the Netherlands); KWF Kankerbestrijding (Amsterdam, the Netherlands); Michael van Vloten Foundation (Rotterdam, the Netherlands) FX One author (SJ) certifies that he has received, an amount less than USD 10,000, from the Anna Foundation (Oegstgeest, the Netherlands), an amount less than USD 10,000 from the De Drie Lichten Foundation (Hilversum, the Netherlands), an amount less than USD 10,000 from the KWF Kankerbestrijding (Amsterdam, the Netherlands), and an amount less than USD 10,000, from the Michael van Vloten Foundation (Rotterdam, the Netherlands). One author (CNvD) certifies that he is a consultant for Smith and Nephew; outside the submitted work. NR 29 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD NOV 1 PY 2016 VL 114 IS 6 BP 691 EP 696 DI 10.1002/jso.24400 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA EB0KG UT WOS:000387032100006 PM 27511611 ER PT J AU Nansel, TR Lipsky, LM Eisenberg, MH Liu, AY Mehta, SN Laffel, LMB AF Nansel, Tonja R. Lipsky, Leah M. Eisenberg, Miriam H. Liu, Aiyi Mehta, Sanjeev N. Laffel, Lon M. B. TI Can Families Eat Better Without Spending More? Improving Diet Quality Does Not Increase Diet Cost in a Randomized Clinical Trial among Youth with Type 1 Diabetes and Their Parents SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Diet quality; Diet cost; Type 1 diabetes; Intervention; Families ID ENERGY-DENSITY; LOW-INCOME; SOCIOECONOMIC-STATUS; HEALTHFUL DIET; UNITED-STATES; FOOD COSTS; US ADULTS; FAT DIETS; NUTRITION; WOMEN AB Background Although cost is a frequently cited barrier to healthful eating, limited prospective data exist. Objective To examine the association of diet cost with diet quality change. Design An 18-month randomized clinical trial evaluated a dietary intervention. Participants and setting Youth with type 1 diabetes duration >= 1 year, age 8.0 to 16.9 years, receiving care at an outpatient tertiary diabetes center in Boston, MA, participated along with a parent from 2010 to 2013 (N=136). Eighty-two percent of participants were from middle- to upper-income households. Intervention The family-based behavioral intervention targeted intake of whole plant foods. Main outcome measures Diet quality as indicated by the Healthy Eating Index 2005 (HEI-2005) (which measures conformance to the 2005 Dietary Guidelines for Americans) and whole plant food density (cup or ounce equivalents per 1,000 kcal target food groups) were calculated from 3-day food records of youth and parent dietary intake at six and four time points, respectively. Food prices were obtained from two online supermarkets common to the study location. Daily diet cost was calculated by summing prices of reported foods. Statistical analyses performed Random effects models estimated treatment group differences in time-varying diet cost. Separate models for youth and parent adjusted for covariates examined associations of time-varying change in diet quality with change in diet cost. Results There was no treatment effect on time-varying diet cost for either youth (0.49, 95% CI -1.07 to 0.08; P=0.10) or parents (beta .24, 95% CI -1.61 to 2.08; P=0.80). In addition, time-varying change in diet quality indicators was not associated with time varying change in diet cost for youth. Among parents, a 1-cup or 1-oz equivalent increase in whole plant food density was associated with a $0.63/day lower diet cost (0.63, 95% CI -1.20 to 0.05; P=0.03). Conclusions Improved diet quality was not accompanied by greater cost for youth with type 1 diabetes and their parents participating in a randomized clinical trial. Findings challenge the prevailing assumption that improving diet quality necessitates greater cost. C1 [Nansel, Tonja R.; Lipsky, Leah M.; Eisenberg, Miriam H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20892 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Mehta, Sanjeev N.; Laffel, Lon M. B.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Laffel, Lon M. B.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. RP Nansel, TR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, 6710B Rockledge Dr,MSC 7004, Bethesda, MD 20892 USA.; Nansel, TR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, Bethesda, MD USA. EM nanselt@mail.nih.gov OI Eisenberg, Miriam/0000-0002-7133-8805; Nansel, Tonja/0000-0002-8298-7595; Liu, Aiyi/0000-0002-6618-5082 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200703434C, HHSN2752008000031/HHSN275002] FX This research was supported by the intramural research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, contract nos. HHSN267200703434C and HHSN2752008000031/HHSN275002. NR 60 TC 0 Z9 0 U1 13 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD NOV PY 2016 VL 116 IS 11 BP 1751 EP 1759 DI 10.1016/j.jand.2016.07.005 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EB2OZ UT WOS:000387203000004 PM 27597745 ER PT J AU Rajiah, P Raza, S Saboo, SS Ghoshhajra, B Abbara, S AF Rajiah, Prabhakar Raza, Samreen Saboo, Sachin S. Ghoshhajra, Brian Abbara, Suhny TI Update on the Role of Cardiac Magnetic Resonance in Acquired Nonischemic Cardiomyopathies SO JOURNAL OF THORACIC IMAGING LA English DT Review DE cardiac magnetic resonance; cardiomyopathy; heart; late gadolinium enhancement ID LATE GADOLINIUM ENHANCEMENT; TAKO-TSUBO CARDIOMYOPATHY; LEFT-VENTRICULAR FUNCTION; BETA-THALASSEMIA MAJOR; RANDOMIZED CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; APICAL BALLOONING SYNDROME; MYOCARDIAL IRON; TAKOTSUBO CARDIOMYOPATHY; DILATED CARDIOMYOPATHY AB Cardiomyopathies refer to a variety of myocardial disorders without underlying coronary artery disease, valvular heart disease, hypertension, or congenital heart disease. Several imaging modalities are available, but cardiac magnetic resonance (CMR) has now established itself as a crucial imaging technique in the evaluation of several cardiomyopathies. It not only provides comprehensive information on structure and function, but also can perform tissue characterization, which helps in establishing the etiology of cardiomyopathy. CMR is also useful in establishing the diagnosis, providing guidance for endomyocardial biopsy, accurate quantification of function, volumes, and fibrosis, prognostic determination, risk stratification, and monitoring response to therapy. In this article, we review the current role of CMR in the evaluation of several acquired nonischemic cardiomyopathies, particularly focusing on recent advances in knowledge. We also discuss in detail a select group of common acquired nonischemic cardiomyopathies. C1 [Rajiah, Prabhakar; Saboo, Sachin S.; Abbara, Suhny] UT Southwestern Med Ctr, Cardiothorac Imaging, Dept Radiol, E6-120A, Dallas, TX 75390 USA. [Raza, Samreen] UT Southwestern Med Ctr, Dept Cardiol, Dallas, TX USA. [Ghoshhajra, Brian] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Abbara, S (reprint author), UT Southwestern Med Ctr, Cardiothorac Imaging, Dept Radiol, E6-120A, Dallas, TX 75390 USA. EM Suhny.abbara@utsouthwestern.edu NR 115 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0883-5993 EI 1536-0237 J9 J THORAC IMAG JI J. Thorac. Imaging PD NOV PY 2016 VL 31 IS 6 BP 348 EP 366 DI 10.1097/RTI.0000000000000226 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EB1AH UT WOS:000387078000009 PM 27438188 ER PT J AU Verdini, D Vargas, D Kuo, A Ghoshhajra, B Kim, P Murillo, H Kirsch, J Lane, M Restrepo, C AF Verdini, Daniel Vargas, Daniel Kuo, Anderson Ghoshhajra, Brian Kim, Phillip Murillo, Horacio Kirsch, Jacobo Lane, Michael Restrepo, Carlos TI Coronary-Pulmonary Artery Fistulas A Systematic Review SO JOURNAL OF THORACIC IMAGING LA English DT Article DE coronary artery anomaly; coronary artery fistula; coronary computed tomography angiography; coronary artery aneurysm ID VENTRICULAR SEPTAL-DEFECT; ANTERIOR DESCENDING ARTERY; SUCCESSFUL SURGICAL REPAIR; COMPUTED-TOMOGRAPHY; MYOCARDIAL-ISCHEMIA; IMAGING MODALITIES; COIL EMBOLIZATION; CT FINDINGS; ATRESIA; ANEURYSM AB Purpose: Coronary-pulmonary arterial fistulas (CPAFs) are rare coronary artery anomalies that have been described only in limited case reports. This study aims to evaluate the clinical presentation and imaging findings of CPAFs collected from 6 participating medical centers along with CPAFs reported in the literature, to discern any general trends present in CPAFs. Materials and Methods: A total of 25 cases of CPAF diagnosed by coronary computed tomography angiography were collected across 6 participating institutions. In addition, utilizing a PubMed literature search, 78 additional CPAF cases were obtained. The imaging findings and relevant clinical history were reviewed. Results: Of the 103 CPAF patients, 60 (63% of patients with sex known) were male, with ages ranging from newborn to 88 years (mean= 46.1 y). The most common symptoms reported were chest pain (n= 40, 39%) and dyspnea (n= 26, 25%), with a murmur as the most common physical examination finding (n= 38, 37%). The most common coronary artery of origin for a CPAF was the left main/left anterior descending (n= 87, 84%), followed by the right coronary artery (n= 39, 38%). The fistula most commonly terminated in the main pulmonary artery (n= 92, 89%). Multiple CPAFs were present in 46 cases (45%). Coronary artery aneurysms were identified in 20 cases (19%). Pediatric CPAF cases were usually associated with pulmonary atresia with ventricular septal defect. Conclusions: CPAFs are seen in a variety of clinical settings, from infants with advanced congenital heart disease to elderly patients who have undergone revascularization surgery. Although coronary artery fistulas have previously been described as rarely involving multiple coronary arteries, with the right coronary artery being most often involved, our series demonstrates that multiple fistulas are commonly present, with the most common pattern being between the left main/left anterior descending and the main pulmonary trunk. C1 [Verdini, Daniel; Kuo, Anderson; Restrepo, Carlos] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Lane, Michael] Methodist Childrens Hosp, San Antonio, TX USA. [Vargas, Daniel] Univ Colorado, Aurora, CO USA. [Ghoshhajra, Brian; Kim, Phillip] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Murillo, Horacio] Sutter Med Grp, Sacramento, CA USA. [Kirsch, Jacobo] Cleveland Clin Florida, Imaging Inst, Weston, FL USA. RP Verdini, D (reprint author), 7703 Floyd Curl Dr,Mail Stop 7800, San Antonio, TX 78229 USA. EM VerdiniD@gmail.com NR 77 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0883-5993 EI 1536-0237 J9 J THORAC IMAG JI J. Thorac. Imaging PD NOV PY 2016 VL 31 IS 6 BP 380 EP 390 DI 10.1097/RTI.0000000000000232 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EB1AH UT WOS:000387078000012 PM 27768631 ER PT J AU Ahsan, ZS Rivlin, M Jupiter, JB AF Ahsan, Zahab S. Rivlin, Michael Jupiter, Jesse B. TI Ulnar-Sided Wrist Pain due to Long Ulnar Styloid: A Case Report SO JOURNAL OF WRIST SURGERY LA English DT Article DE long ulnar styloid; ulnar styloid impaction; ulnocarpal abutment; chronic wrist pain; wrist arthroscopy ID IMPACTION SYNDROME AB Ulnar styloid impaction syndrome involves repetitive friction between an excessively long ulnar styloid and the carpus, resulting in chondromalacia, synovitis, and pain. The arthroscopic diagnosis, evaluation, and management of this syndrome are not well characterized. We present a patient with chronic wrist pain of unknown origin, culminating with arthroscopic findings demonstrating substantial loss of articular cartilage on both the lunate and triquetrum. The patient successfully underwent operative ulnar styloid excision, ultimately resolving chronic wrist pain symptomology. C1 [Ahsan, Zahab S.] Univ Washington, Dept Orthopaed & Sports Med, 325 9th Ave,Box 359798, Seattle, WA 98104 USA. [Rivlin, Michael] Thomas Jefferson Univ, Rothman Inst, Dept Hand & Upper Extrem Surg, Philadelphia, PA 19107 USA. [Jupiter, Jesse B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA USA. RP Ahsan, ZS (reprint author), Univ Washington, Dept Orthopaed & Sports Med, 325 9th Ave,Box 359798, Seattle, WA 98104 USA. EM zahsan@uw.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2163-3916 EI 2163-3924 J9 J WRIST SURG JI J. WRIST SURG. PD NOV PY 2016 VL 5 IS 4 BP 311 EP 314 DI 10.1055/s-0035-1570743 PG 4 WC Orthopedics SC Orthopedics GA EB0KN UT WOS:000387032800013 PM 27777823 ER PT J AU Neto, AS Barbas, CSV Simonis, FD Artigas-Raventos, A Canet, J Determann, RM Anstey, J Hedenstierna, G Hemmes, SNT Hermans, G Hiesmayr, M Hollmann, MW Jaber, S Martin-Loeches, I Mills, GH Pearse, RM Putensen, C Schmid, W Severgnini, P Smith, R Treschan, TA Tschernko, EM Melo, MFV Wrigge, H de Abreu, MG Pelosi, P Schultz, MJ AF Serpa Neto, Ary Barbas, Carmen S. V. Simonis, Fabienne D. Artigas-Raventos, Antonio Canet, Jaume Determann, Rogier M. Anstey, James Hedenstierna, Goran Hemmes, Sabrine N. T. Hermans, Greet Hiesmayr, Michael Hollmann, Markus W. Jaber, Samir Martin-Loeches, Ignacio Mills, Gary H. Pearse, Rupert M. Putensen, Christian Schmid, Werner Severgnini, Paolo Smith, Roger Treschan, Tanja A. Tschernko, Edda M. Melo, Marcos F. V. Wrigge, Hermann de Abreu, Marcelo Gama Pelosi, Paolo Schultz, Marcus J. CA PRoVENT Network Investigator PROVE Network Investigator TI Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study SO LANCET RESPIRATORY MEDICINE LA English DT Article ID ACUTE LUNG INJURY; END-EXPIRATORY PRESSURE; RECEIVING MECHANICAL VENTILATION; LOW TIDAL VOLUMES; PULMONARY COMPLICATIONS; PROTECTIVE-VENTILATION; DRIVING PRESSURE; MORTALITY; METAANALYSIS; EVOLUTION AB Background Scant information exists about the epidemiological characteristics and outcome of patients in the intensive care unit (ICU) at risk of acute respiratory distress syndrome (ARDS) and how ventilation is managed in these individuals. We aimed to establish the epidemiological characteristics of patients at risk of ARDS, describe ventilation management in this population, and assess outcomes compared with people at no risk of ARDS. Methods PRoVENT (PRactice of VENTilation in critically ill patients without ARDS at onset of ventilation) is an international, multicentre, prospective study undertaken at 119 ICUs in 16 countries worldwide. All patients aged 18 years or older who were receiving mechanical ventilation in participating ICUs during a 1-week period between January, 2014, and January, 2015, were enrolled into the study. The Lung Injury Prediction Score (LIPS) was used to stratify risk of ARDS, with a score of 4 or higher defining those at risk of ARDS. The primary outcome was the proportion of patients at risk of ARDS. Secondary outcomes included ventilatory management (including tidal volume [V-T] expressed as mL/kg predicted bodyweight [PBW], and positive end-expiratory pressure [PEEP] expressed as cm H2O), development of pulmonary complications, and clinical outcomes. The PRoVENT study is registered at ClinicalTrials.gov, NCT01868321. The study has been completed. Findings Of 3023 patients screened for the study, 935 individuals fulfilled the inclusion criteria. Of these critically ill patients, 282 were at risk of ARDS (30%, 95% CI 27-33), representing 0.14 cases per ICU bed over a 1-week period. V-T was similar for patients at risk and not at risk of ARDS (median 7.6 mL/kg PBW [IQR 6.7-9.1] vs 7.9 mL/kg PBW [6.8-9.1]; p=0.346). PEEP was higher in patients at risk of ARDS compared with those not at risk (median 6.0 cm H2O [IQR 5.0-8.0] vs 5.0 cm H2O [5.0-7.0]; p<0.0001). The prevalence of ARDS in patients at risk of ARDS was higher than in individuals not at risk of ARDS (19/260 [7%] vs 17/556 [3%]; p=0.004). Compared with individuals not at risk of ARDS, patients at risk of ARDS had higher in-hospital mortality (86/543 [16%] vs 74/232 [32%]; p<0.0001), ICU mortality (62/533 [12%] vs 66/227 [29%]; p<0.0001), and 90-day mortality (109/653 [17%] vs 88/282 [31%]; p<0. 0001). V-T did not differ between patients who did and did not develop ARDS (p=0.471 for those at risk of ARDS; p=0.323 for those not at risk). Interpretation Around a third of patients receiving mechanical ventilation in the ICU were at risk of ARDS. Pulmonary complications occur frequently in patients at risk of ARDS and their clinical outcome is worse compared with those not at risk of ARDS. There is potential for improvement in the management of patients without ARDS. Further refinements are needed for prediction of ARDS. C1 [Serpa Neto, Ary; Simonis, Fabienne D.; Schultz, Marcus J.] Acad Med Ctr, Dept Intens Care, Amsterdam, Netherlands. [Serpa Neto, Ary; Simonis, Fabienne D.; Schultz, Marcus J.] Acad Med Ctr, LEICA, Amsterdam, Netherlands. [Serpa Neto, Ary; Barbas, Carmen S. V.] Hosp Israelita Albert Einstein, Dept Intens Care Med, Sao Paulo, Brazil. [Barbas, Carmen S. V.] Univ Sao Paulo, Fac Med, Dept Pulmonol, Sao Paulo, Brazil. [Artigas-Raventos, Antonio] Corp Sanitaria & Univ Parc Tauli, CIBER Enfermedades Resp, Hosp Sabadell, Dept Intens Care Med, Sabadell, Spain. [Canet, Jaume] Hosp Badalona Germans Trias & Pujol, Dept Anesthesiol, Barcelona, Spain. [Martin-Loeches, Ignacio] St James Hosp, Trinity Ctr Hlth Sci, MICRO, Dept Clin Med, Dublin, Ireland. [Determann, Rogier M.] Westfriesgasthuis, Dept Crit Care, Hoorn, Netherlands. [Anstey, James; Smith, Roger] St Vincents Hosp, Dept Intens Care, Melbourne, Vic, Australia. [Hedenstierna, Goran] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Hemmes, Sabrine N. T.; Hollmann, Markus W.] Acad Med Ctr, Dept Anesthesiol, Amsterdam, Netherlands. [Hermans, Greet] Univ Hosp Leuven, Div Gen Internal Med, Med Intens Care Unit, Leuven, Belgium. [Hermans, Greet] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Intens Care Med, Leuven, Belgium. [Hiesmayr, Michael; Schmid, Werner; Tschernko, Edda M.] Med Univ Vienna, Div Cardiac Thorac & Vasc Anesthesia & Intens Car, Vienna, Austria. [Jaber, Samir] St Eloi Univ Hosp, Dept Crit Care Med & Anesthesiol SAR B, Montpellier, France. [Mills, Gary H.] Sheffield Teaching Hosp, Dept Anaesthesia & Crit Care Med, Sheffield, S Yorkshire, England. [Pearse, Rupert M.] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England. [Putensen, Christian] Univ Hosp Bonn, Dept Anesthesiol & Intens Care Med, Bonn, Germany. [Severgnini, Paolo] Insubria Univ, Dept Biotechnol & Sci Life, Varese, Italy. [Treschan, Tanja A.] Dusseldorf Univ Hosp, Dept Anaesthesiol, Dusseldorf, Germany. [Melo, Marcos F. V.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Wrigge, Hermann] Univ Leipzig, Dept Anesthesiol & Intens Care Med, Leipzig, Germany. [de Abreu, Marcelo Gama] Univ Hosp Carl Gustav Carus, Pulm Engn Grp, Dept Anesthesiol & Intens Care Med, Dresden, Germany. [de Abreu, Marcelo Gama] Tech Univ Dresden, Dresden, Germany. [Pelosi, Paolo] Univ Genoa, IRCCS San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy. RP Neto, AS (reprint author), Hosp Israelita Albert Einstein, Dept Crit Care Med, BR-05652900 Sao Paulo, Brazil. EM aryserpa@terra.com.br RI Pearse, Rupert/H-5426-2011; OI Pearse, Rupert/0000-0002-4373-5934; Cortegiani, Andrea/0000-0003-1416-9993 NR 38 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD NOV PY 2016 VL 4 IS 11 BP 882 EP 893 DI 10.1016/S2213-2600(16)30305-8 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EB4FL UT WOS:000387325200027 PM 27717861 ER PT J AU Varvares, MA Walker, RJ Chiosea, S AF Varvares, Mark A. Walker, Ronald J. Chiosea, Simion TI Does a specimen-based margin analysis of early tongue cancer better predict local control? SO LARYNGOSCOPE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HEAD C1 [Varvares, Mark A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Walker, Ronald J.] St Louis Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, St Louis, MO USA. [Chiosea, Simion] Univ Pittsburg, Med Ctr, Dept Pathol, Pittsburgh, PA USA. Presbyterian Univ Hosp, Pittsburgh, PA USA. RP Varvares, MA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM mark_varvares@meei.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2016 VL 126 IS 11 BP 2426 EP 2427 DI 10.1002/lary.26081 PG 2 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EA9AN UT WOS:000386932400008 PM 27313090 ER PT J AU Bergmark, RW Sedaghat, AR AF Bergmark, Regan W. Sedaghat, Ahmad R. TI Antibiotic prescription for acute rhinosinusitis: Emergency departments versus primary care providers SO LARYNGOSCOPE LA English DT Article DE Antibiotics; sinusitis; emergency service; hospital; healthcare disparities; healthcare delivery; insurance; socioeconomic factors; ambulatory care sensitive condition; primary care ID CLINICAL-PRACTICE GUIDELINE; ACUTE SINUSITIS; RESPIRATORY-INFECTIONS; ADULT SINUSITIS; DIAGNOSIS; POPULATION; CHILDREN AB Objectives/HypothesisWe have previously identified patient characteristics associated with emergency department (ED) rather than primary-care provider (PCP) presentation for uncomplicated acute rhinosinusitis (ARS). Here we investigate potential disparities in prescription of antibiotics for patients presenting to a PCP versus ED for uncomplicated ARS. Study DesignCross-sectional study of the 2005 to 2010 National Ambulatory Medical Care Surveys and National Hospital Ambulatory Medical Care Surveys. MethodsA total of 37,975,715 patient presentations for uncomplicated ARS to PCPs and EDs. The primary outcome measure was prescription of an oral antibiotic, which was tested for association with clinical setting (PCP vs. ED) and clinical, demographic, and socioeconomic patient characteristics. ResultsAmong adult ARS presentations, 57.0% received an antibiotic prescription from a PCP versus 59.1% in the ED. Pediatric patients also were commonly prescribed antibiotics by PCPs (52.9%) and EDs (51.4%). Compared to PCPs, EDs were not associated with antibiotic prescription for adults (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 0.79-1.50, P = 0.613) or children (OR = 0.94, 95% CI: 0.51-1.72, P = 0.840). Among PCP visits, antibiotic prescription was more likely in the Northeast United States (OR = 2.90, 95% CI: .31-6.38, P = 0.009). No other demographic, clinical, or socioeconomic patient characteristics, including insurance status, were associated with antibiotic prescription by PCPs or EDs. ConclusionMore than half of ARS patients presenting to PCPs and EDs are prescribed antibiotics. There was no differential antibiotic prescription for ED versus PCP presentation. ARS patients in the Northeast were more likely to receive antibiotics from PCPs, whereas no such variation was seen for EDs. Interventions targeting PCPs, especially in the Northeast, may reduce excessive antibiotic utilization. Level of Evidence4. Laryngoscope, 126:2439-2444, 2016 C1 [Bergmark, Regan W.; Sedaghat, Ahmad R.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. [Bergmark, Regan W.; Sedaghat, Ahmad R.] Harvard Med Sch, Boston, MA USA. RP Bergmark, RW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM regan_bergmark@meei.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2016 VL 126 IS 11 BP 2439 EP 2444 DI 10.1002/lary.26001 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EA9AN UT WOS:000386932400011 PM 27076067 ER PT J AU Likhterov, I Tuttle, RM Haser, GC Su, HK Bergman, D Alon, EE Bernet, V Brett, E Cobin, R Dewey, EH Doherty, G Dos Reis, LL Klopper, J Lee, SL Lupo, MA Machac, J Mechanick, JI Milas, M Orloff, L Randolph, G Ross, DS Rowe, ME Smallridge, R Terris, D Tufano, RP Urken, ML AF Likhterov, Ilya Tuttle, R. Michael Haser, Grace C. Su, Henry K. Bergman, Donald Alon, Eran E. Bernet, Victor Brett, Elise Cobin, Rhoda Dewey, Eliza H. Doherty, Gerard Dos Reis, Laura L. Klopper, Joshua Lee, Stephanie L. Lupo, Mark A. Machac, Josef Mechanick, Jeffrey I. Milas, Mira Orloff, Lisa Randolph, Gregory Ross, Douglas S. Rowe, Meghan E. Smallridge, Robert Terris, David Tufano, Ralph P. Urken, Mark L. TI Improving the adoption of thyroid cancer clinical practice guidelines SO LARYNGOSCOPE LA English DT Review DE Differentiated thyroid carcinoma; thyroid nodules; clinical practice guidelines; clinical decision making; computer-based support systems ID DECISION-SUPPORT-SYSTEMS; ATA PRACTICE GUIDELINES; UNITED-STATES; STANDARDIZED PRODUCTION; AMERICAN ASSOCIATION; CARE; ENDOCRINOLOGISTS; MANAGEMENT; QUALITY; IMPROVEMENT AB Objectives/HypothesisTo present an overview of the barriers to the implementation of clinical practice guidelines (CPGs) in thyroid cancer management and to introduce a computer-based clinical support system. Data SourcesPubMed. Review Methods: A review of studies on adherence to CPGs was conducted. ResultsAwareness and adoption of CPGs is low in thyroid cancer management. Barriers to implementation include unfamiliarity with the CPGs and financial concerns. Effective interventions to improve adherence are possible, especially when they are readily accessible at the point of care delivery. Computerized clinical support systems show particular promise. The authors introduce the clinical decision making modules (CDMMs) of the Thyroid Cancer Care Collaborative, a thyroid cancer-specific electronic health record. These computer-based modules can assist clinicians with implementation of these recommendations in clinical practice. ConclusionComputer-based support systems can help clinicians understand and adopt the thyroid cancer CPGs. By integrating patient characteristics and guidelines at the point of care delivery, the CDMMs can improve adherence to the guidelines and help clinicians provide high-quality, evidence-based, and individualized patient care in the management of differentiated thyroid cancer. Laryngoscope, 126:2640-2645, 2016 C1 [Likhterov, Ilya; Urken, Mark L.] Mt Sinai Beth Israel, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Tuttle, R. Michael] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Haser, Grace C.; Su, Henry K.; Dewey, Eliza H.; Dos Reis, Laura L.; Rowe, Meghan E.] Thyroid Head & Neck Canc THANC Fdn, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Bergman, Donald; Brett, Elise; Cobin, Rhoda; Machac, Josef; Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Bergman, Donald; Brett, Elise; Cobin, Rhoda; Machac, Josef; Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Radiol, New York, NY 10029 USA. [Bernet, Victor; Smallridge, Robert] Mayo Clin Jacksonville, Dept Endocrinol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Lupo, Mark A.] Florida State Univ, Coll Med, Thyroid & Endocrine Ctr Florida, Sarasota, FL USA. [Doherty, Gerard] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Lee, Stephanie L.] Boston Med Ctr, Dept Med, Sect Endocrinol Diabet & Nutr, Boston, MA USA. [Randolph, Gregory; Ross, Douglas S.] Massachusetts Gen Hosp, Dept Otolaryngol, Boston, MA 02114 USA. [Randolph, Gregory; Ross, Douglas S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Klopper, Joshua] Sch Med, Div Endocrinol, Aurora, CO USA. [Milas, Mira] Banner Univ Med Ctr Phoenix, Dept Surg, Sect Endocrine Surg, Phoenix, AZ USA. [Orloff, Lisa] Stanford Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. [Terris, David] Georgia Regents Univ, Dept Otolaryngol, Augusta, GA USA. [Tufano, Ralph P.] Johns Hopkins Sch Med, Dept Otolaryngol, Baltimore, MD USA. [Alon, Eran E.] Chaim Sheba Med Ctr, Dept Otolaryngol Head & Neck Surg, Tel Hashomer, Israel. RP Haser, GC (reprint author), Thyroid Head & Neck Canc THANC Fdn, 10 Union Sq East,Suite 5B, New York, NY 10003 USA. EM ghaser@thancfoundation.org FU Mount Sinai Health System (New York, NY) FX The authors would like to acknowledge the generous support of the Mount Sinai Health System (New York, NY) in support of this research. All authors are involved in the development and/or management of the Thyroid Cancer Care Collaborative. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 30 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2016 VL 126 IS 11 BP 2640 EP 2645 DI 10.1002/lary.25986 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EA9AN UT WOS:000386932400044 PM 27074952 ER PT J AU Meyer, JD Ellingson, LD Koltyn, KF Stegner, AJ Kim, JS Cook, DB AF Meyer, Jacob D. Ellingson, Laura D. Koltyn, Kelli F. Stegner, Aaron J. Kim, Jee-Seon Cook, Dane B. TI Psychobiological Responses to Preferred and Prescribed Intensity Exercise in Major Depressive Disorder SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ANTIDEPRESSANT RESPONSE; BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF); PREFERRED EXERTION; AFFECT; ACUTE EXERCISE; EXERCISE PRESCRIPTION ID NEUROTROPHIC FACTOR BDNF; MAXIMAL OXYGEN-UPTAKE; PHYSICAL-ACTIVITY; PERCEIVED EXERTION; GRADED-EXERCISE; MOOD STATES; DSM-IV; VALIDITY; QUESTIONNAIRE; PRESCRIPTION AB Exercise acutely improves mood in major depressive disorder (MDD). However, it is unknown whether benefits differ depending on whether exercise intensity is self-selected or prescribed. Purpose This study aimed to compare psychological and biological responses to preferred and prescribed steady-state exercise intensities to a patient-selected preferred intensity. Method Female adults (N = 24, age = 38.6 14.0 yr) diagnosed with MDD completed four 30-min sessions of cycling exercise at three prescribed intensities (RPE of 11, 13, and 15) and one session with a self-selected intensity (preferred). Order was randomized and counterbalanced. Depressed mood (DM) was evaluated before, 10 min, and 30 min postexercise using the Profile of Mood States. Serum brain-derived neurotrophic factor (BDNF) was measured before and within 10 min postexercise. Changes in BDNF and DM for the preferred session were compared with the following prescribed sessions: 1) performed at the most similar intensity (matched on RPE; closest) and 2) with the greatest improvement in DM (greatest). Results Compared with the preferred session, improvement in DM was significantly larger after the greatest session (30 min postexercise: -11.8 +/- 7.4 vs -3.4 +/- 4.8), and the BDNF response was significantly greater after the closest session (5.4 +/- 6.9 vs -1.4 +/- 9.8 ngmL(-1)). Conclusions Permitting patients to select their own exercise intensity did not maximize improvements in mood. Further, preferred intensity exercise was also associated with a smaller BDNF response. Overall, the results suggest that exercise undertaken to improve mood should be prescribed on an individual basis in MDD and not necessarily based on the patient's preferred intensity. Clinicians, psychologists, and other practitioners should consider providing clear exercise intensity recommendations for symptom management in depression rather than allowing patients to self-select their intensity. C1 [Meyer, Jacob D.] Univ Wisconsin, Dept Family Med & Community Hlth, Madison, WI USA. [Meyer, Jacob D.; Koltyn, Kelli F.; Stegner, Aaron J.; Cook, Dane B.] Univ Wisconsin, Dept Kinesiol, Madison, WI USA. [Ellingson, Laura D.] Iowa State Univ, Dept Kinesiol, Ames, IA USA. [Stegner, Aaron J.; Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Kim, Jee-Seon] Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. RP Meyer, JD (reprint author), 2000 Observ Dr, Madison, WI 53706 USA. EM jdmeyer3@wisc.edu FU Virginia Horne Henry Gift Fund; University of Wisconsin-Madison Graduate School; Wisconsin Center for Education Research; National Research Service Award from Health Resources and Services Administration [T32HP10010] FX This project was funded, in part, by the Virginia Horne Henry Gift Fund, the University of Wisconsin-Madison Graduate School, and the Wisconsin Center for Education Research. Jacob Meyer was partially supported by a National Research Service Award from the Health Resources and Services Administration T32HP10010 to the University of Wisconsin Department of Family Medicine and Community Health. None of the funding sources were involved in the study design, collection, analysis, or interpretation of the data. The authors would like to thank Lauren Schlapman, Hannah Feinstein, Shawn Tipple, Matthew Patton, Caroline Wickler, and Rachel Prince for their assistance. The authors report no conflicts of interest. Results of this study do not constitute endorsement by the American College of Sports Medicine. NR 44 TC 0 Z9 0 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD NOV PY 2016 VL 48 IS 11 BP 2207 EP 2215 DI 10.1249/MSS.0000000000001022 PG 9 WC Sport Sciences SC Sport Sciences GA EA4OU UT WOS:000386593200017 PM 27387295 ER PT J AU Ahani, R Roohvand, F Cohan, RA Etemadzadeh, MH Mohajel, N Behdani, M Shahosseini, Z Madani, N Azadmanesh, K AF Ahani, Roshank Roohvand, Farzin Cohan, Reza Ahangari Etemadzadeh, Mohammad Hossein Mohajel, Nasir Behdani, Mahdi Shahosseini, Zahra Madani, Navid Azadmanesh, Kayhan TI Sindbis Virus-Pseudotyped Lentiviral Vectors Carrying VEGFR2-Specific Nanobody for Potential Transductional Targeting of Tumor Vasculature SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE Cancer gene therapy; Lentiviral vectors; Angiogenesis; VEGFR2; Pseudotyping; Nanobody; Transductional targeting ID CANCER-THERAPY; GENE DELIVERY; RETROVIRAL VECTORS; ENDOTHELIAL-CELLS; GROWTH; ANTIBODY; RECEPTOR; VEGF; GLYCOPROTEIN; ANGIOGENESIS AB Introduction of selectivity/specificity into viral-based gene delivery systems, such as lentiviral vectors (LVs), is crucial in their systemic administration for cancer gene therapy. The pivotal role of tumor-associated endothelial cells (TAECs) in tumor angiogenesis and overexpression of vascular endothelial growth factor receptor-2 (VEGFR2 or KDR) in TAECs makes them a potent target in cancer treatment. Herein, we report the development of VEGFR2-targeted LVs pseudotyped with chimeric sindbis virus E2 glycoprotein (cSVE2s). For this purpose, either sequence of a VEGFR2-specific nanobody or its natural ligand (VEGF(121)) was inserted into the binding site of sindbis virus E2 glycoprotein. In silico modeling data suggested that the inserted targeting motifs were exposed in the context of cSVE2s. Western blot analysis of LVs indicated the incorporation of cSVE2s into viral particles. Capture ELISA demonstrated the specificity/functionality of the incorporated cSVE2s. Transduction of 293/KDR (expressing VEGFR2) or 293T cells (negative control) by constructed LVs followed by fluorescent microscopy and flow cytometric analyses indicated selective transduction of 293/KDR cells (30 %) by both targeting motifs compared to 293T control cells (1-2 %). These results implied similar targeting properties of VEGFR2-specific nanobody compared to the VEGF(121) and indicated the potential for transductional targeting of tumor vasculature by the nanobody displaying LVs. C1 [Ahani, Roshank; Roohvand, Farzin; Etemadzadeh, Mohammad Hossein; Mohajel, Nasir; Shahosseini, Zahra; Azadmanesh, Kayhan] Pasteur Inst Iran, Dept Virol, 69 Pasteur Ave,Kargar Ave, Tehran 1316943551, Iran. [Cohan, Reza Ahangari] Pasteur Inst Iran, Dept Pilot Nanobiotechnol, New Technol Res Grp, Tehran, Iran. [Behdani, Mahdi] Pasteur Inst Iran, Venom & Biotherapeut Mol Lab, Biotechnol Res Ctr, Tehran, Iran. [Madani, Navid] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Madani, Navid] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. RP Roohvand, F; Azadmanesh, K (reprint author), Pasteur Inst Iran, Dept Virol, 69 Pasteur Ave,Kargar Ave, Tehran 1316943551, Iran. EM rfarzin@pasteur.ac.ir; k.azadmanesh@gmail.com OI Behdani, Mahdi/0000-0002-4839-5123 FU Pasteur Institute of Iran [BP-8918] FX Funding was provided by Pasteur Institute of Iran (Grant No. BP-8918). NR 49 TC 0 Z9 0 U1 8 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 EI 1559-0305 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD NOV PY 2016 VL 58 IS 11 BP 738 EP 747 DI 10.1007/s12033-016-9973-7 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EB2ZD UT WOS:000387230200005 PM 27647452 ER PT J AU Oliviero, G Brien, GL Waston, A Streubel, G Jerman, E Andrews, D Doyle, B Munawar, N Wynne, K Crean, J Bracken, AP Cagney, G AF Oliviero, Giorgio Brien, Gerard L. Waston, Ariane Streubel, Gundula Jerman, Emilia Andrews, Darrell Doyle, Benjamin Munawar, Nayla Wynne, Kieran Crean, John Bracken, Adrian P. Cagney, Gerard TI Dynamic Protein Interactions of the Polycomb Repressive Complex 2 during Differentiation of Pluripotent Cells SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID EMBRYONAL CARCINOMA-CELLS; TARGET GENES; STEM-CELLS; GENOMIC TARGETS; HISTONE H3; CHROMATIN; PRC2; METHYLATION; ACTIVATION; IDENTITY AB Polycomb proteins assemble to form complexes with important roles in epigenetic regulation. The Polycomb Repressive Complex 2 (PRC2) modulates the di- and trimethylation of lysine 27 on histone H3, each of which are associated with gene repression. Although three sub-units, EZH1/2, SUZ12, and EED, form the catalytic core of PRC2, a wider group of proteins associate with low stoichiometry. This raises the question of whether dynamic variation of the PRC2 interactome results in alternative forms of the complex during differentiation. Here we compared the physical interactions of PRC2 in undifferentiated and differentiated states of NTERA2 pluripotent embryonic carcinoma cells. Label-free quantitative proteomics was used to assess endogenous immunoprecipitation of the EZH2 and SUZ12 subunits of PRC2. A high stringency data set reflecting the endogenous state of PRC2 was produced that included all previously reported core and associated PRC2 components, and several novel interacting proteins. Comparison of the interactomes obtained in undifferentiated and differentiated cells revealed candidate proteins that were enriched in complexes isolated from one of the two states. For example, SALL4 and ZNF281 associate with PRC2 in pluripotent cells, whereas PCL1 and SMAD3 preferentially associate with PRC2 in differentiating cells. Analysis of the mRNA and protein levels of these factors revealed that their association with PRC2 correlated with their cell state-specific expression. Taken together, we propose that dynamic changes to the PRC2 interactome during differentiation may contribute to directing its activity during cell fate transitions. C1 [Oliviero, Giorgio; Waston, Ariane; Andrews, Darrell; Doyle, Benjamin; Munawar, Nayla; Wynne, Kieran; Crean, John; Cagney, Gerard] Univ Coll Dublin, Sch Biomol & Biomed Sci, Dublin 4, Ireland. [Oliviero, Giorgio; Waston, Ariane; Andrews, Darrell; Doyle, Benjamin; Munawar, Nayla; Wynne, Kieran; Crean, John; Cagney, Gerard] Univ Coll Dublin, Conway Inst, Dublin 4, Ireland. [Brien, Gerard L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Brien, Gerard L.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Brien, Gerard L.; Streubel, Gundula; Jerman, Emilia; Bracken, Adrian P.] Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland. RP Cagney, G (reprint author), Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. EM gerard.cagney@ucd.ie FU Science Foundation Ireland [SFI 10/1N.1/B3.19] FX This work was supported by a Science Foundation Ireland Principal Investigator Award (SFI 10/1N.1/B3.19). NR 53 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD NOV PY 2016 VL 15 IS 11 BP 3450 EP 3460 DI 10.1074/mcp.M116.062240 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EB6OX UT WOS:000387505500010 PM 27634302 ER PT J AU An, Q Han, C Zhou, YB Li, F Li, DL Zhang, XJ Yu, ZJ Duan, ZF Kan, QC AF An, Qi Han, Chao Zhou, Yubing Li, Feng Li, Duolu Zhang, Xiaojian Yu, Zujiang Duan, Zhenfeng Kan, Quancheng TI Matrine induces cell cycle arrest and apoptosis with recovery of the expression of miR-126 in the A549 non-small cell lung cancer cell line SO MOLECULAR MEDICINE REPORTS LA English DT Article DE matrine; traditional Chinese medicine; miR-126; non-small-cell lung cancer; vascular endothelial growth factor ID HEPATOCELLULAR-CARCINOMA; CHEMOTHERAPY REGIMENS; RANDOMIZED-TRIALS; CHINESE MEDICINE; IN-VITRO; CHEMORESISTANCE; ANTICANCER; ARTESUNATE; ADHESION; RECEPTOR AB Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality in the United States. Chemotherapy prolongs survival rates among patients with advanced disease, however, this is at the cost of clinically significant adverse effects. Matrine is an active component of traditional Chinese medicine and is a promising alternative drug for the treatment of NSCLC. In the present study, the therapeutic effects and the underlying molecular mechanisms of matrine on the A549 NSCLC cell line were investigated. A high concentration of matrine (1.0 mg/ml) significantly (P<0.05) inhibited cell proliferation, by 52.68 +/- 3.32%, under which cell shrinkage and disruption were observed. Flow cytometric analysis showed that the proportion of G1/G0 cells was significantly increased, whereas the proportions of S and G2/M cells were significantly decreased (P<0.05) following treatment with matrine for 48 h. These results indicated that cell arrest was induced by matrine. Upregulation of the expression of microRNA (miR)-126, followed by downregulation of the expression of its target gene, vascular endothelial growth factor, were detected following treatment with a low concentration of matrine (0.2 mg/ml) using reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. In conclusion, matrine induced cell cycle arrest and apoptosis, and recovered the expression of miR-126 in the A549 NSCLC cell line. C1 [An, Qi; Han, Chao; Zhou, Yubing; Li, Feng; Li, Duolu; Zhang, Xiaojian; Kan, Quancheng] Zhengzhou Univ, Affiliated Hosp 1, Dept Clin Pharmacol, 1 Jianshe East Rd, Zhengzhou 450052, Henan, Peoples R China. [Yu, Zujiang] Zhengzhou Univ, Affiliated Hosp 1, Dept Infect Dis, Zhengzhou 450052, Henan, Peoples R China. [Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Kan, QC (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Clin Pharmacol, 1 Jianshe East Rd, Zhengzhou 450052, Henan, Peoples R China. EM kan-qc@163.com NR 32 TC 0 Z9 0 U1 3 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 EI 1791-3004 J9 MOL MED REP JI Mol. Med. Rep. PD NOV PY 2016 VL 14 IS 5 BP 4042 EP 4048 DI 10.3892/mmr.2016.5753 PG 7 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EB3DD UT WOS:000387241600005 PM 27665734 ER PT J AU Shi, Z Ren, HX Luo, CM Yao, XL Li, P He, CW Kang, JX Wan, JB Yuan, TF Su, HX AF Shi, Zhe Ren, Huixia Luo, Chuanming Yao, Xiaoli Li, Peng He, Chengwei Kang, Jing-X Wan, Jian-Bo Yuan, Ti-Fei Su, Huanxing TI Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Omega-3 polyunsaturated fatty acids; DHA; Ischemia; ROS ID CEREBRAL-ISCHEMIA; NEUROPROTECTION; STROKE; MECHANISMS; DEATH AB Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation. C1 [Shi, Zhe; Ren, Huixia; Luo, Chuanming; Li, Peng; He, Chengwei; Wan, Jian-Bo; Su, Huanxing] Univ Macau, State Key Lab Qual Res Chinese Med, Inst Chinese Med Sci, Macau, Peoples R China. [Yao, Xiaoli] Sun Yat Sen Univ, Dept Neurol, Natl Key Clin Dept, Guangzhou 510080, Guangdong, Peoples R China. [Yao, Xiaoli] Sun Yat Sen Univ, Key Discipline Neurol, Affiliated Hosp 1, Guangzhou 510080, Guangdong, Peoples R China. [Kang, Jing-X] Massachusetts Gen Hosp, Lab Lipid Med & Technol, Dept Med, Boston, MA 02114 USA. [Kang, Jing-X] Harvard Med Sch, Boston, MA USA. [Yuan, Ti-Fei] Nanjing Normal Univ, Sch Psychol, Nanjing 210097, Jiangsu, Peoples R China. RP Su, HX (reprint author), Univ Macau, State Key Lab Qual Res Chinese Med, Inst Chinese Med Sci, Macau, Peoples R China.; Yuan, TF (reprint author), Nanjing Normal Univ, Sch Psychol, Nanjing 210097, Jiangsu, Peoples R China. EM ytf0707@126.com; huanxingsu@umac.mo RI Wan, Jian-Bo/D-8368-2014 OI Wan, Jian-Bo/0000-0002-6750-2617 FU Macao Science and Technology Development Fund [018/2013/A1, MRG003/SHX/2014/ICMS]; University of Macau [MYRG122 (Y1-L3)-ICMS12-SHX, MYRG110 (Y1-L2)- ICMS13-SHX]; "Hundred Talents program," "Qing Lan Project" of Nanjing Normal University; Jiangsu Provincial Natural Science Foundation [BK20140917]; National Natural Science Foundation of China [81501164] FX This study was supported by the Macao Science and Technology Development Fund (018/2013/A1), matching grant project MRG003/SHX/2014/ICMS, and multi-year research grant, University of Macau, MYRG122 (Y1-L3)-ICMS12-SHX and MYRG110 (Y1-L2)- ICMS13-SHX. The work was also supported by the "Hundred Talents program," "Qing Lan Project" of Nanjing Normal University, Jiangsu Provincial Natural Science Foundation (#BK20140917), and National Natural Science Foundation of China (#81501164). NR 24 TC 1 Z9 1 U1 11 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD NOV PY 2016 VL 53 IS 9 BP 6482 EP 6488 DI 10.1007/s12035-015-9554-y PG 7 WC Neurosciences SC Neurosciences & Neurology GA EB2ZO UT WOS:000387231300058 PM 26611833 ER PT J AU Wagner, A Regev, A Yosef, N AF Wagner, Allon Regev, Aviv Yosef, Nir TI Revealing the vectors of cellular identity with single-cell genomics SO NATURE BIOTECHNOLOGY LA English DT Review ID RNA-SEQ REVEALS; GENE-EXPRESSION ANALYSIS; CIRCULATING TUMOR-CELLS; COPY-NUMBER VARIATION; EMBRYONIC STEM-CELLS; MESSENGER-RNA; SEQUENCING DATA; MASS CYTOMETRY; DIFFERENTIAL EXPRESSION; MAMMALIAN-CELLS AB Single-cell genomics has now made it possible to create a comprehensive atlas of human cells. At the same time, it has reopened definitions of a cell's identity and of the ways in which identity is regulated by the cell's molecular circuitry. Emerging computational analysis methods, especially in single-cell RNA sequencing (scRNA-seq), have already begun to reveal, in a data-driven way, the diverse simultaneous facets of a cell's identity, from discrete cell types to continuous dynamic transitions and spatial locations. These developments will eventually allow a cell to be represented as a superposition of ` basis vectors', each determining a different (but possibly dependent) aspect of cellular organization and function. However, computational methods must also overcome considerable challenges-from handling technical noise and data scale to forming new abstractions of biology. As the scale of single-cell experiments continues to increase, new computational approaches will be essential for constructing and characterizing a reference map of cell identities. C1 [Wagner, Allon; Yosef, Nir] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Wagner, Allon; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA USA. [Regev, Aviv] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA. [Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA USA. [Yosef, Nir] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Yosef, Nir] Harvard Univ, Boston, MA 02115 USA. RP Regev, A (reprint author), MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA.; Regev, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM aregev@broadinstitute.org FU US National Institute of Mental Health [U01 MH105979]; Klarman Cell Observatory at the Broad Institute, NIH [P50 HG006193]; National Cancer Institute [P30-CA14051]; NIH BRAIN grant [1U01MH105960-01]; NCI [1U24CA180922]; NIAID [1U24AI118672-01] FX We thank E. Lander, A.K. Shalek, R.B. Fletcher, O. Ram, and D. Stafford for helpful discussions, and L. Gaffney and A. Hupalowska for artwork. A.W. and N.Y. were supported in part by the BRAIN Initiative grant U01 MH105979 from the US National Institute of Mental Health. A.R. is an Investigator of the Howard Hughes Medical Institute and was supported by the Klarman Cell Observatory at the Broad Institute, NIH grant P50 HG006193, Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, NIH BRAIN grant 1U01MH105960-01, NCI grant 1U24CA180922, and NIAID grant 1U24AI118672-01. NR 226 TC 5 Z9 5 U1 28 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD NOV PY 2016 VL 34 IS 11 BP 1145 EP 1160 DI 10.1038/nbt.3711 PG 16 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EB6PG UT WOS:000387506500027 PM 27824854 ER PT J AU Stevens, MM Maire, CL Chou, N Murakami, MA Knoff, DS Kikuchi, Y Kimmerling, RJ Liu, HY Haidar, S Calistri, NL Cermak, N Olcum, S Cordero, NA Idbaih, A Wen, PY Weinstock, DM Ligon, KL Manalis, SR AF Stevens, Mark M. Maire, Cecile L. Chou, Nigel Murakami, Mark A. Knoff, David S. Kikuchi, Yuki Kimmerling, Robert J. Liu, Huiyun Haidar, Samer Calistri, Nicholas L. Cermak, Nathan Olcum, Selim Cordero, Nicolas A. Idbaih, Ahmed Wen, Patrick Y. Weinstock, David M. Ligon, Keith L. Manalis, Scott R. TI Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate SO NATURE BIOTECHNOLOGY LA English DT Article ID RESISTANCE; RECLASSIFICATION; GLIOBLASTOMA; CHEMOTHERAPY; MECHANISMS; MEDICINE; LEUKEMIA; GROWTH; SIZE AB Assays that can determine the response of tumor cells to cancer therapeutics could greatly aid the selection of drug regimens for individual patients. However, the utility of current functional assays is limited, and predictive genetic biomarkers are available for only a small fraction of cancer therapies. We found that the single-cell mass accumulation rate (MAR), profiled over many hours with a suspended microchannel resonator, accurately defined the drug sensitivity or resistance of glioblastoma and B-cell acute lymphocytic leukemia cells. MAR revealed heterogeneity in drug sensitivity not only between different tumors, but also within individual tumors and tumor-derived cell lines. MAR measurement predicted drug response using samples as small as 25 ml of peripheral blood while maintaining cell viability and compatibility with downstream characterization. MAR measurement is a promising approach for directly assaying single-cell therapeutic responses and for identifying cellular subpopulations with phenotypic resistance in heterogeneous tumors. C1 [Stevens, Mark M.; Murakami, Mark A.; Kimmerling, Robert J.; Liu, Huiyun; Cermak, Nathan; Cordero, Nicolas A.; Manalis, Scott R.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Stevens, Mark M.] MIT, Dept Biol, Cambridge, MA USA. [Maire, Cecile L.; Murakami, Mark A.; Knoff, David S.; Liu, Huiyun; Haidar, Samer; Cordero, Nicolas A.; Weinstock, David M.; Ligon, Keith L.] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA. [Chou, Nigel; Kimmerling, Robert J.; Manalis, Scott R.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Kikuchi, Yuki] Hitachi High Technol Corp, Ibaraki, Japan. [Cermak, Nathan] MIT, Program Computat & Syst Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Idbaih, Ahmed] UFMC Univ Paris 06, Sorbonne Univ, CNRS, UMR 7225,INSERM U 1127,UMR S 1127,ICM,Inst Cervea, Paris, France. [Idbaih, Ahmed] Hop Univ La Pitie Salpetriere Charles Foix, AP HP, Serv Neurol Mazarin 2, Faris, France. [Wen, Patrick Y.] Harvard Med Sch, Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA USA. [Weinstock, David M.; Ligon, Keith L.] Broad Inst, Cambridge, MA USA. [Ligon, Keith L.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Manalis, Scott R.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Manalis, SR (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Weinstock, DM; Ligon, KL (reprint author), Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA.; Manalis, SR (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Weinstock, DM; Ligon, KL (reprint author), Broad Inst, Cambridge, MA USA.; Ligon, KL (reprint author), Boston Childrens Hosp, Dept Pathol, Boston, MA USA.; Ligon, KL (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.; Manalis, SR (reprint author), MIT, Dept Mech Engn, Cambridge, MA 02139 USA. EM davidm_weinstock@dfci.harvard.edu; keith_lligon@dfci.harvard.edu; srm@mit.edu OI Knoff, David/0000-0001-6233-2893 FU US National Institutes of Health [R01 CA170592, P50 CA165962, P01 CA112536, R33 CA191113]; National Cancer Institute [U54 CA143874, P30 CA14051, T32 CA009172]; Koch Institute for Integrative Cancer Research at MIT; Dana-Farber/Harvard Cancer Center (DF/HCC); Dana-Farber Cancer Institute Brain Tumor Therapeutics Accelerator Program; Vondation ARC pour la Recherche sur le Cancer; Institut Universitaire de Cancerologie; Onco Neuro Theque; program Investissements d'aveniC [ANR-10-IAIHU-06]; NIHNIGMS [T32 GM008334]; Interdepartmental Biotechnology Training Program grant; National Science Scholarship, Agency for Science, Technology and Research (STAR), Singapore FX These studies were supported by R01 CA170592 (S.R.M., K.L.L.,P.Y.W.), P50 CA165962 (K.L.L., P.Y.W), P01 CA112536 (K.L.L.) and R33 CA191113 (S.R.M., D.M.W.) from the US National Institutes of Health, U54 CA143874 from the National Cancer Institute (S.R.M), and partially by Cancer Center Support (core) Grant P30 CA14051 from the National Cancer Institute, The Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC) (S.R.M,D.M.W.), and the Dana-Farber Cancer Institute Brain Tumor Therapeutics Accelerator Program (P.Y.W., K.L.L.). A.I. acknowledges support from Vondation ARC pour la Recherche sur le Cancer, The Institut Universitaire de Cancerologie, Onco Neuro Theque and the program Investissements d'aveniC ANR-10-IAIHU-06. M.M.S. acknowledges support from the NIHNIGMS T32 GM008334, Interdepartmental Biotechnology Training Program grant, N. Chou acknowledges support from the National Science Scholarship, Agency for Science, Technology and Research (STAR), Singapore. D.M.W. is a Leukemia and Lymphoma Scholar. M.A.M. gratefully acknowledges support from the institutional research training grant T32 CA009172, from the National Cancer Institute. NR 31 TC 1 Z9 1 U1 13 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD NOV PY 2016 VL 34 IS 11 BP 1161 EP + DI 10.1038/nbt.3697 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EB6PG UT WOS:000387506500028 PM 27723727 ER PT J AU Wahlster, L Daley, GQ AF Wahlster, Lara Daley, George Q. TI Progress towards generation of human haematopoietic stem cells SO NATURE CELL BIOLOGY LA English DT Article ID RED-BLOOD-CELLS; ADULT HUMAN FIBROBLASTS; LARGE-SCALE PRODUCTION; DE-NOVO GENERATION; EX-VIVO EXPANSION; IN-VITRO; SELF-RENEWAL; PROGENITOR CELLS; DEFINED FACTORS; HAEMOGENIC ENDOTHELIUM AB De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells. C1 [Wahlster, Lara; Daley, George Q.] Childrens Hosp Boston, Howard Hughes Med Inst, Stem Cell Transplantat Program, Div Pediat Hematol Oncol,Manton Ctr Orphan Dis Re, Boston, MA 02115 USA. [Wahlster, Lara; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wahlster, Lara; Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wahlster, Lara; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Wahlster, Lara] Heidelberg Univ, Dept Gen Pediat, Univ Heidelberg Hosp, D-69120 Heidelberg, Germany. RP Daley, GQ (reprint author), Childrens Hosp Boston, Howard Hughes Med Inst, Stem Cell Transplantat Program, Div Pediat Hematol Oncol,Manton Ctr Orphan Dis Re, Boston, MA 02115 USA.; Daley, GQ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Stem Cell Inst, Boston, MA 02115 USA. EM George.Daley@childrens.harvard.edu FU Young Investigator Award Program at Heidelberg University FX L.W. is supported by the Young Investigator Award Program at Heidelberg University. The authors thank D. Ebrahimi-Fakhari, A. Saffari, M. Cesana, S. Doulatov, R. Sugimura and L. Vo for helpful discussions. NR 87 TC 2 Z9 2 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD NOV PY 2016 VL 18 IS 11 BP 1111 EP 1117 DI 10.1038/ncb3419 PG 7 WC Cell Biology SC Cell Biology GA EB2CV UT WOS:000387165600001 PM 27723718 ER PT J AU Freed-Pastor, W Prives, C AF Freed-Pastor, William Prives, Carol TI Targeting mutant p53 through the mevalonate pathway SO NATURE CELL BIOLOGY LA English DT Editorial Material ID MULTIPLE-MYELOMA; GAIN; DEGRADATION AB It is well established that mutant forms of the p53 tumour suppressor acquire pro-oncogenic activities. Inhibition of the mevalonate pathway is now shown to promote degradation of select oncogenic mutant p53 proteins, indicating that destabilization of mutant p53 could be a promising therapeutic strategy. C1 [Freed-Pastor, William] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 12215 USA. [Prives, Carol] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. RP Freed-Pastor, W (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 12215 USA. EM wfreed-pastor@partners.org; carol@biology.columbia.edu NR 15 TC 2 Z9 2 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD NOV PY 2016 VL 18 IS 11 BP 1122 EP 1124 DI 10.1038/ncb3435 PG 3 WC Cell Biology SC Cell Biology GA EB2CV UT WOS:000387165600005 PM 27784901 ER PT J AU Ni, T Li, XY Lu, N An, T Liu, ZP Fu, R Lv, WC Zhang, YW Xu, XJ Rowe, RG Lin, YS Scherer, A Feinberg, T Zheng, XQ Chen, BA Liu, XS Guo, QL Wu, ZQ Weiss, SJ AF Ni, Ting Li, Xiao-Yan Lu, Na An, Teng Liu, Zhi-Ping Fu, Rong Lv, Wen-Cong Zhang, Yi-Wei Xu, Xiao-Jun Rowe, R. Grant Lin, Yong-Shun Scherer, Amanda Feinberg, Tamar Zheng, Xiao-Qi Chen, Bao-An Liu, X. Shirley Guo, Qing-Long Wu, Zhao-Qiu Weiss, Stephen J. TI Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer SO NATURE CELL BIOLOGY LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; E-CADHERIN REPRESSION; MAMMARY-GLAND; STEM-CELLS; TRANSCRIPTION FACTORS; SNAIL1 EXPRESSION; METASTASIS; INVASION; MICE; DEGRADATION AB The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer. C1 [Ni, Ting; Lu, Na; An, Teng; Fu, Rong; Lv, Wen-Cong; Zhang, Yi-Wei; Xu, Xiao-Jun; Guo, Qing-Long; Wu, Zhao-Qiu] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Dept Basic Med, State Key Lab Nat Med,Jiangsu Prov Key Lab Carcin, Nanjing 210009, Jiangsu, Peoples R China. [Li, Xiao-Yan; Rowe, R. Grant; Lin, Yong-Shun; Scherer, Amanda; Feinberg, Tamar; Weiss, Stephen J.] Univ Michigan, Dept Internal Med, Div Mol Med & Genet, Inst Life Sci, Ann Arbor, MI 48109 USA. [Liu, Zhi-Ping] Gannan Med Univ, Sch Basic Med, Dept Biochem & Mol Biol, Ganzhou 341000, Peoples R China. [Zheng, Xiao-Qi] Shanghai Normal Univ, Dept Math, Shanghai 200234, Peoples R China. [Chen, Bao-An] Southeast Univ, Sch Med, Affiliated Zhongda Hosp, Dept Hematol & Oncol, Nanjing 210009, Jiangsu, Peoples R China. [Liu, X. Shirley] Harvard Univ, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Harvard Sch Publ Hlth, Boston, MA 02115 USA. RP Wu, ZQ (reprint author), China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Dept Basic Med, State Key Lab Nat Med,Jiangsu Prov Key Lab Carcin, Nanjing 210009, Jiangsu, Peoples R China.; Weiss, SJ (reprint author), Univ Michigan, Dept Internal Med, Div Mol Med & Genet, Inst Life Sci, Ann Arbor, MI 48109 USA. EM zqwu@cpu.edu.cn; sjweiss@umich.edu FU Breast Cancer Research Foundation (BCRF); China Pharmaceutical University; National Natural Science Foundation of China [NSFC 81572745, 91539115]; Jiangsu Province Innovative Research Team; State Key Laboratory of Natural Medicines [SKLNMZZJQ201604]; Changjiang Scholar and Innovative Research Team [IRT1193]; US National Institutes of Health [U01 CA180980] FX This research was supported by a grant from the Breast Cancer Research Foundation (BCRF) to S.J.W. as well as the Startup Fund from China Pharmaceutical University, the National Natural Science Foundation of China (NSFC 81572745 and 91539115), and the Jiangsu Province Innovative Research Team and State Key Laboratory of Natural Medicines (SKLNMZZJQ201604) to Z.-Q.W. Additional support was provided by the Changjiang Scholar and Innovative Research Team (IRT1193) to Q.-L.G. and the US National Institutes of Health (U01 CA180980) to X.S.L. We thank M.-D. Lai (China Pharmaceutical University, China) for critically reviewing this manuscript, W. Gu (Columbia University, USA) and P.-C. Yang (Academia Sinica, Taiwan) for providing HA-tagged p53 WT and mutant plasmids, R. Weinberg (Massachusetts Institute of Technology, USA) for sharing human mammary epithelial cells (HMLEs), A. Cano (Universidad Autonoma de Madrid, Spain) for Snaill mutants, Y. Kang and L. Wan (Princeton University, USA) for sharing protocols of mouse mammary epithelial cell isolation, B. Gyorffy (Hungarian Academy of Sciences, Hungary) for assistance with the human breast cancer databases and R. Kuick (University of Michigan, USA) for helpful discussions. NR 70 TC 1 Z9 1 U1 12 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD NOV PY 2016 VL 18 IS 11 BP 1221 EP + DI 10.1038/ncb3425 PG 24 WC Cell Biology SC Cell Biology GA EB2CV UT WOS:000387165600015 PM 27749822 ER PT J AU Rines, AK Sharabi, K Tavares, CDJ Puigserver, P AF Rines, Amy K. Sharabi, Kfir Tavares, Clint D. J. Puigserver, Pere TI Targeting hepatic glucose metabolism in the treatment of type 2 diabetes SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID MITOCHONDRIAL PYRUVATE CARRIER; GLUCAGON RECEPTOR ANTAGONIST; GLYCOGEN-SYNTHASE KINASE-3; SMALL-MOLECULE INHIBITORS; PHOSPHATASE 1B PTP1B; LOWERS BLOOD-GLUCOSE; CYTOSOLIC PHOSPHOENOLPYRUVATE CARBOXYKINASE; HEPATOSELECTIVE GLUCOKINASE ACTIVATOR; REV-ERB-ALPHA; INSULIN-RESISTANCE AB Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes. C1 [Puigserver, Pere] Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) at the US National Institutes of Health (NIH) [F32 DK102293-01]; American Heart Association [15POST22880002]; American Diabetes Association [1-16-PDF-111]; NIH NIDDK [R01 DK069966, DK081418, DK089883]; American Diabetes Association FX A.K.R. received funding from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) at the US National Institutes of Health (NIH) (F32 DK102293-01). K. S. was funded by the American Heart Association (15POST22880002). C.D.J.T. received funding from the American Diabetes Association (1-16-PDF-111). P.P. was funded by the NIH NIDDK (R01 DK069966, DK081418, DK089883) and the American Diabetes Association. NR 252 TC 1 Z9 1 U1 30 U2 30 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2016 VL 15 IS 11 BP 786 EP 804 DI 10.1038/nrd.2016.151 PG 19 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA EB3EG UT WOS:000387244800018 PM 27516169 ER PT J AU Schuster, NM Rapoport, AM AF Schuster, Nathaniel M. Rapoport, Alan M. TI New strategies for the treatment and prevention of primary headache disorders SO NATURE REVIEWS NEUROLOGY LA English DT Review ID GENE-RELATED PEPTIDE; ORALLY INHALED DIHYDROERGOTAMINE; RANDOMIZED CONTROLLED-TRIAL; DIRECT-CURRENT STIMULATION; VAGUS NERVE-STIMULATION; SPINAL-CORD STIMULATION; PROOF-OF-CONCEPT; TRANSCRANIAL MAGNETIC STIMULATION; IONTOPHORETIC TRANSDERMAL SYSTEM; RECEPTOR AGONIST LASMIDITAN AB The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists. Neuromodulation approaches employing noninvasive or implantable devices also show promise for treating primary headache disorders. Noninvasive treatments, such as transcranial magnetic stimulation and transcutaneous peripheral nerve stimulation, are delivered by devices that patients can self-administer. Implantable devices targeting the occipital nerves, sphenopalatine ganglion or high cervical spinal cord are placed using percutaneous and/or surgical procedures, and are powered either wirelessly or by surgically implanted batteries. These new and emerging treatments have the potential to address unmet patient needs and reduce headache-associated disability. C1 [Schuster, Nathaniel M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Ctr Pain Med, 15 Parkman St, Boston, MA 02114 USA. [Rapoport, Alan M.] UCLA, David Geffen Sch Med, Dept Neurol, 710 Westwood Plaza, Los Angeles, CA 90095 USA. RP Schuster, NM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Ctr Pain Med, 15 Parkman St, Boston, MA 02114 USA. EM nschuster@gmail.com OI Schuster, Nathaniel/0000-0002-4970-6296 FU Avanir FX N.M.S. received an American Headache Society travel grant with funding from Avanir. A.M.R. serves on the speaker's bureaus of Avanir, Depomed and Teva, consults for Eli Lilly and serves on the advisory boards of Autonomic Technologies, Doctor Reddy's, Pernix, Teva and Zosano. NR 120 TC 3 Z9 3 U1 13 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD NOV PY 2016 VL 12 IS 11 BP 635 EP 650 DI 10.1038/nrneurol.2016.143 PG 16 WC Clinical Neurology SC Neurosciences & Neurology GA EB2AZ UT WOS:000387160400005 PM 27786243 ER PT J AU Soares, VYR Atai, NA Fujita, T Dilwali, S Sivaraman, S Landegger, LD Hochberg, FH Oliveira, CAPC Bahmad, F Breakefield, XO Stankovic, KM AF Soares, Vitor Y. R. Atai, Nadia A. Fujita, Takeshi Dilwali, Sonam Sivaraman, Sarada Landegger, Lukas D. Hochberg, Fred H. Oliveira, Carlos A. P. C. Bahmad, Fayez Breakefield, Xandra O. Stankovic, Konstantina M. TI Extracellular vesicles derived from human vestibular schwannomas associated with poor hearing damage cochlear cells SO NEURO-ONCOLOGY LA English DT Article DE cochlea; extracellular vesicles; sensorineural hearing loss; transwell culture; vestibular schwannoma ID ACOUSTIC NEUROMAS; TUMOR-GROWTH; EXOSOMES; MICROVESICLES; EXPRESSION; PROTEINS; DISEASE; PROFILE AB Background. Vestibular schwannoma (VS) is a tumor of the vestibular nerve that transmits balance information from the inner ear to the brain. Sensorineural hearing loss occurs in 95% of patients with these tumors, but the cause of this loss is not well understood. We posit a role of VS-secreted extracellular vesicles (EVs) as a major contributing factor in cochlear nerve damage. Methods. Using differential centrifugation, we isolated EVs from VS cell line HEI-193 and primary cultured human VS cells from patients with good hearing or poor hearing. The EVs were characterized using a Nanosight device and transmission electron microscopy and by extracting their RNA content. The EVs' effects on cultured murine spiral ganglion cells and organotypic cochlear cultures were studied using a transwell dual-culture system and by direct labeling of EVs with PKH-67 dye. EV-induced changes in cochlear cells were quantified using confocal immunohistochemistry. Transfection of VS cells with a green fluorescent protein-containing plasmid was confirmed with reverse transcription PCR. Results. Human VS cells, from patients with poor hearing, produced EVs that could damage both cultured murine cochlear sensory cells and neurons. In contrast, EVs derived from VS cells from patients with good hearing did not damage the cultured cochlear cells. Conclusions. This is the first report on EVs derived from VSs and on the capacity of EVs from VSs from patients with hearing loss to selectively damage cochlear cells, thereby identifying a potential novel mechanism of VS-associated sensorineural hearing loss. C1 [Soares, Vitor Y. R.; Fujita, Takeshi; Dilwali, Sonam; Landegger, Lukas D.; Stankovic, Konstantina M.] Massachusetts Eye & Ear, Eaton Peabody Labs, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Soares, Vitor Y. R.; Fujita, Takeshi; Landegger, Lukas D.; Stankovic, Konstantina M.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Soares, Vitor Y. R.; Oliveira, Carlos A. P. C.; Bahmad, Fayez] Univ Brasilia, Hlth Sci Program, Brasilia, DF, Brazil. [Soares, Vitor Y. R.; Oliveira, Carlos A. P. C.; Bahmad, Fayez] Univ Brasilia, Dept Otolaryngol, Brasilia, DF, Brazil. [Atai, Nadia A.] Univ Amsterdam, Amsterdam, Netherlands. [Atai, Nadia A.; Sivaraman, Sarada; Breakefield, Xandra O.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol & Radiol, Charlestown, MA USA. [Atai, Nadia A.; Sivaraman, Sarada; Breakefield, Xandra O.] Harvard Med Sch, Program Neurosci, Charlestown, MA USA. [Dilwali, Sonam; Stankovic, Konstantina M.] Harvard MIT Program Speech & Hearing Biosci & Tec, Boston, MA USA. [Hochberg, Fred H.] Univ Calif San Diego, Dept Neurosurg, San Diego, CA 92103 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear, 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu FU Department of Defense [W81XWH-14-1-0091]; Bertarelli Foundation; Nancy Sayles Day Foundation; Lauer Tinnitus Research Center; National Institute on Deafness and Other Communication Disorders [T32DC00038]; NIH Common Fund NCI [CA179563] FX This work was supported by a Department of Defense grant W81XWH-14-1-0091 (to K.M.S.), the Bertarelli Foundation (to K.M.S.), Nancy Sayles Day Foundation (to K.M.S.), the Lauer Tinnitus Research Center (to K.M.S.), a National Institute on Deafness and Other Communication Disorders grant T32DC00038 (to support S.D.) and the NIH Common Fund NCI CA179563 (to X.O.B.). NR 37 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2016 VL 18 IS 11 BP 1498 EP 1507 DI 10.1093/neuonc/now099 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HC UT WOS:000387330300006 PM 27194145 ER PT J AU Roddy, E Sear, K Felton, E Tamrazi, B Gauvain, K Torkildson, J Del Buono, B Samuel, D Haas-Kogan, DA Chen, J Goldsby, RE Banerjee, A Lupo, JM Molinaro, AM Fullerton, HJ Mueller, S AF Roddy, Erika Sear, Katherine Felton, Erin Tamrazi, Benita Gauvain, Karen Torkildson, Joseph Del Buono, Benedict Samuel, David Haas-Kogan, Daphne A. Chen, Josephine Goldsby, Robert E. Banerjee, Anuradha Lupo, Janine M. Molinaro, Annette M. Fullerton, Heather J. Mueller, Sabine TI Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors SO NEURO-ONCOLOGY LA English DT Article DE cerebral microbleeds; cranial radiation therapy; late effects of tumor therapy; neurocognitive function; pediatric brain tumor survivors ID CHILDHOOD-CANCER SURVIVORS; LONG-TERM SURVIVORS; MEDIAL TEMPORAL-LOBE; WHITE-MATTER LOSS; RADIATION-THERAPY; NEUROCOGNITIVE DEFICITS; COGNITIVE IMPAIRMENT; SELECTIVE ATTENTION; IMAGE REGISTRATION; RECURRENT STROKE AB Background. A specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors. Methods. In a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age <21 years and 16 patients who did not receive CRT, we determined the presence of CMBs on brain MRIs. Neurocognitive function was assessed using a computerized testing program (CogState). We used survival analysis to determine cumulative incidence of CMBs and Poisson regression to examine risk factors for CMBs. Linear regression models were used to assess effect of CMBs on neurocognitive function. Results. The cumulative incidence of CMBs was 48.8% (95% CI: 38.3-60.5) at 5 years. Children who had whole brain irradiation developed CMBs at a rate 4 times greater than those treated with focal irradiation (P < .001). In multivariable analysis, children with CMBs performed worse on the Groton Maze Learning test (GML) compared with those without CMBs (Z-score -1.9; 95% CI: -2.7, -1.1; P < .001), indicating worse executive function when CMBs are present. CMBs in the frontal lobe were associated with worse performance on the GML (Z-score -2.4; 95% CI: -2.9, -1.8; P < .001). Presence of CMBs in the temporal lobes affected verbal memory (Z-score -2.0; 95% CI: -3.3, -0.7; P = .005). Conclusion. CMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation. C1 [Roddy, Erika] Univ Calif San Francisco, Sch Med, Sandler Neurosci Bldg 675 Nelson Rising Lane, San Francisco, CA 94185 USA. [Sear, Katherine; Felton, Erin; Del Buono, Benedict; Fullerton, Heather J.; Mueller, Sabine] UCSF, Dept Neurol, San Francisco, CA USA. [Tamrazi, Benita] Childrens Hosp Los Angeles, Dept Radiol, Los Angeles, CA 90027 USA. [Gauvain, Karen] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Torkildson, Joseph] Benioff Childrens Hosp Oakland, Dept Pediat, Oakland, CA USA. [Samuel, David] Valley Childrens Hosp, Dept Pediat, Madera, CA USA. [Haas-Kogan, Daphne A.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Josephine] UCSF, Dept Radiat Oncol, San Francisco, CA USA. [Goldsby, Robert E.; Banerjee, Anuradha; Mueller, Sabine] UCSF, Dept Pediat, San Francisco, CA USA. [Banerjee, Anuradha; Molinaro, Annette M.; Mueller, Sabine] UCSF, Dept Neurol Surg, San Francisco, CA USA. [Lupo, Janine M.] UCSF, Dept Radiol & Biomed Imaging, San Francisco, CA USA. [Molinaro, Annette M.] UCSF, Dept Biostat & Epidemiol, San Francisco, CA USA. RP Mueller, S (reprint author), Univ Calif San Francisco, Dept Neurol Neurosurg & Pediat, Sandler Neurosci Bldg 675 Nelson Rising Lane, San Francisco, CA 94185 USA. EM sabine.mueller@ucsf.edu FU National Center for Advancing Translational Sciences, National Institutes of Health through UCSF-CTSI grant [KL2TR000143] FX This work was supported by a donation from the LaRoche family (to H.F., S.M.), and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI grant number KL2TR000143 (to S.M.). NR 59 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2016 VL 18 IS 11 BP 1548 EP 1558 DI 10.1093/neuonc/now163 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HC UT WOS:000387330300011 ER PT J AU Jafari-Khouzani, K Loebel, F Bogner, W Rapalino, O Gonzalez, GR Gerstner, E Chi, AS Batchelor, TT Rosen, BR Unkelbach, J Shih, HA Cahill, DP Andronesi, OC AF Jafari-Khouzani, Kourosh Loebel, Franziska Bogner, Wolfgang Rapalino, Otto Gonzalez, Gilberto R. Gerstner, Elizabeth Chi, Andrew S. Batchelor, Tracy T. Rosen, Bruce R. Unkelbach, Jan Shih, Helen A. Cahill, Daniel P. Andronesi, Ovidiu C. TI Volumetric relationship between 2-hydroxyglutarate and FLAIR hyperintensity has potential implications for radiotherapy planning of mutant IDH glioma patients SO NEURO-ONCOLOGY LA English DT Article DE glioma; isocitrate dehydrogenase (IDH) mutation; 2-hydroxyglutarate (2HG); magnetic resonance spectroscopic imaging (MRSI); radiotherapy ID LOW-GRADE GLIOMAS; MAGNETIC-RESONANCE-SPECTROSCOPY; ONCOMETABOLITE 2-HYDROXYGLUTARATE; GLIOBLASTOMA-MULTIFORME; RESPONSE ASSESSMENT; GENETIC PREDICTORS; MUTATIONS; RADIATION; SURVIVAL; NEUROONCOLOGY AB Background. Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Methods. Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. Results. In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Conclusions. Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma. C1 [Jafari-Khouzani, Kourosh; Bogner, Wolfgang; Rosen, Bruce R.; Andronesi, Ovidiu C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA USA. [Loebel, Franziska; Cahill, Daniel P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. [Loebel, Franziska] Charite, Dept Neurosurg, Berlin, Germany. [Bogner, Wolfgang] Med Univ Vienna, High Field MR Ctr, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Rapalino, Otto; Gonzalez, Gilberto R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Gerstner, Elizabeth; Chi, Andrew S.; Batchelor, Tracy T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Pappas Ctr Neurooncol, Boston, MA USA. [Unkelbach, Jan; Shih, Helen A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. RP Andronesi, OC (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Thirteenth St, Charlestown, MA 02129 USA. EM ovidiu@nmr.mgh.harvard.edu FU National Cancer Institute [1K22CA178269-01, 1P50CA165962-01]; Harvard-MIT Bridge Project; Burroughs-Wellcome Career Award; MGH-MIT Grand Challenge 3: Neuroscience FX This work was supported by the National Cancer Institute (1K22CA178269-01 to O.CA., 1P50CA165962-01 to T.T.B and D.P.C), Harvard-MIT Bridge Project (D.P.C. and O.C.A.), Burroughs-Wellcome Career Award (D.P.C.), and MGH-MIT Grand Challenge 3: Neuroscience (O.C.A.). NR 48 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2016 VL 18 IS 11 BP 1569 EP 1578 DI 10.1093/neuonc/now100 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EB4HC UT WOS:000387330300013 PM 27382115 ER PT J AU Duboc, H Tolstanova, G Yuan, PQ Wu, VS Kaji, I Biraud, M Akiba, Y Kaunitz, JD Million, M Tache, Y Larauche, M AF Duboc, H. Tolstanova, G. Yuan, P. -Q. Wu, V. S. Kaji, I. Biraud, M. Akiba, Y. Kaunitz, J. D. Million, M. Tache, Y. Larauche, M. TI Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE bile acids; distal colon; secretion; submucosal neurons; TGR5; Ussing chambers ID ENTERIC NERVOUS-SYSTEM; GUINEA-PIG; SMALL-INTESTINE; ION-TRANSPORT; NITRIC-OXIDE; MOUSE COLON; GASTROINTESTINAL-TRACT; ELECTROLYTE TRANSPORT; MYENTERIC NEURONS; SODIUM-CHANNELS AB BackgroundRecent evidence from rat neuron-free mucosa study suggests that the membrane bile acid receptor TGR5 decreases colonic secretion under basal and stimulated conditions. As submucosal neurons are key players in secretory processes and highly express TGR5, we investigated their role in TGR5 agonist-induced inhibition of secretion and the pathways recruited. MethodsTGR5 expression and localization were assessed in rat proximal (pC) and distal (dC) colon by qPCR and immunohistochemistry with double labeling for cholinergic neurons in whole-mount preparations. The influence of a selective (INT-777) or weak (ursodeoxycholic acid, UDCA) TGR5 agonist on colonic secretion was assessed in Ussing chambers, in dC preparation removing seromuscular submucosal tissues, in the presence of different inhibitors of secretion pathways. Key ResultsTGR5 mRNA is expressed in full thickness dC and pC and immunoreactivity is located in colonocytes and pChAT-positive neurons. Addition of INT-777, and less potently UDCA, decreased colonic secretion in seromuscular stripped dC by -58.17 +/- 2.6%. INT-777 effect on basal secretion was reduced in neuron-free and TTX-treated mucosal-submucosal preparations. Atropine, hexamethonium, indomethacin, and L-NAME all reduced significantly INT-777's inhibitory effect while the 5-HT4 antagonist, RS-39604, and lidocaine abolished it. INT-777 inhibited stimulated colonic secretion induced by nicotine, but not cisapride, carbachol or PGE2. Conclusions & InferencesTGR5 activation inhibits basal and stimulated distal colonic secretion in rats by acting directly on epithelial cells and also inhibiting submucosal neurons. This could represent a counter-regulatory mechanism, at the submucosal level, of the known prosecretory effect of bile acids in the colon. C1 [Duboc, H.; Tolstanova, G.; Yuan, P. -Q.; Wu, V. S.; Biraud, M.; Million, M.; Tache, Y.; Larauche, M.] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [Duboc, H.; Tolstanova, G.; Yuan, P. -Q.; Wu, V. S.; Biraud, M.; Million, M.; Tache, Y.; Larauche, M.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobiol Stress & Resilience, Div Digest Dis,Dept Med, Los Angeles, CA 90095 USA. [Duboc, H.; Tolstanova, G.; Yuan, P. -Q.; Wu, V. S.; Biraud, M.; Akiba, Y.; Kaunitz, J. D.; Million, M.; Tache, Y.; Larauche, M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Duboc, H.] Univ Paris Diderot, Sorbonne Paris Cite, DHU UNITY, INSERM,UMR 1149, Paris, France. [Duboc, H.] Univ Paris Diderot, Sorbonne Paris Cite, Louis Mourier Hosp, AP HP,Dept Gastroenterol & Hepatol, Paris, France. [Tolstanova, G.] Taras Shevchenko Natl Univ Kyiv, Inst Biol, Educ Sci Ctr, Kiev, Ukraine. [Kaji, I.; Akiba, Y.; Kaunitz, J. D.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Kaji, I.; Akiba, Y.; Kaunitz, J. D.] Brentwood Biomed Res Inst, Los Angeles, CA USA. [Kaunitz, J. D.] Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90024 USA. RP Larauche, M (reprint author), West Los Angeles VA Med Ctr, CURE Digest Dis Res Ctr, 11301 Wilshire Blvd,Bldg 115 Rm 111, Los Angeles, CA 90073 USA. EM mlarauche@mednet.ucla.edu FU NIDDK NIH HHS [K01 DK088937, P30 DK041301, P50 DK064539, R01 DK078676] NR 67 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD NOV PY 2016 VL 28 IS 11 BP 1663 EP 1676 DI 10.1111/nmo.12866 PG 14 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA EB0KM UT WOS:000387032700007 PM 27259385 ER PT J AU Biagianti, B Fisher, M Neilands, TB Loewy, R Vinogradov, S AF Biagianti, Bruno Fisher, Melissa Neilands, Torsten B. Loewy, Rachel Vinogradov, Sophia TI Engagement With the Auditory Processing System During Targeted Auditory Cognitive Training Mediates Changes in Cognitive Outcomes in Individuals With Schizophrenia SO NEUROPSYCHOLOGY LA English DT Article DE cognitive training; target engagement; auditory processing; schizophrenia; neuroplasticity ID CLINICAL HIGH-RISK; VERBAL MEMORY; REMEDIATION; PSYCHOSIS; VALIDITY; METAANALYSIS; METHODOLOGY; RELIABILITY; PERSPECTIVE; DYSFUNCTION AB Background: Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. Method: 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. Results: We observed significant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed interindividual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20 and 40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. Conclusions: There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of interindividual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. C1 [Biagianti, Bruno; Fisher, Melissa; Loewy, Rachel; Vinogradov, Sophia] Univ Calif San Francisco, Dept Psychiat, 513 Parnassus Ave,S362, San Francisco, CA 94134 USA. [Biagianti, Bruno; Fisher, Melissa; Vinogradov, Sophia] San Francisco VA Med Ctr, Dept Mental Hlth, San Francisco, CA USA. [Biagianti, Bruno] Univ Milan, Dept Psychiat, I-20122 Milan, Italy. [Neilands, Torsten B.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Biagianti, B (reprint author), Univ Calif San Francisco, Dept Psychiat, 513 Parnassus Ave,S362, San Francisco, CA 94134 USA. EM bruno.biagianti@ucsf.edu FU Posit Science; National Institute of Health [R01MH82818-01A2, MH068725-06A2]; Stanley Foundation [06TAF-972] FX The cognitive training software used in these studies was supplied to the last author free of charge by Posit Science. Vinogradov is a site PI on an SBIR grant to Posit Science, a company with a commercial interest in the cognitive training software used in these studies. Biagianti is a post-doctoral research fellow partially funded through Posit Science. None of the other authors have any financial interest in Brain Plasticity Inc. or Posit Science. Vinogradov serves on an advisory board for Forum pharmaceuticals. This work was supported by National Institute of Health grants R01MH82818-01A2, MH068725-06A2 and by the Stanley Foundation grant 06TAF-972 NR 46 TC 0 Z9 0 U1 2 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 EI 1931-1559 J9 NEUROPSYCHOLOGY JI Neuropsychology PD NOV PY 2016 VL 30 IS 8 BP 998 EP 1008 DI 10.1037/neu0000311 PG 11 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA EB3DI UT WOS:000387242200011 PM 27617637 ER PT J AU Puram, SV Bhattacharyya, N AF Puram, Sidharth V. Bhattacharyya, Neil TI Quality Indicators for Head and Neck Oncologic Surgery: Academic versus Nonacademic Outcomes SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE head and neck; otolaryngology; academic; teaching; quality outcomes ID AORTIC-VALVE-REPLACEMENT; NONTEACHING HOSPITALS; UNITED-STATES; CANCER CARE; MORTALITY; PATTERNS AB Objectives to determine national benchmarks for established quality indicators in head and neck cancer (HNCA) surgery, focusing on differences between academic and nonacademic institutions. Study Design Cross-sectional analysis of national database. Subjects and Methods HNCA surgery admissions from the 2009-2011 Nationwide Inpatient Sample were analyzed for preoperative characteristics and postoperative outcomes. Multivariate analyses were used to identify factors influencing quality indicators after HNCA surgery. Quality metricsincluding length of stay (LOS), inpatient death, return to the operating room (OR), wound infection, and transfusionwere compared for academic versus nonacademic institutions. Results A total of 38,379 HNCA surgery inpatient admissions (mean age, 56.5 years; 52.4% male) were analyzed (28,288 teaching vs 10,091 nonteaching). Nationally representative quality metrics for HNCA surgery were as follows: mean LOS, 4.26 0.12 days; return to OR, 3.3% +/- 0.2%; inpatient mortality, 0.7% +/- 0.1%; wound infection rate, 0.9% +/- 0.1%; wound complication rate, 4.3% +/- 0.2%; and transfusion rate, 4.3% +/- 0.3%. HNCA surgery patients at teaching hospitals had a greater proportion of males, radiation history, and high-acuity procedures and greater comorbidity scores (all P < .001). Multivariate analyses adjusting for age, sex, income, payer, prior radiation, comorbidity scores, and procedural acuity demonstrated that teaching hospitals had a slightly increased LOS (+0.30 days; P = .009) and odds ratio for wound infection (1.54; 95% CI: 1.22-1.94) versus nonteaching hospitals. There were no significant differences in return to OR (P = .271), inpatient mortality (P = .686), or transfusion rate (P = .960). Conclusion Despite caring for substantially more complex HNCA surgery patients with greater comorbidities, teaching hospitals demonstrate only a marginally increased LOS and wound complication rate versus nonteaching hospitals, while other established quality metrics are similar. C1 [Puram, Sidharth V.; Bhattacharyya, Neil] Brigham & Womens Hosp, Dept Otolaryngol, 75 Francis St, Boston, MA 02115 USA. [Puram, Sidharth V.; Bhattacharyya, Neil] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. RP Puram, SV (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Sid_Puram@meei.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD NOV PY 2016 VL 155 IS 5 BP 733 EP 739 DI 10.1177/0194599816654689 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EB3NL UT WOS:000387271700004 PM 27329425 ER PT J AU Bergmark, RW Sedaghat, AR AF Bergmark, Regan W. Sedaghat, Ahmad R. TI Presentation to Emergency Departments for Acute Rhinosinusitis: Disparities in Symptoms by Race and Insurance Status SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE sinusitis; emergency service; hospital; health care disparities; health care delivery; insurance; socioeconomic factors; ambulatory care sensitive conditions; symptoms; pain; race; ethnicity ID UNCOMPLICATED ACUTE RHINOSINUSITIS; PRIMARY-CARE ACCESS; SOCIOECONOMIC DISPARITIES; HEALTH-CARE; ETHNIC DISPARITIES; PAIN SCORES; ED PATIENTS; NONURGENT; SINUSITIS; MEDICAID AB Objective Medicaid and self-pay insurance statuses and race are associated with emergency department (ED) presentation for uncomplicated acute rhinosinusitis (ARS). We investigated whether ARS symptomatology could explain this disproportionate ED use. Study Design 2006-2010 National Hospital Ambulatory Medical Care Surveys. Setting EDs in the United States. Subjects and Methods The data comprise 1,632,826 adult visits for uncomplicated ARS at hospital EDs. Patient-reported reasons for presentation included constitutional symptoms, facial pain or headache, sinonasal symptoms, head cold or flu-like symptoms, cough or sputum production, and sore throat. Patient-reported pain level was also included. Symptoms were assessed for associations with insurance status and race after controlling for clinical, demographic, and socioeconomic characteristics. Results Medicaid patients had similar symptomatology and levels of pain when compared with privately insured patients. Self-pay patients reported higher pain levels (P = .033) and were less likely to report head cold or flu-like symptoms (P = .018) but were equally likely to report other symptomatology. Relative to white patients, Hispanic patients were more likely to complain of facial pain and headaches (P = .033) and less likely to complain of other classical ARS symptoms, such as cough or sputum production (P = .013), sinonasal symptoms (P = .019), or head cold or flu-like symptoms (P = .019). Black patients were also less likely to complain of sinonasal symptoms (P = .038). Conclusion Symptomatology does not explain disproportionate ED use for ARS by Medicaid patients, while higher self-reported pain levels may explain self-pay patients' disproportionate ED utilization. Likewise, ED presentation for ARS among Hispanic patients may be related to symptomatology that is less specific for ARS, such as headache and facial pain. C1 [Bergmark, Regan W.; Sedaghat, Ahmad R.] Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02115 USA. RP Bergmark, RW (reprint author), Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02115 USA. EM regan_bergmark@meei.harvard.edu NR 34 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD NOV PY 2016 VL 155 IS 5 BP 790 EP 796 DI 10.1177/0194599816658018 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EB3NL UT WOS:000387271700014 PM 27436418 ER PT J AU Garcia, JA Benboujja, F Beaudette, K Rogers, D Maurer, R Boudoux, C Hartnick, CJ AF Garcia, Jordan A. Benboujja, Fouzi Beaudette, Kathy Rogers, Derek Maurer, Rie Boudoux, Caroline Hartnick, Christopher J. TI Collagen Content Limits Optical Coherence Tomography Image Depth in Porcine Vocal Fold Tissue SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE optical coherence tomography; vocal fold scarring; collagen ID LAMINA PROPRIA; CLOSTRIDIUM-HISTOLYTICUM; MECHANICAL CHARACTERIZATION; EXTRACELLULAR-MATRIX; HYALURONIC-ACID; IN-VIVO; MATURATION; MICROSCOPY; VIBRATION; VERSICAN AB Objective Vocal fold scarring, a condition defined by increased collagen content, is challenging to treat without a method of noninvasively assessing vocal fold structure in vivo. The goal of this study was to observe the effects of vocal fold collagen content on optical coherence tomography imaging to develop a quantifiable marker of disease. Study Design Excised specimen study. Setting Massachusetts Eye and Ear Infirmary. Subjects and Methods Porcine vocal folds were injected with collagenase to remove collagen from the lamina propria. Optical coherence tomography imaging was performed preinjection and at 0, 45, 90, and 180 minutes postinjection. Mean pixel intensity (or image brightness) was extracted from images of collagenase- and control-treated hemilarynges. Texture analysis of the lamina propria at each injection site was performed to extract image contrast. Two-factor repeated measure analysis of variance and t tests were used to determine statistical significance. Picrosirius red staining was performed to confirm collagenase activity. Results Mean pixel intensity was higher at injection sites of collagenase-treated vocal folds than control vocal folds (P < .0001). Fold change in image contrast was significantly increased in collagenase-treated vocal folds than control vocal folds (P = .002). Picrosirius red staining in control specimens revealed collagen fibrils most prominent in the subepithelium and above the thyroarytenoid muscle. Specimens treated with collagenase exhibited a loss of these structures. Conclusion Collagen removal from vocal fold tissue increases image brightness of underlying structures. This inverse relationship may be useful in treating vocal fold scarring in patients. C1 [Garcia, Jordan A.] Harvard Med Sch, Boston, MA USA. [Benboujja, Fouzi; Beaudette, Kathy; Boudoux, Caroline] Polytech Montreal, Dept Engn Phys, Montreal, PQ, Canada. [Rogers, Derek] Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Maurer, Rie] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. RP Garcia, JA (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM jordan_garcia@hms.harvard.edu FU Massachusetts Eye and Ear Infirmary; Scholars in Medicine Office at Harvard Medical School FX Funding for the project was provided largely by internal research funding at Massachusetts Eye and Ear Infirmary. The first author was also funded in part by the Scholars in Medicine Office at Harvard Medical School. NR 49 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD NOV PY 2016 VL 155 IS 5 BP 829 EP 836 DI 10.1177/0194599816658005 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EB3NL UT WOS:000387271700020 PM 27352894 ER PT J AU Frank, MM Zuraw, B Banerji, A Bernstein, JA Craig, T Busse, P Christiansen, S Davis-Lorton, M Li, HH Lumry, WR Riedl, M AF Frank, Michael M. Zuraw, Bruce Banerji, Aleena Bernstein, Jonathan A. Craig, Timothy Busse, Paula Christiansen, Sandra Davis-Lorton, Marc Li, H. Henry Lumry, William R. Riedl, Marc CA US Hereditary Angioedema Assoc Med TI Management of Children With Hereditary Angioedema Due to C1 Inhibitor Deficiency SO PEDIATRICS LA English DT Article ID ANGIONEUROTIC-EDEMA; ESTERASE INHIBITOR; C1-INHIBITOR DEFICIENCY; ACUTE ATTACKS; C1-ESTERASE INHIBITOR; SEX-HORMONES; THERAPY; CONCENTRATE; SYMPTOMS; DANAZOL AB Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE. C1 [Frank, Michael M.] Duke Univ, Med Ctr, Durham, NC USA. [Zuraw, Bruce; Christiansen, Sandra; Riedl, Marc] Univ Calif Med Ctr, San Diego, CA USA. [Banerji, Aleena] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bernstein, Jonathan A.] Univ Cincinnati, Sch Med, Cincinnati, OH USA. [Craig, Timothy] Penn State Univ, Sch Med, Hershey, PA USA. [Busse, Paula] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Davis-Lorton, Marc] Winthrop Univ Hosp, Mineola, NY 11501 USA. [Li, H. Henry] Inst Asthma & Allergy, Chevy Chase, MD USA. [Lumry, William R.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Frank, MM (reprint author), Duke Med Ctr, Dept Pediat, Room 131,Erwin Rd, Durham, NC 27710 USA. EM frank007@mc.duke.edu NR 57 TC 0 Z9 0 U1 3 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2016 VL 138 IS 5 AR e20160575 DI 10.1542/peds.2016-0575 PG 9 WC Pediatrics SC Pediatrics GA EB5UV UT WOS:000387447000015 ER PT J AU Scheffer, AL Patel, PR Manaloor, JJ AF Scheffer, Ashley L. Patel, Palka R. Manaloor, John J. TI Case 2: Shoulder Pain in 7-year-old Girl SO PEDIATRICS IN REVIEW LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; COMMUNITY-ACQUIRED PNEUMONIA; CHILDREN C1 [Scheffer, Ashley L.] Univ Arizona, Coll Med Phoenix, Dept Child Hlth, Phoenix, AZ 85004 USA. [Scheffer, Ashley L.] Phoenix Childrens Hosp, Dept Pediat Crit Care, Phoenix, AZ 85016 USA. [Patel, Palka R.] Massachusetts Gen Hosp, Global Primary Care Program, MGH Global Hlth, Boston, MA 02114 USA. [Manaloor, John J.] Indiana Univ Sch Med, Riley Hosp Children, Ryan White Ctr Pediat Infect Dis & Global Hlth, Clin Pediat, Indianapolis, IN 46202 USA. [Manaloor, John J.] Indiana Univ Sch Med, Riley Hosp Children, Ryan White Ctr Pediat Infect Dis & Global Hlth, Pediat Antimicrobial Stewardship Program, Indianapolis, IN 46202 USA. RP Scheffer, AL (reprint author), Univ Arizona, Coll Med Phoenix, Dept Child Hlth, Phoenix, AZ 85004 USA.; Scheffer, AL (reprint author), Phoenix Childrens Hosp, Dept Pediat Crit Care, Phoenix, AZ 85016 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0191-9601 EI 1526-3347 J9 PEDIATR REV JI Pediatr. Rev. PD NOV PY 2016 VL 37 IS 11 BP 494 EP 497 DI 10.1542/pir.2016-0048 PG 4 WC Pediatrics SC Pediatrics GA EB5TF UT WOS:000387442600006 PM 27803146 ER PT J AU Kimmel, SE Troxel, AB French, B Loewenstein, G Doshi, JA Hecht, TEH Laskin, M Brensinger, CM Meussner, C Volpp, K AF Kimmel, Stephen E. Troxel, Andrea B. French, Benjamin Loewenstein, George Doshi, Jalpa A. Hecht, Todd E. H. Laskin, Mitchell Brensinger, Colleen M. Meussner, Chris Volpp, Kevin TI A randomized trial of lottery-based incentives and reminders to improve warfarin adherence: the Warfarin Incentives (WIN2) Trial SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE anticoagulants; trials; incentives; economics; behavioral; pharmacoepidemiology; pharmacoepidemiology ID IN-RANGE; ANTICOAGULATION AB BackgroundPrevious research has suggested that daily lottery incentives could improve medication adherence. Such daily incentives include implicit reminders. However, the comparative effectiveness of reminders alone versus daily incentives has not been tested. MethodsA total of 270 patients on warfarin were enrolled in a four-arm, multi-center, randomized controlled trial comparing a daily lottery-based incentive, a daily reminder, and a combination of the two against a control group (usual care). ResultsParticipants in the reminder group had the lowest percentage of time out of target international normalized ratio (INR) range, the primary outcome, with an adjusted odds of an out-of-range INR 36% lower than among those in the control group, 95%CI [7%, 55%]. No other group had a statistically significant improvement in anticoagulation control relative to the control group or to each other. The only group that had significant improvement in incorrect adherence was the lottery group (incorrect adherence: 12.1% compared with 23.7% in the control group, difference of -7.4% 95%CI [-14%, -0.3%]). However, there was no relationship between changes in adherence and anticoagulation control in the lottery group. ConclusionsAutomated reminders led to the largest improvements in anticoagulation control, although without impacting measured adherence. Lottery-based reminders improved measured adherence but did not lead to improved anticoagulation control. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Kimmel, Stephen E.] Univ Penn, Ctr Therapeut Effectiveness Res, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Kimmel, Stephen E.; Troxel, Andrea B.; French, Benjamin; Brensinger, Colleen M.; Meussner, Chris] Univ Penn, Dept Biostat & Epidemiol, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Kimmel, Stephen E.; Doshi, Jalpa A.; Hecht, Todd E. H.; Volpp, Kevin] Univ Penn, Dept Med, Perelman Sch Med, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Kimmel, Stephen E.; Troxel, Andrea B.; French, Benjamin; Loewenstein, George; Doshi, Jalpa A.; Volpp, Kevin] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent & Behav Econ, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Loewenstein, George] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. [Laskin, Mitchell] Hosp Univ Penn, Dept Pharm Serv, 3400 Spruce St, Philadelphia, PA 19104 USA. [Volpp, Kevin] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin] Univ Penn, Dept Hlth Care Management, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Volpp, Kevin] Univ Penn, Dept Med Eth & Hlth Policy, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. RP Kimmel, SE (reprint author), Univ Penn, Sch Med, Med & Epidemiol, 923 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM stevek@mail.med.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU National Institutes of Health, National Heart Lung Blood Institute (NHLBI) [R01-HL-090929] FX Funded by the National Institutes of Health, National Heart Lung Blood Institute (NHLBI), grant # R01-HL-090929. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD NOV PY 2016 VL 25 IS 11 BP 1219 EP 1227 DI 10.1002/pds.4094 PG 9 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EB1OX UT WOS:000387124000001 PM 27592594 ER PT J AU Conhaim, RL Segal, GS Watson, KE AF Conhaim, Robert L. Segal, Gilad S. Watson, Kal E. TI Arterio-venous anastomoses in isolated, perfused rat lungs SO PHYSIOLOGICAL REPORTS LA English DT Article DE Alveolar capillary; arterio-venous anastomoses; pulmonary circulation; pulmonary microcirculation; sheet flow ID INTERALVEOLAR PERFUSION; HEALTHY HUMANS; MICROVESSELS; EXERCISE; FLOW AB Several studies have suggested that large-diameter (>25 mu m) arterio-venous shunt pathways exist in the lungs of rats, dogs, and humans. We investigated the nature of these pathways by infusing specific-diameter fluorescent latex particles (4, 7, 15, 30, or 50 mu m) into isolated, ventilated rat lungs perfused at constant pressure. All lungs received the same mass of latex (5 mg), which resulted in infused particle numbers that ranged from 1.7 x 10(7) 4 mu m particles to 7.5 x 10(4) 50 mu m particles. Particles were infused over 2 min. We used a flow cytometer to count particle appearances in venous effluent samples collected every 0.5 min for 12 min from the start of particle infusion. Cumulative percentages of infused particles that appeared in the samples averaged 3.17 +/- 2.46% for 4 mu m diameter particles, but ranged from 0.01% to 0.17% for larger particles. Appearances of 4 mu m particles followed a rapid upslope beginning at 30 sec followed by a more gradual downslope that lasted for up to 12 min. All other particle diameters also began to appear at 30 sec, but followed highly irregular time courses. Infusion of 7 and 15 mu m particles caused transient but significant perfusate flow reductions, while infusion of all other diameters caused insignificant reductions in flow. We conclude that small numbers of bypass vessels exist that can accommodate particle diameters of 7-to-50 mu m. We further conclude that our 4 mu m particle data are consistent with a well-developed network of serial and parallel perfusion pathways at the acinar level. C1 [Conhaim, Robert L.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Conhaim, Robert L.; Segal, Gilad S.; Watson, Kal E.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. RP Conhaim, RL (reprint author), William S Middleton Mem Vet Adm Med Ctr, Res Off, 2500 Overlook Terrace, Madison, WI 53705 USA. EM rconhaim@wisc.edu NR 20 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2051-817X J9 PHYSIOL REP JI PHYSIOL. REP. PD NOV PY 2016 VL 4 IS 21 AR e13023 DI 10.14814/phy2.13023 PG 9 WC Physiology SC Physiology GA EB5UP UT WOS:000387446300001 ER PT J AU Deng, NJ Hoyte, A Mansour, YE Mohamed, MS Fuchs, JR Engelman, AN Kvaratskhelia, M Levy, R AF Deng, Nanjie Hoyte, Ashley Mansour, Yara E. Mohamed, Mosaad S. Fuchs, James R. Engelman, Alan N. Kvaratskhelia, Mamuka Levy, Ronald TI Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies SO PROTEIN SCIENCE LA English DT Article DE HIV-1 integrase; allosteric HIV-1 integrase inhibitor; protein-protein docking; protein-ligand binding ID HYDROPHOBIC ENCLOSURE; HOT-SPOTS; BI 224436; REPLICATION; MECHANISM; BINDING; MATURATION; COMPLEXES; REVEALS; POTENCY AB Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) bind at the dimer interface of the IN catalytic core domain (CCD), and potently inhibit HIV-1 by promoting aberrant, higher-order IN multimerization. Little is known about the structural organization of the inhibitor-induced IN multimers and important questions regarding how ALLINIs promote aberrant IN multimerization remain to be answered. On the basis of physical chemistry principles and from our analysis of experimental information, we propose that inhibitor-induced multimerization is mediated by ALLINIs directly promoting inter-subunit interactions between the CCD dimer and a C-terminal domain (CTD) of another IN dimer. Guided by this hypothesis, we have built atomic models of inter-subunit interfaces in IN multimers by incorporating information from hydrogen-deuterium exchange (HDX) measurements to drive protein-protein docking. We have also developed a novel free energy simulation method to estimate the effects of ALLINI binding on the association of the CCD and CTD. Using this structural and thermodynamic modeling approach, we show that multimer inter-subunit interface models can account for several experimental observations about ALLINI-induced multimerization, including large differences in the potencies of various ALLINIs, the mechanisms of resistance mutations, and the crucial role of solvent exposed R-groups in the high potency of certain ALLINIs. Our study predicts that CTD residues Tyr226, Trp235 and Lys266 are involved in the aberrant multimer interfaces. The key finding of the study is that it suggests the possibility of ALLINIs facilitating inter-subunit interactions between an external CTD and the CCD-CCD dimer interface. C1 [Deng, Nanjie; Levy, Ronald] Temple Univ, Dept Chem, Ctr Biophys & Computat Biol ICMS, Philadelphia, PA 19122 USA. [Hoyte, Ashley; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Hoyte, Ashley; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA. [Mansour, Yara E.; Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Mansour, Yara E.; Mohamed, Mosaad S.] Helwan Univ, Dept Organ Pharmaceut Chem, Fac Pharm, Cairo, Egypt. [Engelman, Alan N.] Harvard Med Sch, Dept Canc Immunol & Virol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Engelman, Alan N.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. RP Deng, NJ (reprint author), Temple Univ, Dept Chem, Ctr Biophys & Computat Biol ICMS, Philadelphia, PA 19122 USA. EM nanjie.deng@gmail.com FU NIH P50 HIVE center [P50GM103368]; NIH [GM30580, R01AI110310] FX Grant sponsor: NIH P50 HIVE center; Grant number: P50GM103368 (to RML, ANE and MK); Grant sponsor: NIH R01; Grant numbers: GM30580 (to RML), R01AI110310 (to MK and JRF). NR 29 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2016 VL 25 IS 11 BP 1911 EP 1917 DI 10.1002/pro.2997 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB1YE UT WOS:000387151900001 PM 27503276 ER PT J AU Waldinger, RJ Schulz, MS AF Waldinger, Robert J. Schulz, Marc S. TI The Long Reach of Nurturing Family Environments: Links With Midlife Emotion-Regulatory Styles and Late-Life Security in Intimate Relationships SO PSYCHOLOGICAL SCIENCE LA English DT Article DE emotion regulation; attachment; family environment; life-span development; aging; coping ID ATTACHMENT REPRESENTATIONS; HEALTH; CONSEQUENCES; STABILITY; OLD AB Does the warmth of children's family environments predict the quality of their intimate relationships at the other end of the life span? Using data collected prospectively on 81 men from adolescence through the eighth and ninth decades of life, this study tested the hypotheses that warmer relationships with parents in childhood predict greater security of attachment to intimate partners in late life, and that this link is mediated in part by the degree to which individuals in midlife rely on emotion-regulatory styles that facilitate or inhibit close relationship connections. Findings supported this mediational model, showing a positive link between more nurturing family environments in childhood and greater security of attachment to spouses more than 60 years later. This link was partially mediated by reliance on more engaging and less distorting styles of emotion regulation in midlife. The findings underscore the far-reaching influence of childhood environment on well-being in adulthood. C1 [Waldinger, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St, Boston, MA 02115 USA. [Waldinger, Robert J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Schulz, Marc S.] Bryn Mawr Coll, Dept Psychol, Bryn Mawr, PA 19010 USA. RP Waldinger, RJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St, Boston, MA 02115 USA. EM rwaldinger@mgh.harvard.edu FU National Institute of Mental Health [R01MH42248]; National Institute on Aging [R01AG045230] FX This work was supported by grants from the National Institute of Mental Health (R01MH42248) and the National Institute on Aging (R01AG045230). NR 41 TC 0 Z9 0 U1 10 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 EI 1467-9280 J9 PSYCHOL SCI JI Psychol. Sci. PD NOV PY 2016 VL 27 IS 11 BP 1443 EP 1450 DI 10.1177/0956797616661556 PG 8 WC Psychology, Multidisciplinary SC Psychology GA EB4HU UT WOS:000387332500003 PM 27634005 ER PT J AU Katz, LS AF Katz, Lori S. TI Efficacy of Warrior Renew Group Therapy for Female Veterans Who Have Experienced Military Sexual Trauma SO PSYCHOLOGICAL SERVICES LA English DT Article DE sexual trauma; women veterans; military sexual trauma; group therapy ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL THERAPY; WOMEN VETERANS; MENTAL-HEALTH; PROLONGED EXPOSURE; PRIMARY-CARE; GENDER-DIFFERENCES; WAR VETERANS; PTSD; AFGHANISTAN AB This is a program evaluation of the Warrior Renew treatment protocol delivered in an outpatient therapy group for survivors of military sexual trauma (MST) at a Department of Veterans Affairs medical center. The group was delivered via a manualized protocol with 12 weekly topics. It includes coping skills for affect management (e.g., triggers and anxiety) and addresses unique aspects of MST including anger/resentments because of injustice and lack of closure, betrayal, and self-blame. It also addresses interpersonal factors such as relationship patterns and healthy interpersonal skills. This evaluation was conducted as part of routine clinical care in a naturalistic setting. Forty-three female veterans started and 34 completed treatment (21% dropout rate). Of the 34 graduates, 32 opted to complete pre- and posttreatment assessments. Findings revealed significant decreases in symptoms of anxiety, depression, posttraumatic negative thinking, and posttraumatic stress disorder (PTSD) all with large effect sizes. In addition, 75% of the sample had a reliable clinical change at the 95% confidence interval. These results are promising and further investigation is warranted to examine Warrior Renew to address the unique issues related to MST. C1 [Katz, Lori S.] VA Puget Sound Hlth Care Syst, 9600 Vet Dr SW, Tacoma, WA 98493 USA. [Katz, Lori S.] Univ Southern Calif, Ctr Innovat & Res Vet & Mil Families, Los Angeles, CA 90089 USA. RP Katz, LS (reprint author), VA Puget Sound Hlth Care Syst, 9600 Vet Dr SW, Tacoma, WA 98493 USA. EM lori.katz@va.gov NR 55 TC 0 Z9 0 U1 7 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1541-1559 EI 1939-148X J9 PSYCHOL SERV JI Psychol. Serv. PD NOV PY 2016 VL 13 IS 4 BP 364 EP 372 DI 10.1037/ser0000103 PG 9 WC Psychology, Clinical SC Psychology GA EB3EE UT WOS:000387244600005 PM 27537615 ER PT J AU Pruiksma, KE Taylor, DJ Wachen, JS Mintz, J Young-McCaughan, S Peterson, AL Yarvis, JS Borah, EV Dondanville, KA Litz, BT Hembree, EA Resick, PA AF Pruiksma, Kristi E. Taylor, Daniel J. Wachen, Jennifer Schuster Mintz, Jim Young-McCaughan, Stacey Peterson, Alan L. Yarvis, Jeffrey S. Borah, Elisa V. Dondanville, Katherine A. Litz, Brett T. Hembree, Elizabeth A. Resick, Patricia A. CA STRONG STAR Consortium TI Residual Sleep Disturbances Following PTSD Treatment in Active Duty Military Personnel SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE insomnia; nightmares; posttraumatic stress disorder; cognitive processing therapy; military ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL THERAPY; INSOMNIA; METAANALYSIS; SYMPTOMS; VETERANS; TRIAL AB Objective: Sleep disturbances, including nightmares and insomnia, are frequently reported symptoms of posttraumatic stress disorder (PTSD). Insomnia is one of the most common symptoms to persist after evidence-based PTSD treatment. The purpose of this study was to examine the prevalence of sleep disturbances in a sample of active duty military personnel before and after receiving therapy for PTSD in a clinical trial and to explore the associations of insomnia and nightmares with PTSD diagnosis after treatment. Method: Sleep parameters were evaluated with the PTSD Checklist in 108 active duty U.S. Army soldiers who had completed at least one deployment in support of the wars in Iraq and Afghanistan and who participated in a randomized clinical trial comparing Group Cognitive Processing Therapy-Cognitive Only Version with Group Present-Centered Therapy. Results: Insomnia was the most frequently reported symptom before and after treatment, with 92% reporting insomnia at baseline and 74%-80% reporting insomnia at follow-up. Nightmares were reported by 69% at baseline and by 49%-55% at follow-up. Among participants who no longer met criteria for PTSD following treatment, 57% continued to report insomnia, but only 13% continued to report nightmares. At baseline, 54% were taking sleep medications, but sleep medication use did not affect the overall results. Conclusions: Insomnia was found to be one of the most prevalent and persistent problems among service members receiving PTSD treatment. Nightmares were relatively more positively responsive to treatment. For some service members with PTSD, the addition of specific treatments targeting insomnia and/or nightmares may be indicated. C1 [Pruiksma, Kristi E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Taylor, Daniel J.] Univ N Texas, Dept Psychol, Denton, TX 76203 USA. [Wachen, Jennifer Schuster] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Wachen, Jennifer Schuster; Litz, Brett T.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Mintz, Jim; Young-McCaughan, Stacey; Peterson, Alan L.; Dondanville, Katherine A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Mintz, Jim] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX USA. [Peterson, Alan L.] South Texas Vet Hlth Care Syst, Off Res & Dev, San Antonio, TX USA. [Yarvis, Jeffrey S.] Carl R Darnall Army Med Ctr, Ft Hood, TX USA. [Borah, Elisa V.] Univ Texas Austin, Sch Social Work, Austin, TX 78712 USA. [Litz, Brett T.] VA Boston Healthcare Syst, VA Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hembree, Elizabeth A.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Resick, Patricia A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. RP Pruiksma, KE (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. EM pruiksma@uthscsa.edu OI Pruiksma, Kristi/0000-0001-6585-4670 FU U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program [W81XWH-08-02-109, W81XWH-08-02-0116, W81XWH-10-1-0828, W81XWH-08-02-0114] FX The views expressed in this article are solely those of the authors and do not reflect an endorsement by or the official policy or position of the U.S. Army, the Department of Defense, the Department of Veterans Affairs, or the U.S. Government. Funding for this work was made possible by the U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program awards W81XWH-08-02-109 (Alan L. Peterson), W81XWH-08-02-0116 (Patricia A. Resick), W81XWH-10-1-0828 (Daniel J. Taylor), and W81XWH-08-02-0114 (Brett T. Litz). NR 22 TC 0 Z9 0 U1 7 U2 7 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD NOV PY 2016 VL 8 IS 6 BP 697 EP 701 DI 10.1037/tra0000150 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EB1XG UT WOS:000387149000007 PM 27243567 ER PT J AU Liu, CA Sui, JH Cote, CJ Anderson, TA AF Liu, Chang Amber Sui, Jinghu Cote, Charles J. Anderson, Thomas A. TI The Use of Epinephrine in Caudal Anesthesia Increases Stroke Volume and Cardiac Output in Children SO REGIONAL ANESTHESIA AND PAIN MEDICINE LA English DT Article ID PEDIATRIC REGIONAL ANESTHESIA; ELECTRICAL VELOCIMETRY; EPIDURAL-ANESTHESIA; NETWORK PRAN; DOUBLE-BLIND; HEART; ECHOCARDIOGRAPHY; DOPPLER; INFANTS; CARDIOMETRY AB Background and Objectives: Caudal anesthesia is a common and effective regional anesthesia technique in pediatric patients. The addition of epinephrine to local anesthetics in caudal anesthesia is a frequent practice; however, changes in hemodynamic and cardiac parameters produced by epinephrine in caudal anesthesia are not well studied. Using data collected with the ICON noninvasive cardiac output monitor, we examined the hemodynamic changes associated with the administration of epinephrine containing local anesthetics during caudal anesthesia in children. Methods: We performed a retrospective analysis of 40 patients who received caudal anesthesia among 402 patients from whom we prospectively collected continuous noninvasive cardiac output data using the ICON monitor, which estimates cardiac output by measuring changes in thoracic bioimpedance during the cardiac cycle. Twenty-three children received epinephrine with local anesthetic (ELA), and 17 children received only local anesthetic (OLA) in their caudal blocks. We compared heart rate (HR), stroke volume (SV), cardiac output (CO), and cardiac index (CI) changes from baseline before caudal injection to 1-minute intervals over 15 minutes after caudal injection for both ELA and OLA groups (Table, Supplemental Digital Content 1, http://links.lww.com/AAP/A179). We also performed subgroup analysis of the same parameters comparing both ELA and OLA groups in infants younger than 6 months and in children 6 months or older. Results: Stroke volume, CO, and CI are significantly increased after caudal injection in the ELA group compared with baseline values at caudal injection time. Conversely, there were no statistically significant changes in SV, CO, and CI in the OLA group. There were no significant HR or blood pressure changes observed in either the ELA or OLA group within 15 minutes compared with baseline caudal injection time. In infants younger than 6 months, no significant differences were found in HR, SV, and CI in children in the ELA group compared with the OLA group. In children 6 months or older, SV and CI increased significantly in the ELA group compared with the OLA group. Conclusions: Epinephrine added to local anesthetic injected for caudal anesthesia produces significant increases in SV, CO, and CI in children. Stroke volume and CI changes from epinephrine added to local anesthetic for caudal anesthesia seem to take place only in children 6 months or older. C1 [Liu, Chang Amber; Sui, Jinghu; Cote, Charles J.; Anderson, Thomas A.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. RP Liu, CA (reprint author), Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, 3401 Civ Ctr Blvd,Room 9329, Philadelphia, PA 19104 USA. EM amber.chang.liu@gmail.com FU People's Republic of China FX Support was provided solely from institutional and/or departmental sources. JS was supported by a research training grant from the People's Republic of China. OsypkaMedical provided no financial support and had no role in the data collection or analysis, but it did provide an ICON monitor with which to conduct the study. NR 35 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1098-7339 EI 1532-8651 J9 REGION ANESTH PAIN M JI Region. Anesth. Pain Med. PD NOV-DEC PY 2016 VL 41 IS 6 BP 780 EP 786 DI 10.1097/AAP.0000000000000498 PG 7 WC Anesthesiology SC Anesthesiology GA EB1BQ UT WOS:000387081700022 PM 27755489 ER PT J AU Winterhalter, C Safai, S Grassberger, C Oxley, D Weber, DC Lomax, T AF Winterhalter, Carla Safai, Sairos Grassberger, Clemens Oxley, David Weber, Damien C. Lomax, Tony TI Monte Carlo model of a gantry for proton pencil beam scanning SO STRAHLENTHERAPIE UND ONKOLOGIE LA English DT Meeting Abstract CT 2nd Joint Meeting of the SASRO/SGSMP CY AUG 25-27, 2016 CL Sursee, SWITZERLAND SP SASRO, SGSMP C1 [Winterhalter, Carla; Safai, Sairos; Oxley, David; Weber, Damien C.; Lomax, Tony] Paul Scherrer Inst, Ctr Proton Therapy, CH-5232 Villigen, Switzerland. [Grassberger, Clemens] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Grassberger, Clemens] Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 EI 1439-099X J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD NOV PY 2016 VL 192 IS 11 MA 3.3 BP 837 EP 837 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB1TT UT WOS:000387138700028 ER PT J AU Karlsson, P Cole, BF Price, KN Gelber, RD Coates, AS Goldhirsch, A Castiglione, M Colleoni, M Gruber, G AF Karlsson, Per Cole, Bernard F. Price, Karen N. Gelber, Richard D. Coates, Alan S. Goldhirsch, Aron Castiglione, Monica Colleoni, Marco Gruber, Gunther TI Timing of radiotherapy and chemotherapy after breast-conserving surgery for node-positive breast cancer: long term results from IBCSG Trials VI and VII SO STRAHLENTHERAPIE UND ONKOLOGIE LA English DT Meeting Abstract CT 2nd Joint Meeting of the SASRO/SGSMP CY AUG 25-27, 2016 CL Sursee, SWITZERLAND SP SASRO, SGSMP C1 [Karlsson, Per] Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Dept Oncol, Gothenburg, Sweden. [Cole, Bernard F.] Univ Vermont, Dept Math & Stat, Burlington, VT 05405 USA. [Price, Karen N.] Frontier Sci & Technol Res Fdn Inc, IBCSG Stat Ctr, Boston, MA USA. [Gelber, Richard D.] Harvard TF Chan Sch Publ Hlth, Frontier Sci & Technol Res Fdn, Dana Farber Canc Inst, IBCSG Stat Ctr,Dept Biostat & Computat Biol, Boston, MA USA. [Coates, Alan S.] IBCSG, Sydney, NSW, Australia. [Coates, Alan S.] Univ Sydney, Sydney, NSW, Australia. [Goldhirsch, Aron] European Inst Oncol, Program Breast Hlth Senol, Milan, Italy. [Goldhirsch, Aron; Colleoni, Marco] IBCSG, Milan, Italy. [Castiglione, Monica] IBCSG, Bern, Switzerland. [Colleoni, Marco] European Inst Oncol, Div Med Senol, Milan, Italy. [Gruber, Gunther] Klin Hirslanden, Inst Radiotherapy, Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 1 U2 1 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 EI 1439-099X J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD NOV PY 2016 VL 192 IS 11 MA 4.1 BP 839 EP 839 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB1TT UT WOS:000387138700033 ER PT J AU Oflazoglu, K Koenrades, N Somford, MP van den Bekerom, MPJ AF Oflazoglu, Kamilcan Koenrades, Nienke Somford, Matthijs P. van den Bekerom, Michel P. J. TI Recognizing the elbow prosthesis on conventional radiographs SO STRATEGIES IN TRAUMA AND LIMB RECONSTRUCTION LA English DT Article DE Elbow; Arthroplasty; Prosthesis; Radiograph ID RHEUMATOID-ARTHRITIS; ARTHROPLASTY AB The objective of this study was to make an overview that can be useful in determining which type and brand of prosthesis a patient has when visiting the emergency department or outpatient clinic with a periprosthetic fracture, dislocation, or implant failure. The commonly used prostheses in Europe are opted for this list. The radiographs used for this list are obtained either from the company or from our own patients. This list contains the Coonrad/Morrey total elbow prosthesis, the Nexel total elbow prosthesis, the GSB III Elbow Prosthesis, the iBP Total Elbow System, the Discovery Elbow System, the NESimplavit Elbow System, the Latitude Elbow prosthesis, the Solar Elbow, and the Souter-Strathclyde total elbow. The characteristics of each prosthesis are described. C1 [Oflazoglu, Kamilcan] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Koenrades, Nienke; Somford, Matthijs P.] Med Spectrum Twente, Dept Orthopaed Surg, Haaksbergerstr 55, NL-7513 ER Enschede, Netherlands. [van den Bekerom, Michel P. J.] Onze Lieve Vrouwe Gasthuis Amsterdam, Dept Orthopaed Surg, Oosterpk 9, NL-1091 AC Amsterdam, Netherlands. RP Oflazoglu, K (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM k.oflazoglu@gmail.com; nienkekoen@hotmail.com; mp_somford@hotmail.com; bekerom@gmail.com NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1828-8928 EI 1828-8936 J9 STRATEG TRAUMA LIMB JI Strateg. Trauma Limb Reconstr. PD NOV PY 2016 VL 11 IS 3 BP 161 EP 168 DI 10.1007/s11751-016-0263-5 PG 8 WC Orthopedics SC Orthopedics GA EB2HL UT WOS:000387178400003 PM 27663584 ER PT J AU Vespa, P Hanley, D Betz, J Hoffer, A Engh, J Carter, R Nakaji, P Ogilvy, C Jallo, J Selman, W Bistran-Hall, A Lane, K McBee, N Saver, J Thompson, RE Martin, N AF Vespa, Paul Hanley, Daniel Betz, Joshua Hoffer, Alan Engh, Johnathan Carter, Robert Nakaji, Peter Ogilvy, Chris Jallo, Jack Selman, Warren Bistran-Hall, Amanda Lane, Karen McBee, Nichol Saver, Jeffery Thompson, Richard E. Martin, Neil CA ICES Investigators TI ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial SO STROKE LA English DT Article DE coma; endoscopic surgery; hemorrhagic; intracerebral hemorrhage; stroke ID SPONTANEOUS INTRACEREBRAL HEMORRHAGE; ASSOCIATION/AMERICAN STROKE ASSOCIATION; INITIAL CONSERVATIVE TREATMENT; HEALTH-CARE PROFESSIONALS; PERIHEMATOMAL EDEMA; CLINICAL-TRIAL; EVACUATION; VOLUME; STICH; THROMBOLYSIS AB Background and Purpose-Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. Methods-We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. Results-The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68 +/- 21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). Conclusions-Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. C1 [Vespa, Paul; Saver, Jeffery; Martin, Neil] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA. [Vespa, Paul; Saver, Jeffery; Martin, Neil] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Hanley, Daniel; Betz, Joshua; Bistran-Hall, Amanda; Lane, Karen; McBee, Nichol; Thompson, Richard E.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Hoffer, Alan; Selman, Warren] Case Western Univ, Dept Neurosurg, Cleveland, OH USA. [Engh, Johnathan; Nakaji, Peter] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15260 USA. [Carter, Robert] Univ Calif San Diego, Dept Neurosurg, San Diego, CA 92103 USA. [Ogilvy, Chris] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Jallo, Jack] Thomas Jefferson Univ, Dept Neurosurg, Philadelphia, PA 19107 USA. RP Vespa, P (reprint author), Ronald Reagan UCLA Med Ctr, Dept Neurosurg, 757 Westwood Blvd,Room 63236A, Los Angeles, CA 90095 USA.; Vespa, P (reprint author), Ronald Reagan UCLA Med Ctr, Dept Neurol, 757 Westwood Blvd,Room 63236A, Los Angeles, CA 90095 USA. EM Pvespa@mednet.ucla.edu OI Betz, Joshua/0000-0003-4488-9799 FU National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) [R01NS046309]; UCLA Spotrias Grant [NINDS NS 044378] FX ICES was part of the overall MISTIE II study, which was supported by grant R01NS046309 awarded to Dr Daniel Hanley from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS). ICES was a component of the UCLA Spotrias Grant awarded to Drs Neil Martin and Paul (NINDS NS 044378). NR 20 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2016 VL 47 IS 11 BP 2749 EP 2755 DI 10.1161/STROKEAHA.116.013837 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EA8WH UT WOS:000386920000025 PM 27758940 ER PT J AU Li, ZX Wang, CJ Zhao, XQ Liu, LP Wang, CX Li, H Shen, HP Liang, L Bettger, J Yang, Q Wang, D Wang, AX Pan, YS Jiang, Y Yang, XM Zhang, CQ Fonarow, GC Schwamm, LH Hu, B Peterson, ED Xian, Y Wang, YL Wang, YJ AF Li, Zixiao Wang, Chunjuan Zhao, Xingquan Liu, Liping Wang, Chunxue Li, Hao Shen, Haipeng Liang, Li Bettger, Janet Yang, Qing Wang, David Wang, Anxin Pan, Yuesong Jiang, Yong Yang, Xiaomeng Zhang, Changqing Fonarow, Gregg C. Schwamm, Lee H. Hu, Bo Peterson, Eric D. Xian, Ying Wang, Yilong Wang, Yongjun CA China Natl Stroke Registries TI Substantial Progress Yet Significant Opportunity for Improvement in Stroke Care in China SO STROKE LA English DT Article DE China; hospitals; quality improvement; registries; stroke ID TRANSIENT ISCHEMIC ATTACK; GUIDELINES-STROKE; SECONDARY PREVENTION; ASSOCIATION; PERFORMANCE; MORTALITY; OUTCOMES; PROFESSIONALS; REGISTRY; QUALITY AB Background and Purpose-Stroke is a leading cause of death in China. Yet the adherence to guideline-recommended ischemic stroke performance metrics in the past decade has been previously shown to be suboptimal. Since then, several nationwide stroke quality management initiatives have been conducted in China. We sought to determine whether adherence had improved since then. Methods-Data were obtained from the 2 phases of China National Stroke Registries, which included 131 hospitals (12173 patients with acute ischemic stroke) in China National Stroke Registries phase 1 from 2007 to 2008 versus 219 hospitals (19604 patients) in China National Stroke Registries phase 2 from 2012 to 2013. Multiple regression models were developed to evaluate the difference in adherence to performance measure between the 2 study periods. Results-The overall quality of care has improved over time, as reflected by the higher composite score of 0.76 in 2012 to 2013 versus 0.63 in 2007 to 2008. Nine of 13 individual performance metrics improved. However, there were no significant improvements in the rates of intravenous thrombolytic therapy and anticoagulation for atrial fibrillation. After multivariate analysis, there remained a significant 1.17-fold (95% confidence interval, 1.14-1.21) increase in the odds of delivering evidence-based performance metrics in the more recent time periods versus older data. The performance metrics with the most significantly increased odds included stroke education, dysphagia screening, smoking cessation, and antithrombotics at discharge. Conclusions-Adherence to stroke performance metrics has increased over time, but significant opportunities remain for further improvement. Continuous stroke quality improvement program should be developed as a national priority in China. C1 [Li, Zixiao; Zhao, Xingquan; Zhang, Changqing; Wang, Yongjun] Capital Med Univ, Beijing TianTan Hosp, Div Vasc Neurol, Dept Neurol, Beijing, Peoples R China. [Li, Zixiao; Wang, Chunjuan; Li, Hao; Wang, Anxin; Pan, Yuesong; Jiang, Yong; Yang, Xiaomeng; Wang, Yilong] Capital Med Univ, Beijing TianTan Hosp, Tiantan Clin Trial & Res Ctr Stroke, Dept Neurol, 6 Tiantanxili, Beijing 100050, Peoples R China. [Liang, Li] Capital Med Univ, Beijing TianTan Hosp, Neurointens Care Unit, Dept Neurol, Beijing, Peoples R China. [Wang, Chunxue] Capital Med Univ, Beijing TianTan Hosp, Dept Neuropsychiat & Behav Neurol & Clin Psychol, Beijing, Peoples R China. [Wang, Yilong; Wang, Yongjun] China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China. [Li, Zixiao; Zhao, Xingquan] Beijing Inst Brain Disorders, Ctr Stroke, Beijing, Peoples R China. [Wang, Chunjuan] Beijing Key Lab Translat Med Cerebrovasc Dis, Beijing, Peoples R China. [Shen, Haipeng] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC USA. [Bettger, Janet; Peterson, Eric D.; Xian, Ying] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Bettger, Janet; Yang, Qing] Duke Univ, Sch Nursing, Durham, NC USA. [Wang, David] Univ Illinois, Coll Med, OSF Healthcare Syst, INI Stroke Network, Peoria, IL 61656 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Hu, Bo] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA. RP Wang, YL (reprint author), Capital Med Univ, Beijing TianTan Hosp, Tiantan Clin Trial & Res Ctr Stroke, Dept Neurol, 6 Tiantanxili, Beijing 100050, Peoples R China.; Wang, YJ (reprint author), Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, 6 Tiantanxili, Beijing 100050, Peoples R China. EM yilong528@gmail.com; yongjunwang1962@gmail.com FU Ministry of Science and Technology; Ministry of Health of the People's Republic of China (National S & T Major Project of China) [2006BA101A11, 2011BAI08B02]; National Key Technology Research and Development Program of the Ministry of Science and Technology of China [2013BAI09B03]; Beijing Municipal Committee of Science and Technology [Z161100000516223]; Beijing Institute for Brain Disorders [BIBD-PXM2013_014226_07_000084] FX This study was supported by grants from the Ministry of Science and Technology and the Ministry of Health of the People's Republic of China (National S & T Major Project of China: 2006BA101A11 and 2011BAI08B02), the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2013BAI09B03), Beijing Municipal Committee of Science and Technology (Z161100000516223), and Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084). NR 21 TC 1 Z9 1 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2016 VL 47 IS 11 BP 2843 EP 2849 DI 10.1161/STROKEAHA.116.014143 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EA8WH UT WOS:000386920000038 PM 27758941 ER PT J AU Blackledge, C Graham, LA Gullick, AA Richman, J Stahl, R Grams, J AF Blackledge, Camille Graham, Laura A. Gullick, Allison A. Richman, Joshua Stahl, Richard Grams, Jayleen TI Outcomes associated with preoperative weight loss after laparoscopic Roux-en-Y gastric bypass SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Obesity; Bariatric surgery; Preoperative weight loss; Outcomes; Laparoscopic Roux-en-Y gastric bypass ID TYPE-2 DIABETES-MELLITUS; BARIATRIC SURGERY; COMPLICATIONS; METAANALYSIS; OBESITY AB Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for achieving and maintaining weight loss and for improving obesity-related comorbidities. As part of the approval process for bariatric surgery, many insurance companies require patients to have documented recent participation in a supervised weight loss program. The goal of this study was to evaluate the relationship of preoperative weight changes with outcomes following LRYGB. A retrospective review was conducted of adult patients undergoing LRYGB between 2008 and 2012 at a single institution. Patients were stratified into quartiles based on % excess weight gain (0-4.99 % and aeyen5 % EWG) and % excess weight loss (0-4.99 % and aeyen5 % EWL). Generalized linear models were used to examine differences in postoperative weight outcomes at 6, 12, and 24 months. Covariates included in the final adjusted models were determined using backwards stepwise selection. Of the 300 patients included in the study, there were no significant demographic differences among the quartiles. However, there was an increased time to operation for patients who gained or lost aeyen5 % excess body weight (p < 0.001). Although there was no statistical significance in postoperative complications, there was a higher rate of complications in patients with aeyen5 % EWG compared to those with aeyen5 % EWL (12.5 vs. 4.8 %, respectively; p = 0.29). Unadjusted and adjusted generalized linear models showed no statistically significant association between preoperative % excess weight change and weight loss outcomes at 24 months. Patients with the greatest % preoperative excess weight change had the longest intervals from initial visit to operation. No significant differences were seen in perioperative and postoperative outcomes. This study suggests preoperative weight loss requirements may delay the time to operation without improving postoperative outcomes or weight loss. C1 [Blackledge, Camille; Graham, Laura A.; Gullick, Allison A.; Richman, Joshua; Stahl, Richard; Grams, Jayleen] Univ Alabama Birmingham, Dept Surg, 1720 2nd Ave South,KB 401, Birmingham, AL 35294 USA. [Graham, Laura A.; Richman, Joshua] Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL USA. [Blackledge, Camille; Grams, Jayleen] Birmingham Vet Affairs Med Ctr, Dept Surg, Birmingham, AL 35233 USA. RP Grams, J (reprint author), Univ Alabama Birmingham, Dept Surg, 1720 2nd Ave South,KB 401, Birmingham, AL 35294 USA.; Grams, J (reprint author), Birmingham Vet Affairs Med Ctr, Dept Surg, Birmingham, AL 35233 USA. EM jgrams@uab.edu FU Foundation for Surgical Fellowships FX Dr. Camille Blackledge was sponsored in part by the Foundation for Surgical Fellowships. NR 27 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 EI 1432-2218 J9 SURG ENDOSC JI Surg. Endosc. PD NOV PY 2016 VL 30 IS 11 BP 5077 EP 5083 DI 10.1007/s00464-016-4856-3 PG 7 WC Surgery SC Surgery GA EB2XJ UT WOS:000387225600048 PM 26969666 ER PT J AU Bashshur, RL Krupinski, EA Thrall, JH Bashshur, N AF Bashshur, Rashid L. Krupinski, Elizabeth A. Thrall, James H. Bashshur, Noura TI The Empirical Foundations of Teleradiology and Related Applications: A Review of the Evidence SO TELEMEDICINE AND E-HEALTH LA English DT Review DE cost; evidence; telemedicine; teleradiology ID INTERVENTIONAL RADIOLOGY; COLORECTAL-CANCER; EMERGENCY-DEPARTMENT; INTRACRANIAL HEMORRHAGE; TELEMEDICINE SYSTEMS; DIGITAL-MAMMOGRAPHY; STROKE NEUROLOGISTS; COST-EFFECTIVENESS; DECISION-SUPPORT; GENERAL-PRACTICE AB Introduction: Radiology was founded on a technological discovery by Wilhelm Roentgen in 1895. Teleradiology also had its roots in technology dating back to 1947 with the successful transmission of radiographic images through telephone lines. Diagnostic radiology has become the eye of medicine in terms of diagnosing and treating injury and disease. This article documents the empirical foundations of teleradiology. Methods: A selective review of the credible literature during the past decade (2005-2015) was conducted, using robust research design and adequate sample size as criteria for inclusion. Findings: The evidence regarding feasibility of teleradiology and related information technology applications has been well documented for several decades. The majority of studies focused on intermediate outcomes, as indicated by comparability between teleradiology and conventional radiology. A consistent trend of concordance between the two modalities was observed in terms of diagnostic accuracy and reliability. Additional benefits include reductions in patient transfer, rehospitalization, and length of stay. C1 [Bashshur, Rashid L.; Bashshur, Noura] Univ Michigan Hlth Syst, 300 N Ingles, Ann Arbor, MI 48109 USA. [Krupinski, Elizabeth A.] Emory Univ, Dept Radiol & Imaging Sci, Atlanta, GA 30322 USA. [Thrall, James H.] Harvard, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Bashshur, RL (reprint author), Univ Michigan Hlth Syst, 300 N Ingles, Ann Arbor, MI 48109 USA. EM bashshur@med.umich.edu FU National Library of Medicine (The National Institutes of Health) [F037249] FX The research leading to this publication was supported by the National Library of Medicine (The National Institutes of Health in the form of Intergovernmental Personnel Act #F037249 to R.L.B.), and is gratefully acknowledged. The authors wish to acknowledge the valuable assistance rendered by Whitney A. Townsend for the systematic search and organization of the literature. The authors of this article are responsible for the literature selection, analysis, accuracy, and interpretation of the data presented here. NR 155 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD NOV PY 2016 VL 22 IS 11 BP 868 EP 898 DI 10.1089/tmj.2016.0149 PG 31 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB2UN UT WOS:000387218200002 PM 27585301 ER PT J AU Morales-Oyarvide, V Mino-Kenudson, M Ferrone, CR Warshaw, AL Lillemoe, KD Pergolini, I Attiyeh, M Rezaee, N Allen, PJ Wolfgang, CL Fernandez-Del Castillo, C AF Morales-Oyarvide, V. Mino-Kenudson, M. Ferrone, C. R. Warshaw, A. L. Lillemoe, K. D. Pergolini, I. Attiyeh, M. Rezaee, N. Allen, P. J. Wolfgang, C. L. Fernandez-Del Castillo, C. TI Intraductal Papillary Mucinous Neoplasms in Young Patients Exhibit Distinct Biology, Clinicopathological Characteristics, and Favorable Prognosis SO PANCREAS LA English DT Meeting Abstract C1 [Morales-Oyarvide, V.; Ferrone, C. R.; Warshaw, A. L.; Lillemoe, K. D.; Pergolini, I.; Fernandez-Del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Attiyeh, M.; Allen, P. J.] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. [Rezaee, N.; Wolfgang, C. L.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1526 EP 1527 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400154 ER PT J AU Morales-Oyarvide, V Pergolini, I Ferrone, CR Mino-Kenudson, M Warshaw, AL Lillemoe, KD Fernandez-Del Castillo, C AF Morales-Oyarvide, V. Pergolini, I. Ferrone, C. R. Mino-Kenudson, M. Warshaw, A. L. Lillemoe, K. D. Fernandez-Del Castillo, C. TI Main Pancreatic Duct Size Independently Predicts Histological Main Duct Involvement, Intestinal Phenotype, and Malignancy in Intraductal Papillary Mucinous Neoplasm SO PANCREAS LA English DT Meeting Abstract C1 [Morales-Oyarvide, V.; Pergolini, I.; Ferrone, C. R.; Warshaw, A. L.; Lillemoe, K. D.; Fernandez-Del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1526 EP 1526 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400153 ER PT J AU Fadlallah, A Chelala, E Robinson, S Melki, S AF Fadlallah, Ali Chelala, Elias Robinson, Steven Melki, Samir TI Femtosecond laser intrastromal incisions as fiducial marks for alignment of toric IOLs SO ACTA OPHTHALMOLOGICA LA English DT Letter C1 [Fadlallah, Ali; Robinson, Steven; Melki, Samir] Boston Eye Grp, Boston, MA USA. [Fadlallah, Ali; Melki, Samir] Harvard Med Sch, Boston, MA USA. [Fadlallah, Ali; Melki, Samir] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Chelala, Elias] St Joseph Univ, Fac Med, Beirut, Lebanon. RP Melki, S (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM samir_melki@meei.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD NOV PY 2016 VL 94 IS 7 BP E673 EP E674 DI 10.1111/aos.13063 PG 2 WC Ophthalmology SC Ophthalmology GA EA5BI UT WOS:000386631400037 PM 27126175 ER PT J AU Kobrin, KL Moody, O Arena, DT Moore, CF Heinrichs, SC Kaplan, GB AF Kobrin, Kendra L. Moody, Olivia Arena, Danielle T. Moore, Catherine F. Heinrichs, Stephen C. Kaplan, Gary B. TI Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons SO ADDICTION BIOLOGY LA English DT Article DE Conditioned place preference; dendrite; morphine; nucleus accumbens; plasticity; spine ID ADULT RATS; REWARD; ARBORIZATION; STIMULATION; EXPRESSION; DOPAMINE; SPINES; SHELL; SENSITIZATION; REACTIVATION AB Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine-conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction. C1 [Kobrin, Kendra L.; Moody, Olivia; Arena, Danielle T.; Moore, Catherine F.; Heinrichs, Stephen C.] VA Boston Healthcare Syst, Res Serv, Boston, MA 02130 USA. [Kobrin, Kendra L.; Moore, Catherine F.; Kaplan, Gary B.] VA Boston Healthcare Syst, Mental Hlth Serv, 150 South Huntington Ave, Boston, MA 02130 USA. [Kaplan, Gary B.] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA. RP Kaplan, GB (reprint author), VA Boston Healthcare Syst, Mental Hlth Serv, 150 South Huntington Ave, Boston, MA 02130 USA. EM Gary.Kaplan@va.gov OI Moore, Catherine/0000-0003-0198-4788 FU Department of Veterans Affairs FX This research was supported by a Merit Review Grant from the Department of Veterans Affairs to GK. NR 43 TC 3 Z9 3 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD NOV PY 2016 VL 21 IS 6 BP 1086 EP 1096 DI 10.1111/adb.12273 PG 11 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA EA9NX UT WOS:000386972100003 PM 26096355 ER PT J AU Georgette, N Siedner, MJ Zanoni, B Sibaya, T Petty, CR Carpenter, S Haberer, JE AF Georgette, Nathan Siedner, Mark J. Zanoni, Brian Sibaya, Thobekile Petty, Carter R. Carpenter, Stephen Haberer, Jessica E. TI The Acceptability and Perceived Usefulness of a Weekly Clinical SMS Program to Promote HIV Antiretroviral Medication Adherence in KwaZulu-Natal, South Africa SO AIDS AND BEHAVIOR LA English DT Article DE HIV; SMS program; Adherence; mHealth; KwaZulu-Natal; Routine care ID RANDOMIZED CONTROLLED-TRIAL; SUB-SAHARAN AFRICA; CROSS-SECTIONAL SURVEY; TEXT MESSAGES; RURAL UGANDA; FOLLOW-UP; THERAPY; REMINDERS; COMMUNICATION; METAANALYSIS AB Short message service (SMS) text messages have been used to remind and encourage patients to take ART in research studies. However, few studies have assessed the feasibility and acceptability of SMS in routine clinical practice. We report patient perspectives on a weekly SMS adherence support program after implementation into clinical care at an HIV clinic in KwaZulu-Natal, South Africa. We conducted structured interviews with a cross-sectional convenience sample of 100 adult patients who were invited to join the program, 88 of whom had received a program SMS. Of these respondents, 81 (92 %) would recommend the program to a friend. Sixty-eight (77 %) felt the program helped them remember clinic appointments, a response associated with male gender [odds ratio (OR) 5.88, 95 % confidence interval (CI) 1.52-23.26, P = 0.011] and HIV disclosure outside the home [OR 3.40, 95 %CI 1.00-11.60, P = 0.050]. This clinical SMS adherence program was found to have high patient-perceived usefulness. C1 [Georgette, Nathan; Siedner, Mark J.; Zanoni, Brian; Haberer, Jessica E.] Harvard Med Sch, Boston, MA 02115 USA. [Siedner, Mark J.; Zanoni, Brian; Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. [Siedner, Mark J.; Zanoni, Brian; Haberer, Jessica E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sibaya, Thobekile] Univ KwaZulu Natal, Durban, South Africa. [Petty, Carter R.] Boston Childrens Hosp, Boston, MA USA. [Carpenter, Stephen] Don McKenzie Hosp, Bothas Hill, South Africa. RP Haberer, JE (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Haberer, JE (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA.; Haberer, JE (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM jhaberer@partners.org FU Harvard Medical School Scholars in Medicine Program, NIH [K23 MH087228, K23 MH099916, T32 AI007433]; Harvard Catalyst; Harvard Clinical and Translational Science Center (NCRR, NIH) [UL1 TR001102]; Harvard Clinical and Translational Science Center (NCATS, NIH) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX This study received financial support from the Harvard Medical School Scholars in Medicine Program, NIH Grant K23 MH087228, K23 MH099916, T32 AI007433. This work was conducted with support from Harvard Catalyst. The Harvard Clinical and Translational Science Center (NCRR and NCATS, NIH Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The authors would like to thank the staff of Ethembeni clinic for welcoming and assisting the research team, the interview participants for their time and feedback, student volunteers (including Marco Grossi, Grace Hansen-Gilmour, April Kim, and Bessie Zhang) for assistance with data capture, and the leadership staff of Sawubona Health (including Majahonkhe Shabangu, Roy Zhang, Dario Sava, and Antony Bett) for their insights into the SMS program. NR 38 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2016 VL 20 IS 11 BP 2629 EP 2638 DI 10.1007/s10461-016-1287-z PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EA3KA UT WOS:000386499800015 PM 26781866 ER PT J AU Musinguzi, N Muwonge, T Thomas, K Baeten, JM Bangsberg, DR Haberer, JE AF Musinguzi, Nicholas Muwonge, Timothy Thomas, Katherine Baeten, Jared M. Bangsberg, David R. Haberer, Jessica E. TI Does Adherence Change When No One is Looking? Comparing Announced and Unannounced Tenofovir Levels in a PrEP Trial SO AIDS AND BEHAVIOR LA English DT Article DE Announced adherence; Unannounced adherence; Prep; Tenofovir; Emtricitabine ID PREEXPOSURE PROPHYLAXIS; DISOPROXIL FUMARATE; ANTIRETROVIRAL PROPHYLAXIS; HEALTHY-VOLUNTEERS; HIV-INFECTION; WOMEN; PHARMACOKINETICS; MEN AB Differences between unannounced and announced tenofovir levels as measures of PrEP adherence are not well understood. In an ancillary adherence study involving one urban site (Kampala) and two rural sites (Kabwohe and Tororo) from the Partners PrEP study, 268 specimen pairs from chronologically proximal clinic and home visits were tested for plasma tenofovir levels. Comparing clinic and home specimens, 89 versus 89 % were classified as detectable (> 0.31 ng/ml; p = 0.77), 87 versus 86 % as recent dosing (> 10 ng/ml; p = 0.80), and 82 versus 80 % as steady-state (> 40 ng/ml; p = 0.44). Mean difference between announced and unannounced drug levels, adjusted for specimen collection time was 3.2 ng/ml (p = 0.50) for Kabwohe, 23.2 ng/ml (p = 0.003) for Kampala and -3.3 ng/ml p = 0.69) for Tororo. In the setting of high adherence, plasma tenofovir levels tested at the clinic were categorically similar as levels tested at home; however, differences were seen between urban and rural settings. C1 [Musinguzi, Nicholas; Bangsberg, David R.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Muwonge, Timothy] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Thomas, Katherine; Baeten, Jared M.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Baeten, Jared M.] Univ Washington, Dept Med, Seattle, WA USA. [Baeten, Jared M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bangsberg, David R.; Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.; Haberer, Jessica E.] Harvard Med Sch, Boston, MA USA. [Bangsberg, David R.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. RP Musinguzi, N (reprint author), Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. EM nmusinguzi@gmail.com FU Bill and Melinda Gates Foundation FX The Bill and Melinda Gates Foundation funded this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2016 VL 20 IS 11 BP 2639 EP 2643 DI 10.1007/s10461-016-1292-2 PG 5 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EA3KA UT WOS:000386499800016 PM 26781865 ER PT J AU Rodriguez-Hart, C Liu, HJ Nowak, RG Orazulike, I Zorowitz, S Crowell, TA Baral, SD Blattner, W Charurat, M AF Rodriguez-Hart, Cristina Liu, Hongjie Nowak, Rebecca G. Orazulike, Ifeanyi Zorowitz, Sam Crowell, Trevor A. Baral, Stefan D. Blattner, William Charurat, Man TI Serosorting and Sexual Risk for HIV Infection at the Ego-Alter Dyadic Level: An Egocentric Sexual Network Study Among MSM in Nigeria SO AIDS AND BEHAVIOR LA English DT Article DE HIV serosorting; men who have sex with men; sexual behavior; egocentric network; Nigeria ID UNPROTECTED ANAL INTERCOURSE; REDUCTION PRACTICES; MEN; PREVALENCE; PARTNERS; GAY; INDIVIDUALS; SWITZERLAND; EJACULATION; PREVENTION AB The objective of this egocentric network study was to investigate engagement in serosorting by HIV status and risk for HIV between seroconcordant and serodiscordant ego-alter dyads. Respondent-driving sampling was used to recruit 433 Nigerian men who have sex with men (MSM) from 2013 to 2014. Participant (ego) characteristics and that of five sex partners (alters) were collected. Seroconcordancy was assessed at the ego level and for each dyad. Among 433 egos, 18 % were seroconcordant with all partners. Among 880 dyads where participants knew their HIV status, 226 (25.7 %) were seroconcordant, with 11.7 % of HIV positive dyads seroconcordant and 37.0 % of HIV negative dyads seroconcordant. Seroconcordant dyads reported fewer casual sex partners, less partner concurrency, and partners who had ever injected drugs, but condom use did not differ significantly. Serosorting may be a viable risk reduction strategy among Nigerian MSM, but awareness of and communication about HIV status should be increased. Future studies should assess serosorting on a partner-by-partner basis. C1 [Rodriguez-Hart, Cristina; Nowak, Rebecca G.; Blattner, William; Charurat, Man] Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. [Rodriguez-Hart, Cristina; Baral, Stefan D.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Liu, Hongjie] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Orazulike, Ifeanyi] Int Ctr Advocacy & Rights Hlth, Abuja, Nigeria. [Zorowitz, Sam] Massachusetts Gen Hosp, Dept Psychiat, Div Neurotherapeut, Boston, MA 02114 USA. [Zorowitz, Sam] Harvard Med Sch, Boston, MA USA. [Crowell, Trevor A.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Crowell, Trevor A.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. RP Rodriguez-Hart, C (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA.; Rodriguez-Hart, C (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM crodri32@jhu.edu FU NIAID NIH HHS [R01 AI120913]; NIMH NIH HHS [R01 MH099001] NR 34 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2016 VL 20 IS 11 BP 2762 EP 2771 DI 10.1007/s10461-016-1311-3 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EA3KA UT WOS:000386499800029 PM 26910338 ER PT J AU Maree, RD Marcum, ZA Saghafi, E Weiner, DK Karp, JF AF Maree, Rachel D. Marcum, Zachary A. Saghafi, Ester Weiner, Debra K. Karp, Jordan F. TI A Systematic Review of Opioid and Benzodiazepine Misuse in Older Adults SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Review DE Aging; geriatrics; prescription drug abuse; primary care; substance abuse ID SUBSTANCE-ABUSE TREATMENT; DRUG-MONITORING PROGRAMS; PRESCRIPTION OPIOIDS; BRIEF INTERVENTION; NONMEDICAL USE; USERS; CARE; DISCONTINUATION; PREVALENCE; DEPENDENCE AB Objective: The authors assessed the prevalence of opioid and benzodiazepine prescription drug misuse in older adults, the risk factors associated with misuse, and age-appropriate interventions. Methods: Following PRISMA guidelines, a literature search of PubMed, PsycINFO, and EMBASE for peer-reviewed journal articles in English through April 2014 with updates through November 2015 was conducted for reports on misuse of prescription benzodiazepines and opioids in older adults. Relevant publications were reviewed that included participants age >= 65 years. Reference listswere manually searched for key identified articles and geriatric journals through April 2016. Information on the study design, sample, intervention, comparators, outcome, time frame, and risk of bias were abstracted for each article. Results: Of 4,932 reviewed reports, 15 were included in this systematic review. Thirteen studies assessed the prevalence of prescription drug misuse and included studies related to opioid shopping behavior, assessment of morbidity and mortality associated with opioid and/or benzodiazepine use, frequency and characteristics of opioid prescribing, frequency of substance use disorders and nonprescription use of pain relievers, and health conditions and experiences of longterm benzodiazepine users. One study identified risk factors for misuse, and one study described the effects of provider education and an electronic support tool as an intervention. Conclusion: There is a dearth of high quality research on prescription drug misuse in older adults. Existing studies are heterogeneous, making it difficult to draw broad conclusions. The need for further research specific to prescription drug misuse among older adults is discussed. C1 [Maree, Rachel D.; Weiner, Debra K.; Karp, Jordan F.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Weiner, Debra K.; Karp, Jordan F.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Weiner, Debra K.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Saghafi, Ester] Univ Pittsburgh, Sch Med, Dept Informat Sci, Pittsburgh, PA 15213 USA. [Marcum, Zachary A.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Weiner, Debra K.; Karp, Jordan F.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Karp, JF (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM karpjf@upmc.edu FU NIH [AG033575, MH101371] FX Dr. Marcum is a consultant for Purdue Pharma. Dr. Karp has received medication supplies for investigator initiated trials from Invidior and Pfizer. Funding was provided in part by NIH grants AG033575 and MH101371 (to JFK). NR 65 TC 0 Z9 0 U1 18 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2016 VL 24 IS 11 BP 949 EP 963 DI 10.1016/j.jagp.2016.06.003 PG 15 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EA6XA UT WOS:000386771200002 PM 27567185 ER PT J AU Van Cott, EM Smock, KJ Chen, D Hsu, P Zantek, ND Meijer, P AF Van Cott, Elizabeth M. Smock, Kristi J. Chen, Dong Hsu, Peihong Zantek, Nicole D. Meijer, Piet TI Testing for dabigatran and rivaroxaban by clinical laboratories SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID SPECIALIZED COAGULATION LABORATORIES; THROMBIN INHIBITOR DABIGATRAN; EX-VIVO SAMPLES; HEMOSTASIS TESTS; IN-VITRO; ASSAYS; APIXABAN; QUALITY AB Rivaroxaban and dabigatran are among the newest anticoagulants, and measuring their concentration in patients is a new challenge for clinical laboratories. We analyzed data from the ECAT proficiency program to determine how well the assays are performing in clinical laboratories internationally. Most laboratories received a passing grade (Z score <3) for the results of their dabigatran and rivaroxaban testing. Failing Z scores were not associated with any particular method. With dabigatran, some homemade calibrators gave higher results than the commercially available calibrators. There were no significant differences among the instruments or the 5 reagents in use, but results showed inter-laboratory variability that could have clinical significance. The 3 reagents with the lowest number of users had poor inter-laboratory precision. Ten different anti-Xa reagents were in use for rivaroxaban testing. One reagent gave lower results than other reagents at 100 ng/mL but not at 300 ng/mL. There were no significant differences among the different rivaroxaban calibrators or instruments. In conclusion, inter-laboratory precision could be improved for both dabigatran and rivaroxaban assays. Homemade dabigatran calibrators differed from commercially available calibrators, and there was a statistically significant difference between some of the rivaroxaban reagents. About 10% of results received failing Z scores or passed but fell in a range that require the laboratory to investigate for bias or other inaccuracy in their method. (C) 2016 Wiley Periodicals, Inc. C1 [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Smock, Kristi J.] Univ Utah, Dept Pathol, ARUP Labs, Salt Lake City, UT USA. [Chen, Dong] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Hsu, Peihong] Hofstra Northwell Sch Med, Dept Pathol Lab Med, Lake Success, NY USA. [Zantek, Nicole D.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Meijer, Piet] ECAT Fdn, Voorschoten, Netherlands. RP Van Cott, EM (reprint author), Massachusetts Gen Hosp, GRJ235 55 Fruit St, Boston, MA 02114 USA. NR 15 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2016 VL 91 IS 11 BP E464 EP E467 DI 10.1002/ajh.24494 PG 4 WC Hematology SC Hematology GA EA8UY UT WOS:000386915900001 PM 27458812 ER PT J AU Martins, YC Freeman, BD Ndunge, OBA Weiss, LM Tanowitz, HB Desruisseaux, MS AF Martins, Yuri C. Freeman, Brandi D. Ndunge, Oscar B. Akide Weiss, Louis M. Tanowitz, Herbert B. Desruisseaux, Mahalia S. TI Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65 SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HUMAN CEREBROMICROVASCULAR ENDOTHELIUM; BLOOD-BRAIN-BARRIER; FALCIPARUM-MALARIA; RECEPTOR ANTAGONIST; COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID; IMPROVES SURVIVAL; MURINE MODELS; AMYLOID-BETA; EXPRESSION AB Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10(6) PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed Leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM. C1 [Martins, Yuri C.; Freeman, Brandi D.; Ndunge, Oscar B. Akide; Weiss, Louis M.; Tanowitz, Herbert B.; Desruisseaux, Mahalia S.] Albert Einstein Coll Med, Dept Pathol, 1300 Morris Pk Ave,Golding 704, Bronx, NY 10461 USA. [Weiss, Louis M.; Tanowitz, Herbert B.; Desruisseaux, Mahalia S.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Martins, Yuri C.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Desruisseaux, MS (reprint author), Albert Einstein Coll Med, Dept Pathol, 1300 Morris Pk Ave,Golding 704, Bronx, NY 10461 USA. EM m.desruis@einstein.yu.edu FU NIH Interhemispheric Research/Training in Infectious Disease training grant [D43-TW007129]; Geographic Medicine and Emerging Infections training grant [T32-AI070117]; NIH National Institute of Allergy and Infectious Diseases [R01-AI076248, R01-AI93220]; Burroughs-Wellcome Fund's Career Awards for Medical Scientists; Einstein-Montefiore Institute for Clinical and Translational Research Career Development Award; NIH National Institute of Neurological Disorders and Stroke grant [R01-NS0695771] FX Supported by NIH Interhemispheric Research/Training in Infectious Disease training grant D43-TW007129 (Y.C.M.); Geographic Medicine and Emerging Infections training grant T32-AI070117 (B.D.F.); NIH National Institute of Allergy and Infectious Diseases grants R01-AI076248 (H.B.T.) and R01-AI93220 (L.M.W.); NIH National Institute of Neurological Disorders and Stroke grant R01-NS0695771 (M.S.D.); the Burroughs-Wellcome Fund's Career Awards for Medical Scientists (M.S.D.); and the Einstein-Montefiore Institute for Clinical and Translational Research Career Development Award (M.S.D.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2016 VL 186 IS 11 BP 2957 EP 2969 DI 10.1016/j.ajpath.2016.07.020 PG 13 WC Pathology SC Pathology GA EA9TG UT WOS:000386987000016 PM 27640146 ER PT J AU Hogaboom, NS Huang, BL Worobey, LA Koontz, AM Boninger, ML AF Hogaboom, Nathan S. Huang, Bernice L. Worobey, Lynn A. Koontz, Alicia M. Boninger, Michael L. TI Cross-Sectional Investigation of Acute Changes in Ultrasonographic Markers for Biceps and Supraspinatus Tendon Degeneration After Repeated Wheelchair Transfers in People With Spinal Cord Injury SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Spinal Cord Injuries; Wheelchairs; Ultrasonography; Cumulative Trauma Disorders; Tendinopathy ID ROTATOR CUFF TENDINOPATHY; QUANTITATIVE ULTRASOUND; SHOULDER PATHOLOGY; TRANSFER SKILLS; USERS; INDIVIDUALS; PAIN; ABNORMALITIES; PARAPLEGIA; PREVALENCE AB Objective The objectives of this work were to investigate how wheelchair transfers influence acute changes in ultrasound markers for biceps and supraspinatus tendon degeneration and to determine how such changes correlate with transfer technique and demographic characteristics. Design Participants underwent quantitative ultrasound examinations for markers of biceps and supraspinatus tendon degeneration (tendon width, echogenicity, variance, and contrast) before and after a stressful repeated-transfers protocol. The Transfer Assessment Instrument was completed for each participant to identify transfer skills. Linear regression tested whether demographics and transfer skills correlated with ultrasound measures. Results Sixty-two wheelchair users with spinal cord injury were included (39 with paraplegia and 23 with tetraplegia). Biceps tendon width increased after repeated transfers (P < 0.001). Participants with greater body weight experienced greater increases in biceps width after transfers ( = 0.109, P < 0.05). Skills evaluating body position relative to the target surface and safe and stable hand and arm positions affected changes in biceps and supraspinatus width and echogenicity (P < 0.05). Conclusions Repeated transfers caused measurable changes in biceps tendon width in a subset of participants. Changes in biceps and supraspinatus ultrasound measures were related to body weight and performance of specific transfer skills. Further testing is needed to confirm whether the clinical meaning of the observed relationships and whether using certain transfer skills and reducing body weight can attenuate the development of tendinopathy. C1 [Hogaboom, Nathan S.; Worobey, Lynn A.; Koontz, Alicia M.; Boninger, Michael L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [Worobey, Lynn A.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Hogaboom, Nathan S.; Koontz, Alicia M.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Huang, Bernice L.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Boninger, ML (reprint author), Human Engn Res Labs, 6425 Penn Ave,Suite 400, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X FU National Institute on Disability and Rehabilitation Research, Office of Special Education and Rehabilitation Services, US Department of Education [H133N110011]; National Science Foundation Graduate Research Fellowship [1247842] FX This material is the result of work supported with resources and the use of facilities at the Human Engineering Research Laboratories, VA Pittsburgh Healthcare System. This project was supported by the National Institute on Disability and Rehabilitation Research, Office of Special Education and Rehabilitation Services, US Department of Education (H133N110011). This material is based on work supported by the National Science Foundation Graduate Research Fellowship (Grant #1247842). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the view of the National Science Foundation. The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government. NR 31 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD NOV PY 2016 VL 95 IS 11 BP 818 EP 830 DI 10.1097/PHM.0000000000000509 PG 13 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EA6TK UT WOS:000386761700011 PM 27088477 ER PT J AU Salloum, RG Getz, KR Tan, ASL Carter-Harris, L Young-Wolff, KC George, TJ Shenkman, EA AF Salloum, Ramzi G. Getz, Kayla R. Tan, Andy S. L. Carter-Harris, Lisa Young-Wolff, Kelly C. George, Thomas J., Jr. Shenkman, Elizabeth A. TI Use of Electronic Cigarettes Among Cancer Survivors in the US SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article AB Introduction: The population-level patterns of electronic cigarette (e-cigarette) use among cancer survivors in the U.S. are unknown. The objective of this study was to examine the prevalence and correlates of e-cigarette use among cancer survivors in a nationally representative sample. Methods: A cross-sectional analysis was conducted of the 2014 National Health Interview Survey of the U.S. non-institutionalized civilian population. The main study outcomes were the prevalence and correlates of ever and current e-cigarette use among adults with self-reported history of cancer, excluding non-melanoma skin cancer (N=2,695). Multivariable logistic regression analyses examined whether e-cigarette use differed by cigarette smoking status and demographic subgroups. The analyses were performed in 2015. Results: The prevalence of e-cigarette use among adult cancer survivors was lower than the general population: 2.8% of cancer survivors reported currently using e-cigarettes and an additional 6.3% had previously used e-cigarettes but were not currently using them. Use of e-cigarettes was most common among cancer survivors who currently smoked cigarettes: 34.3% of current smokers were ever e-cigarette users and 15.6% were current e-cigarette users, compared with former smokers (2.7% ever and 1.4% current e-cigarette users) and never smokers (small sample/estimates unavailable). Conclusions: E-cigarettes are not part of current evidence-based smoking-cessation strategies. However, the finding that cancer survivors who currently smoke cigarettes are more likely to use e-cigarettes highlights the importance of addressing e-cigarette use in patient-provider communications around tobacco cessation. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Salloum, Ramzi G.; Getz, Kayla R.; George, Thomas J., Jr.; Shenkman, Elizabeth A.] Univ Florida, Coll Med, Dept Hlth Outcomes & Policy, POB 100177, Gainesville, FL 32610 USA. [Salloum, Ramzi G.; Getz, Kayla R.; George, Thomas J., Jr.; Shenkman, Elizabeth A.] Univ Florida, Coll Med, Inst Child Hlth Policy, Gainesville, FL USA. [Tan, Andy S. L.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Hlth, Boston, MA USA. [Tan, Andy S. L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Carter-Harris, Lisa] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Young-Wolff, Kelly C.] Kaiser Permanente Northern Calif Div Res, Oakland, CA USA. [George, Thomas J., Jr.] Univ Florida, Coll Med, Dept Med, Div Hematol Oncol, Gainesville, FL USA. RP Salloum, RG (reprint author), Univ Florida, Coll Med, Dept Hlth Outcomes & Policy, POB 100177, Gainesville, FL 32610 USA. EM rsalloum@ufl.edu FU Florida Department of Health (James and Esther King Biomedical Research Program) [4KB16] FX This research was supported in part by grant 4KB16 from the Florida Department of Health (James and Esther King Biomedical Research Program). The sponsor had no part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. NR 11 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2016 VL 51 IS 5 BP 762 EP 766 DI 10.1016/j.amepre.2016.04.015 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EA7CG UT WOS:000386785100019 PM 27242079 ER PT J AU Berra, L Rodriguez-Lopez, J Rezoagli, E Yu, BL Fisher, DF Semigran, MJ Bloch, DB Channick, RN Zapol, WM AF Berra, Lorenzo Rodriguez-Lopez, Josanna Rezoagli, Emanuele Yu, Binglan Fisher, Daniel F. Semigran, Marc J. Bloch, Donald B. Channick, Richard N. Zapol, Warren M. TI Electric Plasma-generated Nitric Oxide: Hemodynamic Effects in Patients with Pulmonary Hypertension SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 [Berra, Lorenzo; Rodriguez-Lopez, Josanna; Rezoagli, Emanuele; Yu, Binglan; Fisher, Daniel F.; Semigran, Marc J.; Bloch, Donald B.; Channick, Richard N.; Zapol, Warren M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. FU NHLBI NIH HHS [U01 HL105562]; NIDDK NIH HHS [R01 DK082971] NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD NOV 1 PY 2016 VL 194 IS 9 BP 1168 EP 1170 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EA8DX UT WOS:000386866600021 PM 27797618 ER PT J AU Kawamoto, K Miyoshi, H Yoshida, N Takizawa, J Sone, H Ohshima, K AF Kawamoto, Keisuke Miyoshi, Hiroaki Yoshida, Noriaki Takizawa, Jun Sone, Hirohito Ohshima, Koichi TI Clinicopathological, Cytogenetic, and Prognostic Analysis of 131 Myeloid Sarcoma Patients SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE myeloid sarcoma; CXCR4; CD44; CD56; extramedullary AML ID ACUTE MYELOGENOUS LEUKEMIA; CHEMOKINE RECEPTOR CXCR4; T-CELL RECEPTOR; GRANULOCYTIC SARCOMA; BONE-MARROW; LYMPHOBLASTIC-LEUKEMIA; SIGNAL-TRANSDUCTION; PERIPHERAL-BLOOD; STEM-CELLS; EXPRESSION AB Myeloid sarcoma (MS) is an extramedullary tumor of immature myeloid cells. We analyzed 131 patients with MS, including: (1) de novo MS; (2) MS with concomitant acute myeloid leukemia (AML); (3) MS following myelodysplastic syndrome, myeloproliferative neoplasm, or chronic myelogenous leukemia; and (4) MS as a recurrence of AML. The most common development site was the lymph node. Testicular lesions were statistically more frequent in MS as a recurrence of AML than in other types of MS (P = 0.0183). MS tended to lack myeloid markers (myeloperoxidase was present in 63.2%, CD68 in 51.3%, CD13 in 48.7%, and CD33 in 48.7% of patients) and express T-cell markers such as CD3 (20.7%) and CD5 (34.2%). All T-cell marker-positive MS cases were negative for the alpha beta and gamma delta T-cell receptors on immunohistochemistry. Underlying myelodysplastic syndrome or myeloproliferative neoplasm was a poor prognostic factor (vs. de novo MS: P = 0.0383; vs. MS with concomitant AML: P = 0.0143). However, there was no statistical difference in prognosis between de novo MS and MS with concomitant AML (P = 0.288). There were no significant differences in prognosis between the prognoses of T-cell marker-positive and T-cell marker-negative MS cases. In addition, CXCR4 expression was a poor prognostic factor in MS (P = 0.0229). This study involves the largest MS cohort to date and expands the clinical and pathologic knowledge of the disease. C1 [Kawamoto, Keisuke; Takizawa, Jun; Sone, Hirohito] Niigata Univ, Fac Med, Dept Hematol Endocrinol & Metab, Niigata, Japan. [Kawamoto, Keisuke; Miyoshi, Hiroaki; Yoshida, Noriaki; Ohshima, Koichi] Kurume Univ, Sch Med, Dept Pathol, 67 Asahi Machi, Kurume, Fukuoka, Japan. [Yoshida, Noriaki] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. RP Miyoshi, H (reprint author), Kurume Univ, Sch Med, Dept Pathol, 67 Asahi Machi, Kurume, Fukuoka, Japan. EM miyoshi_hiroaki@med.kurume-u.ac.jp NR 61 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2016 VL 40 IS 11 BP 1473 EP 1483 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA EA8WQ UT WOS:000386921000003 PM 27631510 ER PT J AU Hohmann, EL AF Hohmann, Elizabeth L. TI Are Microbial Politics Local? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CLOSTRIDIUM-DIFFICILE INFECTION; TRANSPLANTATION C1 [Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hohmann, EL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02115 USA. EM ehohmann@partners.org NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 1 PY 2016 VL 165 IS 9 BP 667 EP 668 DI 10.7326/M16-1784 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EA8SJ UT WOS:000386908600010 PM 27548329 ER PT J AU Khamashta, M Merrill, JT Werth, VP Furie, R Kalunian, K Illei, GG Drappa, J Wang, LW Greth, W AF Khamashta, Munther Merrill, Joan T. Werth, Victoria P. Furie, Richard Kalunian, Kenneth Illei, Gabor G. Drappa, Jorn Wang, Liangwei Greth, Warren CA CD1067 Study Investigators TI Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID INDUCIBLE GENE-EXPRESSION; DISEASE-ACTIVITY INDEX; REVISED CRITERIA; PHASE-I; THERAPY; SLE; CLASSIFICATION; ACTIVATION; SIGNATURES; BLOCKADE AB Objectives The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. C1 [Khamashta, Munther] Kings Coll London, Rayne Inst, St Thomas Hosp, Graham Hughes Lupus Res Lab,Div Womens Hlth, Lambeth Wing 4th Floor, London SE1 7EH, England. [Merrill, Joan T.] Oklahoma Med Res Fdn, Clin Pharmacol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Werth, Victoria P.] Philadelphia VA Med Ctr, Lupus Res Inst, Philadelphia, PA USA. [Werth, Victoria P.] Univ Penn, Philadelphia, PA 19104 USA. [Furie, Richard] Northwell Hlth, Div Rheumatol, Great Neck, NY USA. [Kalunian, Kenneth] UCSD Sch Med, Dept Rheumatol, La Jolla, CA USA. [Illei, Gabor G.; Drappa, Jorn; Greth, Warren] MedImmune, Clin Dev Resp Inflammat & Autoimmun, Gaithersburg, MD USA. [Wang, Liangwei] MedImmune, Dept Biostat, Gaithersburg, MD USA. RP Khamashta, M (reprint author), Kings Coll London, Rayne Inst, St Thomas Hosp, Graham Hughes Lupus Res Lab,Div Womens Hlth, Lambeth Wing 4th Floor, London SE1 7EH, England. EM munther.khamashta@kcl.ac.uk FU MedImmune FX The study was funded by MedImmune. NR 37 TC 24 Z9 24 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2016 VL 75 IS 11 BP 1909 EP 1916 DI 10.1136/annrheumdis-2015-208562 PG 8 WC Rheumatology SC Rheumatology GA EA3AH UT WOS:000386469300006 PM 27009916 ER PT J AU Deng, Y Zhao, J Sakurai, D Sestak, AL Osadchiy, V Langefeld, CD Kaufman, KM Kelly, JA James, JA Petri, MA Bae, SC Alarcon-Riquelme, ME Alarcon, GS Anaya, JM Criswell, LA Freedman, BI Kamen, DL Gilkeson, GS Jacob, CO Merrill, JT Gaffney, PM Sivils, KM Niewold, TB Ramsey-Goldman, R Reveille, JD Scofield, RH Stevens, AM Boackle, SA Vila, LM Sohn, IIW Lee, S Chang, DM Song, YW Vyse, TJ Harley, JB Brown, EE Edberg, JC Kimberly, RP Cantor, RM Hahn, BH Grossman, JM Tsao, BP AF Deng, Yun Zhao, Jian Sakurai, Daisuke Sestak, Andrea L. Osadchiy, Vadim Langefeld, Carl D. Kaufman, Kenneth M. Kelly, Jennifer A. James, Judith A. Petri, Michelle A. Bae, Sang-Cheol Alarcon-Riquelme, Marta E. Alarcon, Graciela S. Anaya, Juan-Manuel Criswell, Lindsey A. Freedman, Barry I. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Merrill, Joan T. Gaffney, Patrick M. Sivils, Kathy Moser Niewold, Timothy B. Ramsey-Goldman, Rosalind Reveille, John D. Scofield, R. Hal Stevens, Anne M. Boackle, Susan A. Vila, Luis M. Sohn, I. I. Woong Lee, Seung Chang, Deh-Ming Song, Yeong Wook Vyse, Timothy J. Harley, John B. Brown, Elizabeth E. Edberg, Jeffrey C. Kimberly, Robert P. Cantor, Rita M. Hahn, Bevra H. Grossman, Jennifer M. Tsao, Betty P. TI Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID MESSENGER-RNA DECAY; WHOLE-GENOME ASSOCIATION; HUMAN PREFRONTAL CORTEX; GENE-EXPRESSION; WIDE ASSOCIATION; DISEASE-ACTIVITY; TARGET GENES; HUMAN BRAIN; ERYTHEMATOSUS; SUSCEPTIBILITY AB Objectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4x10(-8), OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1x10(-3) and 6.8x10(-8), respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0x10(-5) and 2.0x10(-4), respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis. C1 [Deng, Yun; Zhao, Jian; Sakurai, Daisuke; Osadchiy, Vadim; Hahn, Bevra H.; Grossman, Jennifer M.; Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Div Rheumatol, Los Angeles, CA 90095 USA. [Sestak, Andrea L.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73190 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Dept Biostat Sci, Winston Salem, NC USA. [Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Kelly, Jennifer A.; James, Judith A.; Alarcon-Riquelme, Marta E.; Gaffney, Patrick M.; Sivils, Kathy Moser; Scofield, R. Hal] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [James, Judith A.; Sivils, Kathy Moser] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [James, Judith A.; Scofield, R. Hal] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Petri, Michelle A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Bae, Sang-Cheol; Sohn, I. I. Woong; Lee, Seung] Hanyang Univ Hosp Rheumat Dis, Dept Rheumatol, Seoul, South Korea. [Alarcon-Riquelme, Marta E.] Univ Granada Junta de Andalucia, Pfizer, Ctr Genom & Oncol Res, Granada, Spain. [Alarcon, Graciela S.; Brown, Elizabeth E.; Edberg, Jeffrey C.; Kimberly, Robert P.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Anaya, Juan-Manuel] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia. [Criswell, Lindsey A.] Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA. [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Kamen, Diane L.; Gilkeson, Gary S.] Med Univ South Carolina, Div Rheumatol & Immunol, Charleston, SC USA. [Jacob, Chaim O.] Univ Southern Calif, Dept Med, Los Angeles, CA USA. [Merrill, Joan T.] Oklahoma Med Res Fdn, Dept Clin Pharmacol, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Niewold, Timothy B.] Mayo Clin, Div Rheumatol, Rochester, MN USA. [Niewold, Timothy B.] Mayo Clin, Dept Immunol, Rochester, MN USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Dept Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. [Scofield, R. Hal] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Stevens, Anne M.] Univ Washington, Dept Pediat, Div Rheumatol, Seattle, WA 98195 USA. [Stevens, Anne M.] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA. [Boackle, Susan A.] Univ Colorado, Sch Med, Div Rheumatol, Aurora, CO USA. [Boackle, Susan A.] US Dept Vet Affairs, Med Ctr, Denver, CO USA. [Vila, Luis M.] Univ Puerto Rico, Dept Med, Div Rheumatol, Med Sci Campus, San Juan, PR 00936 USA. [Chang, Deh-Ming] Taipei Vet Gen Hosp, Taipei, Taiwan. [Song, Yeong Wook] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea. [Song, Yeong Wook] Seoul Natl Univ, Coll Med, Med Res Ctr, Seoul, South Korea. [Vyse, Timothy J.] Kings Coll London, Div Genet & Mol Med & Immunol, London, England. [Brown, Elizabeth E.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL USA. [Cantor, Rita M.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. RP Tsao, BP (reprint author), Med Univ South Carolina, Dept Med, Div Rheumatol & Immunol, 96 Jonathan Lucas St,Clin Sci Bldg Suite 936C, Charleston, SC 29425 USA. EM tsaob@musc.edu OI Kimberly, Robert/0000-0002-5330-3086; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154; Anaya, Juan-Manuel/0000-0002-6444-1249 FU US NIH [R01AR043814, R21AR065626, P01AI083194, P01AR049084, R01AR064820, P30GM103510, P30AR053483, U01AI101934, U19AI082714, R01CA141700, RC1AR058621, P60AR053308, UL1TR000004, P60AR062755, UL1RR029882, R01AR057172, R01AI063274, R01AR043274, K08AI083790, LRPAI071651, UL1RR024999, R01AR43727, K24AR002138, P60AR066464, 1U54TR001018, U54RR023417, R01AR051545, UL1RR025014, R21AI070304, R01AR042460, N01AR062277, P20RR020143, R37AI024717, P30AR048311, P30AR055385, R01AR033062]; Lupus Foundation of America; Alliance for Lupus Research; Lupus Research Institute; US Department of Veterans Affairs; US Department of Defense [PR094002]; Arthritis National Research Foundation; Arthritis Foundation; Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea [HI13C2124]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI13C1754]; European Science Foundation RNP (BIOLUPUS Research Network); Wellcome Trust; Arthritis Research UK; Kirkland Scholar Award; Wake Forest School of Medicine Center for Public Health Genomics; University of California Los Angeles (UCLA) Clinical and Translational Science Institute (CTSI) [UL1RR033176, UL1TR000124]; NIH [P30AI028697] FX This work was supported by the US NIH (R01AR043814 and R21AR065626 (BPT), P01AI083194 (JBH, KMS, RPK, LAC, TJV, MEAR, COJ, BPT and PMG), P01AR049084 (RPK, JCE, EEB, GSA, JDR, RRG and MAP), R01AR064820 (EEB, MAP, RRG, JDR and LMV), P30GM103510, P30AR053483, U01AI101934 and U19AI082714 (JAJ), R01CA141700 and RC1AR058621 (MEAR), P60AR053308 and UL1TR000004 (LAC), P60AR062755 and UL1RR029882 (GSG and DLK), R01AR057172 (COJ), R01AI063274 (PMG), R01AR043274 (KMS), K08AI083790, LRPAI071651 and UL1RR024999 (TBN), R01AR43727 (MAP), K24AR002138, P60AR066464 and 1U54TR001018 (RRG), U54RR023417 (JDR), R01AR051545 and UL1RR025014 (AMS), R21AI070304 (SAB), R01AR042460, N01AR062277, P20RR020143 and R37AI024717 (JBH), P30AR048311 and P30AR055385 (EEB), R01AR033062 (RPK)), the Lupus Foundation of America (BPT), the Alliance for Lupus Research (BPT, YD, KMS, TBN, LAC, COJ and SAB), the Lupus Research Institute (TBN), the US Department of Veterans Affairs (Merit Awards; JBH and GSG), the US Department of Defense (PR094002, JBH), the Arthritis National Research Foundation (Eng Tan Scholar Award; JZ and TBN), the Arthritis Foundation (AMS and PMG), the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI13C2124; SCB), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI13C1754; YWS), the European Science Foundation RNP (BIOLUPUS Research Network), the Wellcome Trust (TJV), Arthritis Research UK (TJV), a Kirkland Scholar Award (LAC), the Wake Forest School of Medicine Center for Public Health Genomics (CDL) and University of California Los Angeles (UCLA) Clinical and Translational Science Institute (CTSI) UL1RR033176 and UL1TR000124. Some RNA samples of healthy controls used in this study were provided by the UCLA/Center for AIDS Research Virology Core Lab which was supported by the NIH grant P30AI028697. NR 47 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2016 VL 75 IS 11 BP 2007 EP 2013 DI 10.1136/annrheumdis-2015-208441 PG 7 WC Rheumatology SC Rheumatology GA EA3AH UT WOS:000386469300020 PM 26783109 ER PT J AU Munroe, ME Lu, RF Zhao, YD Fife, DA Robertson, JM Guthridge, JM Niewold, TB Tsokos, GC Keith, MP Harley, JB James, JA AF Munroe, Melissa E. Lu, Rufei Zhao, Yan D. Fife, Dustin A. Robertson, Julie M. Guthridge, Joel M. Niewold, Timothy B. Tsokos, George C. Keith, Michael P. Harley, John B. James, Judith A. TI Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CONNECTIVE-TISSUE DISEASE; IMMUNE-COMPLEXES; RHEUMATOID-ARTHRITIS; IFN-GAMMA; ACTIVATION; CELLS; ALPHA; HYDROXYCHLOROQUINE; PATHOGENESIS; CHEMOKINES AB Objectives The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-alpha) activity, and IFN-associated soluble mediators to disease development leading to SLE. Methods Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (+/-5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-a activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models. Results In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-a activity in growth curve models, with elevated IFN-a activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p <= 0.005). Cases were distinguished by multivariate random forest models incorporating IFN-gamma, macrophage chemoattractant protein (MCP)-3, antichromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification). Conclusions Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-a activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials. C1 [Munroe, Melissa E.; Lu, Rufei; Fife, Dustin A.; Robertson, Julie M.; Guthridge, Joel M.; James, Judith A.] Oklahoma Med Res Fdn, Dept Arthrit & Clin Immunol, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Lu, Rufei; James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Dept Med & Pathol, Oklahoma City, OK USA. [Zhao, Yan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Biostat & Epidemiol, Oklahoma City, OK USA. [Niewold, Timothy B.] Mayo Clin, Dept Immunol, Rochester, MN USA. [Niewold, Timothy B.] Mayo Clin, Div Rheumatol, Rochester, MN USA. [Tsokos, George C.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Rheumatol, Boston, MA USA. [Keith, Michael P.] Walter Reed Natl Mil Med Ctr, Dept Rheumatol, Bethesda, MD USA. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RP James, JA (reprint author), Oklahoma Med Res Fdn, Arthrit & Clin Immunol, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM Judith-James@omrf.org OI Niewold, Timothy/0000-0003-3532-6660; Munroe, Melissa/0000-0002-6933-9745 FU National Institute of Allergy, Immunology and Infectious Diseases; Office of Research on Women's Health; National Institute of General Medical Sciences; National Institute of Arthritis, Musculoskeletal and Skin Diseases [U01AI101934, U19AI082714, U54GM104938, P30GM103510, P30AR053483, S10RR026735, AI071651, AR060861]; US Department of Veterans Affairs; NIH [U01HG006828, UL1TR000077, R37AI024717, R21AI103980, P01AI083194, P01AI049084] FX Research reported in this publication was supported by the National Institute of Allergy, Immunology and Infectious Diseases, Office of Research on Women's Health, National Institute of General Medical Sciences and the National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers U01AI101934, U19AI082714, U54GM104938, P30GM103510, P30AR053483 and S10RR026735. This material is also the result of work supported with resources and the use of facilities through the Department of Veterans Affairs. Additional support was provided by the National Institute of Allergy, Immunology and Infectious Diseases and National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers AI071651 and AR060861 (TBN). JBH would like to acknowledge support from the US Department of Veterans Affairs and NIH grants U01HG006828, UL1TR000077, R37AI024717, R21AI103980, P01AI083194 and P01AI049084. NR 41 TC 7 Z9 7 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2016 VL 75 IS 11 BP 2014 EP 2021 DI 10.1136/annrheumdis-2015-208140 PG 8 WC Rheumatology SC Rheumatology GA EA3AH UT WOS:000386469300021 PM 27088255 ER PT J AU Duran-Struuck, R Matar, AJ Crepeau, RL Teague, AGS Horner, BM Pathiraja, V Spitzer, TR Fishman, JA Bronson, RT Sachs, DH Huang, CA AF Duran-Struuck, Raimon Matar, Abraham J. Crepeau, Rebecca L. Teague, Alexander G. S. Horner, Benjamin M. Pathiraja, Vimukthi Spitzer, Thomas R. Fishman, Jay A. Bronson, Roderick T. Sachs, David H. Huang, Christene A. TI Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Mixed chimerism; MHC defined miniature swine; Donor leukocyte infusion; Lymphohematopoietic graft-versus-host responses; Graft-versus-leukemia and graft-versus-host disease ID BONE-MARROW-TRANSPLANTATION; WHOLE-BODY IRRADIATION; LARGE-ANIMAL-MODEL; ANTIBODY MAB INJECTIONS; MIXED CHIMERISM; MINIATURE SWINE; MONOCLONAL-ANTIBODIES; LEUKOCYTE INFUSIONS; ALLOGRAFT TOLERANCE; THYMIC IRRADIATION AB We previously described successful hematopoietic stem cell engraftment across MHC barriers in miniature swine without graft-versus-host disease (GVHD) using novel reduced-intensity conditioning regimens consisting of partial transient recipient T cell-depletion, thymic or low-dose total body irradiation, and a short course of cyclosporine A. Here we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI)-mediated GVH effects. Of 33 total DLIs in tolerant chimeras at clinical doses, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GVHD. We attempted to overcome this resistance to conversion through several mechanisms, including using sensitized donor lymphocytes, increasing the DLI dose, removing chimeric host peripheral blood cells through extensive recipient leukapheresis before DLI, and using fully mismatched lymphocytes. Despite our attempts, the resistance to conversion in our model was robust, and when conversion was achieved, it was associated with GVHD in most animals. Our studies suggest that delivery of unmodified hematopoietic stem cell doses under reduced intensity conditioning can induce a potent, GVHD-free, immune tolerant state that is strongly resistant to DLI. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Duran-Struuck, Raimon] Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA. [Duran-Struuck, Raimon; Matar, Abraham J.; Crepeau, Rebecca L.; Teague, Alexander G. S.; Horner, Benjamin M.; Pathiraja, Vimukthi; Sachs, David H.; Huang, Christene A.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Matar, Abraham J.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. [Spitzer, Thomas R.] Massachusetts Gen Hosp, Ctr Canc, Bone Marrow Transplant Program, Boston, MA USA. [Fishman, Jay A.] Massachusetts Gen Hosp, MGH Transplantat Ctr, Boston, MA 02114 USA. [Fishman, Jay A.] Massachusetts Gen Hosp, Transplant Infect Dis & Compromised Host Program, Boston, MA USA. [Bronson, Roderick T.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Duran-Struuck, R (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, 3800 Spruce St,Old Vet Quadrangle,Suite 177E, Philadelphia, PA 19107 USA. EM Rduranst@gmail.com NR 42 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2016 VL 22 IS 11 BP 1953 EP 1960 DI 10.1016/j.bbmt.2016.08.011 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EA3YC UT WOS:000386544200007 PM 27543159 ER PT J AU Treister, N Li, SL Kim, H Lerman, M Sultan, A Alyea, EP Armand, P Cutler, C Ho, V Koreth, J Antin, JH Soiffer, R AF Treister, Nathaniel Li, Shuli Kim, Haesook Lerman, Mark Sultan, Ahmed Alyea, Edwin P. Armand, Philippe Cutler, Corey Ho, Vincent Koreth, John Antin, Joseph H. Soiffer, Robert TI An Open-Label Phase II Randomized Trial of Topical Dexamethasone and Tacrolimus Solutions for the Treatment of Oral Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host disease (GVHD); Oral chronic GVHD; Ancillary care; Supportive care; Oral medicine ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; CHRONIC GVHD; CRITERIA; TRANSPLANTATION; STABILITY; THERAPY AB The objective of this study was to evaluate the safety and efficacy of single-agent dexamethasone or tacrolimus topical solution as first-line treatment for symptomatic oral chronic graft-versus-host disease (cGVHD). This was a prospective, single-center, open-label, randomized phase II trial of patients with symptomatic oral cGVHD without prior topical therapy. Subjects were randomly assigned 1:1 to either topical dexamethasone (.5 mg/mL) or tacrolimus (.5 mg/mL) solution and instructed to rinse with 5 mL for 5 minutes, 4 times a day, for 4 weeks. Oral cGVHD assessments (National Institutes of Health [NIH] criteria) were completed at baseline and end of treatment (NIH criteria, global response, and tolerability). The primary endpoint was the response rate defined as >= 3-point reduction in patient-reported sensitivity score (range, 0 to 10). A parallel 2-stage design was employed so that a less efficacious arm could be terminated early. The accrual goal was 60 evaluable patients; 30 in each arm), accruing 14 in the first stage and 16 in the second stage. If both arms were regarded as efficacious, a "pick-the-winner" method would be employed to choose a better treatment for future investigation. Forty-six subjects were randomized to receive either dexamethasone (n = 28) or tacrolimus (n = 18). Six subjects were excluded from the analysis because of changes in systemic immunosuppression (dexamethasone = 1, tacrolimus =3) or lack of end-of-treatment visit (1 per arm). After the first stage evaluation, the tacrolimus arm was terminated because of lack of activity (3 of 14 responses; response rate, 21%). Twenty-six subjects in the dexamethasone arm completed both study visits and were included in the response analysis, with a 58% (15 of 26) response rate, compared with 21% (3 of 14) in the tacrolimus arm (P = .05). The response rates according to the NIH score in the dexamethasone and tacrolimus arms were 50% (13 of 26) and 2% (2 of 14), respectively (P = .04). From the onset of therapy, 31% versus 21% patients reported feeling "much better" and 38% versus 36% reported feeling "slightly better," giving an overall global response rate ("much better" or "slightly better") of 81% (21 of 26) versus 71% (10 of 14), in the dexamethasone and tacrolimus arms, respectively. Dexamethasone rinses were well tolerated and taste was reported as "very pleasant" or "tolerable" in most subjects (96%). Intensive topical therapy with dexamethasone solution is effective for managing patients with new-onset symptomatic oral cGVHD and should be considered for first-line therapy. Topical tacrolimus solution appears less effective, at least for first-line therapy. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Treister, Nathaniel; Sultan, Ahmed] Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,BC 3-028, Boston, MA 02120 USA. [Treister, Nathaniel; Sultan, Ahmed] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Li, Shuli; Kim, Haesook] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Lerman, Mark] Tufts Univ, Sch Dent Med, Dept Diagnost Sci, Boston, MA 02111 USA. [Alyea, Edwin P.; Armand, Philippe; Cutler, Corey; Ho, Vincent; Koreth, John; Antin, Joseph H.; Soiffer, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Treister, N (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,BC 3-028, Boston, MA 02120 USA. EM ntreister@partners.org OI Sultan, Ahmed S./0000-0001-5286-4562 FU Dana Farber Cancer Institute Ted and Eileen Pasquarello Research Fund; [5 P01-CA142106-07]; [R01-CA183559] FX This study was supported by the Dana Farber Cancer Institute Ted and Eileen Pasquarello Research Fund and grants 5 P01-CA142106-07 and R01-CA183559. NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2016 VL 22 IS 11 BP 2084 EP 2091 DI 10.1016/j.bbmt.2016.08.020 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EA3YC UT WOS:000386544200024 PM 27590106 ER PT J AU Hanna, N Speed, JM AF Hanna, Nawar Speed, Jacqueline M. TI Radical cystectomy and venous thromboembolism: are we doing enough? SO BJU INTERNATIONAL LA English DT Editorial Material ID CANCER-SURGERY; PROPHYLAXIS C1 [Hanna, Nawar] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. RP Hanna, N (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD NOV PY 2016 VL 118 IS 5 BP 667 EP 669 DI 10.1111/bju.13487 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EA3AB UT WOS:000386468600003 PM 27753468 ER PT J AU Tan, J Linos, E Sendelweck, MA van Zuuren, EJ Ersser, S Dellavalle, RP Williams, H AF Tan, J. Linos, E. Sendelweck, M. A. van Zuuren, E. J. Ersser, S. Dellavalle, R. P. Williams, H. TI Shared decision making and patient decision aids in dermatology SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID FRAMEWORK; PSORIASIS AB Shared decision making combines individual patient interests and values with clinical best evidence under the guiding principle of patient autonomy. Patient decision aids can support shared decision making and facilitate decisions that have multiple options with varying outcomes for which patients may attribute different values. Given the variable psychosocial impact of skin disease on individuals and relative uncertainty regarding best treatments and their adherence in many dermatological conditions, informed shared decision making, supported by patient decision aids, should constitute a central component of dermatological care. C1 [Tan, J.] Western Univ, London, ON, Canada. [Linos, E.] Univ Calif San Francisco, Sch Med, Dept Dermatol, San Francisco, CA USA. [Sendelweck, M. A.] Univ Colorado, Aurora, CO USA. [van Zuuren, E. J.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Ersser, S.] Univ Leeds, Sch Healthcare, Leeds, W Yorkshire, England. [Dellavalle, R. P.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Williams, H.] Univ Nottingham, Ctr Evidence Based Dermatol, Nottingham, England. RP Tan, J (reprint author), Western Univ, London, ON, Canada. EM jerrytan@bellnet.ca RI van Zuuren, Esther/A-9512-2011 OI van Zuuren, Esther/0000-0002-4780-0182 NR 18 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD NOV PY 2016 VL 175 IS 5 BP 1045 EP 1048 DI 10.1111/bjd.14803 PG 4 WC Dermatology SC Dermatology GA EA2ZD UT WOS:000386465300042 PM 27790692 ER PT J AU Brunner, AM Li, SL Fathi, AT Wadleigh, M Ho, VT Collier, K Connolly, C Ballen, KK Cutler, CS Dey, BR El-Jawahri, A Nikiforow, S McAfee, SL Koreth, J Deangelo, DJ Alyea, EP Antin, JH Spitzer, TR Stone, RM Soiffer, RJ Chen, YB AF Brunner, Andrew M. Li, Shuli Fathi, Amir T. Wadleigh, Martha Ho, Vincent T. Collier, Kerry Connolly, Christine Ballen, Karen K. Cutler, Corey S. Dey, Bimalangshu R. El-Jawahri, Areej Nikiforow, Sarah McAfee, Steven L. Koreth, John Deangelo, Daniel J. Alyea, Edwin P. Antin, Joseph H. Spitzer, Thomas R. Stone, Richard M. Soiffer, Robert J. Chen, Yi-Bin TI Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE acute myeloid leukaemia; fms-Like Tyrosine Kinase 3; allogeneic transplantation; maintenance chemotherapy; sorafenib ID INTERNAL TANDEM DUPLICATION; IMPROVES CLINICAL-OUTCOMES; ACUTE MYELOGENOUS LEUKEMIA; ALLOGENEIC TRANSPLANTATION; IMPACT; RECOMMENDATIONS; MUTATIONS; PROGNOSIS; PHASE-2; DISEASE AB We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD)acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow-up was 272months post-HCT for sorafenib survivors, and 384months for controls (P=0021). The median time to initiating sorafenib was 68days post-HCT; 43 controls were alive without relapse at this cut-off. Sorafenib patients had improved 2-year OS in the d+68 landmark analysis (81% vs. 62%, P=0029). Sorafenib was associated with improved 2-year PFS (82% vs. 53%, P=00081) and lower 2-year cumulative incidence of relapse (82% vs. 377%, P=00077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 026, P=0021] and PFS (HR 025, P=0016). There was no difference in 2-year non-relapse mortality (98% vs. 93%, P=082) or 1-year chronic graft-versus-host disease (555% vs. 372%, P=028). These findings suggest potential benefit of post-HCT sorafenib in FLT3-ITD AML, and support further evaluation of post-HCT FLT3 inhibition. C1 [Brunner, Andrew M.; Fathi, Amir T.; Collier, Kerry; Connolly, Christine; Ballen, Karen K.; Dey, Bimalangshu R.; El-Jawahri, Areej; McAfee, Steven L.; Spitzer, Thomas R.; Chen, Yi-Bin] Massachusetts Gen Hosp, Yawkey 9E, Boston, MA 02114 USA. [Brunner, Andrew M.; Li, Shuli; Wadleigh, Martha; Ho, Vincent T.; Cutler, Corey S.; Nikiforow, Sarah; Koreth, John; Deangelo, Daniel J.; Alyea, Edwin P.; Antin, Joseph H.; Stone, Richard M.; Soiffer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Yawkey 9E, Boston, MA 02114 USA. EM ychen6@partners.org FU National Institutes of Health (NIH) [T32 CA 071345-18, CA 006516] FX This study was presented in part at the 2015 ASH Annual Meeting, Orlando, FL, and the 2016 ASBMT Tandem Meeting, Honolulu, HI. A.M.B. is supported in part by the National Institutes of Health (NIH) grant T32 CA 071345-18. S.L. is partially supported by National Institutes of Health (NIH) grant CA 006516. NR 31 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2016 VL 175 IS 3 BP 496 EP 504 DI 10.1111/bjh.14260 PG 9 WC Hematology SC Hematology GA EA8SG UT WOS:000386908300018 PM 27434660 ER PT J AU Baggish, A La Gerche, A AF Baggish, Aaron La Gerche, Andre TI Sports Cardiology: Comprehensive Clinical Care for Athletes and Highly Active Individuals Preface SO CARDIOLOGY CLINICS LA English DT Editorial Material C1 [Baggish, Aaron] Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. [La Gerche, Andre] Baker IDI Heart & Diabet Inst, Sports Cardiol, 75 Commercial Rd, Melbourne, Vic 3004, Australia. RP Baggish, A (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. EM abaggish@partners.org; Andre.lagerche@bakeridi.edu.au NR 0 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8651 EI 1558-2264 J9 CARDIOL CLIN JI Cardiol. Clin. PD NOV PY 2016 VL 34 IS 4 BP XI EP XII DI 10.1016/j.ccl.2016.08.003 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA3ZH UT WOS:000386547300001 PM 27692229 ER PT J AU Beaudry, R Haykowsky, MJ Baggish, A La Gerche, A AF Beaudry, Rhys Haykowsky, Mark J. Baggish, Aaron La Gerche, Andre TI A Modern Definition of the Athlete's Heart-for Research and the Clinic SO CARDIOLOGY CLINICS LA English DT Article DE Athlete; Heart; Cardiac; Remodeling; Hypertrophy ID LEFT-VENTRICULAR MORPHOLOGY; CROSS-COUNTRY SKIERS; ETHNIC-DIFFERENCES; ENDURANCE; EXERCISE; RESISTANCE; METAANALYSIS; HYPERTROPHY; DYSFUNCTION; ADAPTATION AB Exercise training can have a profound effect on cardiac structure. Recent evidence suggests that the greatest determinants of exercise-induced cardiac remodeling are the intensity, duration, and frequency of training. This also has overlap with athlete fitness. There are many additional factors that are important in determining cardiac remodeling, but while further refinements evolve, the authors argue that the best means of predicting the degree of expected physiologic remodeling is to either quantify training (intensity times total training time) or its by-product (exercise capacity). A uniform approach to estimating the degree of exercise-induced cardiac remodeling will enable more consistent research. C1 [Beaudry, Rhys; Haykowsky, Mark J.; La Gerche, Andre] Baker IDI Heart & Diabet Inst, Dept Sports Cardiol, 99 Commercial Rd, Melbourne, Vic 3004, Australia. [Beaudry, Rhys; Haykowsky, Mark J.] Univ Texas Arlington, Coll Nursing & Hlth Innovat, South Nedderman Dr, Arlington, TX 76019 USA. [Baggish, Aaron] Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. [La Gerche, Andre] Alfred Hosp, Dept Cardiol, Melbourne, Vic, Australia. RP La Gerche, A (reprint author), Baker IDI Heart & Diabet Inst, Sports Cardiol, Alfred Ctr, Level4,99 Commercial Rd, Melbourne, Vic 3004, Australia. EM Andre.LaGerche@bakeridi.edu.au NR 33 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8651 EI 1558-2264 J9 CARDIOL CLIN JI Cardiol. Clin. PD NOV PY 2016 VL 34 IS 4 BP 507 EP + DI 10.1016/j.ccl.2016.06.001 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA3ZH UT WOS:000386547300002 PM 27692220 ER PT J AU Fu, WX Wang, L Kim, S Li, J Dynlacht, BD AF Fu, Wenxiang Wang, Lei Kim, Sehyun Li, Ji Dynlacht, Brian David TI Role for the IFT-A Complex in Selective Transport to the Primary Cilium SO CELL REPORTS LA English DT Article ID RETROGRADE INTRAFLAGELLAR TRANSPORT; SENSENBRENNER SYNDROME; CILIARY LOCALIZATION; DIFFUSION BARRIER; WDR35 CAUSE; PROTEIN; CILIOGENESIS; TRAFFICKING; ARL13B; CILIOPATHY AB Intraflagellar transport sub-complex A (IFT-A) is known to regulate retrograde IFT in the cilium. To rigorously assess its other possible roles, we knocked out an IFT-A subunit, IFT121/WDR35, in mammalian cells and screened the localization of more than 50 proteins. We found that Wdr35 regulates cilium assembly by selectively regulating transport of distinct cargoes. Beyond its role in retrograde transport, we show that Wdr35 functions in fusion of Rab8 vesicles at the nascent cilium, protein exit from the cilium, and centriolar satellite organization. Furthermore, we show that Wdr35 is essential for entry of many membrane proteins into the cilium through robust interactions with cargoes and other IFT-A subunits, but the actin network functions to dampen this transport. Wdr35 is mutated in several ciliopathies, and we find that certain disease mutations impair interactions with cargo and other IFT-A subunits. Together, our data link defects in IFT-A mediated cargo transport with disease. C1 [Fu, Wenxiang; Wang, Lei; Kim, Sehyun; Dynlacht, Brian David] NYU, Sch Med, Dept Pathol, Smilow Res Bldg,522 First Ave, New York, NY 10016 USA. [Fu, Wenxiang; Wang, Lei; Kim, Sehyun; Dynlacht, Brian David] NYU, Sch Med, Perlmutter Canc Ctr, Smilow Res Bldg,522 First Ave, New York, NY 10016 USA. [Li, Ji] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Ji] Broad Inst, Cambridge, MA 02142 USA. [Kim, Sehyun] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. RP Dynlacht, BD (reprint author), NYU, Sch Med, Dept Pathol, Smilow Res Bldg,522 First Ave, New York, NY 10016 USA.; Dynlacht, BD (reprint author), NYU, Sch Med, Perlmutter Canc Ctr, Smilow Res Bldg,522 First Ave, New York, NY 10016 USA. EM brian.dynlacht@nyumc.org FU NIH [HD069647, R01 GM 120776-05A1] FX We are very grateful to the following researchers who have shared plasmids and antibodies: Heleen H. Arts (Radboud University Nijmegen Medical Centre), Steve Caplan (University of Nebraska Medical Center), Shuhei Chiba (Tohoku University), Erica E. Davis (Duke University Medical Center), Jonathan Eggenschwiler (University of Georgia), Joseph G. Gleeson (Rockefeller University), Peter K. Jackson (Stanford University School of Medicine), Toshiaki Katada (University of Tokyo), Nicholas Katsanis (Duke University Medical Center), Kensaku Mizuno (Tohoku University), Kunsoo Rhee (Seoul National University), Johan Peranen (University of Helsinki), Rytis Prekeris (University of Colorado), Jeremy F. Reiter (University of California, San Francisco), Ronald Roepman (Radboud University Nijmegen Medical Centre), Seongjin Seo (University of Iowa), Tang K. Tang (Institute of Biomedical Sciences), and Mark von Zastrow (University of California, San Francisco). We thank Kristen Dancel, Chris Petzold, and Feng-Xia Liang at the NYU Imaging Center for help with electron microscopy. Work in B.D.D.'s laboratory was supported by NIH grants HD069647 and R01 GM 120776-05A1. B.D.D. dedicates this work to the memory of Zdzislaw (Sigmund) Dynlacht. NR 64 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD NOV 1 PY 2016 VL 17 IS 6 BP 1505 EP 1517 DI 10.1016/j.celrep.2016.10.018 PG 13 WC Cell Biology SC Cell Biology GA EA9BS UT WOS:000386936200005 PM 27806291 ER PT J AU Moon, AM Dominitz, JA Ioannou, GN Lowy, E Beste, LA AF Moon, Andrew M. Dominitz, Jason A. Ioannou, George N. Lowy, Elliott Beste, Lauren A. TI Use of Antibiotics Among Patients With Cirrhosis and Upper Gastrointestinal Bleeding Is Associated With Reduced Mortality SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE MELD; VA System; NAFLD; Treatment ID OF-VETERANS-AFFAIRS; STAGE LIVER-DISEASE; VARICEAL HEMORRHAGE; PORTAL-HYPERTENSION; BACTERIAL-INFECTION; RANDOMIZED-TRIAL; ENDOSCOPIC SCLEROTHERAPY; HEPATOCELLULAR-CARCINOMA; ESOPHAGEAL-VARICES; PROPHYLAXIS AB BACKGROUND & AIMS: Prophylactic antibiotics are recommended for all patients with cirrhosis hospitalized for upper gastrointestinal bleeding (UGIB). We evaluated the association between use of antibiotics, outcomes of re-admissions, and mortality in these patients. METHODS: We performed a retrospective study of 6451 patients with cirrhosis (mean age, 60.6 y) in the Veterans Affairs health care system hospitalized for UGIB from January 1, 2005, through December 31, 2013 (8655 hospitalizations). We collected information on patients' baseline features, hospitalizations, etiology of UGIB, antibiotics given, hospital re-admission within 30 days of discharge, and mortality. We defined timely administration of antibiotics as receipt from 8 hours before admission through 48 hours afterward. RESULTS: Timely administration of antibiotics occurred during 48.6% of admissions (n = 4210), increasing from 30.6% in 2005 to 58.1% in 2013. Independent predictors of antibiotic receipt included ascites, high model for end-stage liver disease score, esophageal variceal hemorrhage, and administration of octreotide or intravenous proton pump inhibitors. Variables associated with decreased odds of antibiotic provision included black race and nonalcoholic fatty liver disease. In multivariate analysis, timely administration of antibiotics was associated with a reduced 30-day mortality rate (adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.93; P = .012). CONCLUSIONS: In a study of patients with cirrhosis and UGIB in the VA health care system, timely administration of antibiotics was associated with a 30% reduction in 30-day mortality. The proportion of patients with cirrhosis and UGIB receiving timely antibiotics nearly doubled from 2005 to 2013, but many patients-particularly those with less-advanced cirrhosis-did not receive this intervention. Targeted efforts are needed to promote the appropriate use of antibiotics among patients with cirrhosis and UGIB C1 [Moon, Andrew M.; Dominitz, Jason A.; Ioannou, George N.; Beste, Lauren A.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Lowy, Elliott] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Dominitz, Jason A.; Ioannou, George N.; Lowy, Elliott; Beste, Lauren A.] VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-111-GI, Seattle, WA 98108 USA. RP Beste, LA (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-111-GI, Seattle, WA 98108 USA. EM lab25@uw.edu FU HIV, Hepatitis, and Public Health Pathogens Program of the Office of Public Health, Veterans Health Administration; VA Puget Sound Health Care System (Seattle, Washington) FX Supported by the HIV, Hepatitis, and Public Health Pathogens Program of the Office of Public Health, Veterans Health Administration (L.B. and E.L.).; This material is the result of work supported by resources from the VA Puget Sound Health Care System (Seattle, Washington). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 34 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD NOV PY 2016 VL 14 IS 11 BP 1629 EP + DI 10.1016/j.cgh.2016.05.040 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA6SV UT WOS:000386760200022 PM 27311621 ER PT J AU Fu, ZL Zhang, J Liu, M Li, Z Li, Q AF Fu, Zhanli Zhang, Jin Liu, Meng Li, Ziao Li, Qian TI Diagnosis of Primary Intestinal-Type Adenocarcinoma in the Nasal Cavity by F-18-FDG PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE intestinal-type adenocarcinoma (ITAC); nasal cavity; F-18-FDG; PET/CT ID WOOD DUST; EXPOSURE; SINUSES AB A soft-tissue lesion in the left nasal cavity was found on a 70-year-old man, which was pathologically proved to be an intestinal-type adenocarcinoma (ITAC) by biopsy. F-18-FDG PET/CT scan was performed to exclude the possibilities of metastasis from the other primary adenocarcinomas, but the nasal tumor was found to be the only lesion with F-18-FDG avidity. The primary ITAC in the nasal cavity was diagnosed, and it was resected successfully. C1 [Fu, Zhanli; Liu, Meng; Li, Ziao] Peking Univ, Dept Nucl Med, Hosp 1, 8 Xishiku St, Beijing 100034, Peoples R China. [Zhang, Jin] Beijing Univ Chinese Med, Dongzhimen Hosp, Dept Nucl Med, Beijing, Peoples R China. [Li, Qian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Fu, ZL (reprint author), Peking Univ, Dept Nucl Med, Hosp 1, 8 Xishiku St, Beijing 100034, Peoples R China. EM fuzhanli2002@163.com NR 8 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD NOV PY 2016 VL 41 IS 11 BP 888 EP 889 DI 10.1097/RLU.0000000000001363 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EA4GU UT WOS:000386569900022 PM 27607163 ER PT J AU Moon, C Phelan, CH Lauver, DR Bratzke, LC AF Moon, Chooza Phelan, Cynthia H. Lauver, Diane R. Bratzke, Lisa C. TI A Narrative Review of How Sleep-Related Breathing Disorders and Cardiovascular Diseases Are Linked An Update for Advanced Practice Registered Nurses SO CLINICAL NURSE SPECIALIST LA English DT Article DE advanced practice registered nurses; apnea syndromes; cardiovascular diseases ID POSITIVE AIRWAY PRESSURE; CORONARY-ARTERY-DISEASE; CONGESTIVE-HEART-FAILURE; ADAPTIVE SERVO-VENTILATION; ACUTE ISCHEMIC-STROKE; BLOOD-PRESSURE; RISK-FACTOR; ATRIAL-FIBRILLATION; APNEA SYNDROME; FOLLOW-UP AB Purpose/Objectives: Sleep-related breathing disorders (SRBDs), including obstructive sleep apnea and central sleep apnea, are common among patients with cardiovascular disease (CVD), but clinicians often do not pay enough attention to SRBDs. The purpose of this narrative review is to update advanced practice registered nurses on the literature focusing on the relationship between SRBDs and CVD (eg, hypertension, heart failure, coronary artery disease, arrhythmias, and stroke) and on treatments that can improve SRBDs in patients with CVD. Description of the Project: We conducted an electronic search of the literature published between 1980 and 2016 from PubMed, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Academic Search Premier, and related health resource Web sites to address the aims of this study. Outcomes: Fifty-six primary research articles (42 observational studies and 14 experimental and quasi-experimental studies) were selected based on our study aims and inclusion criteria. The studies revealed that individuals with CVD are at a greater risk for SRBDs and that SRBDs can worsen CVD. The findings from the studies also suggest that positive airway treatment could improve both SRBDs and CVD. Conclusions: This review found a close relationship between SRBDs and CVD. Advanced practice registered nurses are in key positions to identify and help patients manage SRBDs. In particular, advanced practice registered nurses can educate staff and establish standards of practice to improve outcomes for patients with CVD. C1 [Moon, Chooza; Lauver, Diane R.; Bratzke, Lisa C.] Univ Wisconsin, Sch Nursing, 701 Highland Ave 3156, Madison, WI 53705 USA. [Phelan, Cynthia H.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI USA. RP Moon, C (reprint author), Univ Wisconsin, Sch Nursing, 701 Highland Ave 3156, Madison, WI 53705 USA. EM cmoon4@wisc.edu OI Moon, Chooza/0000-0002-4828-5143 FU National Institute of Nursing Research [R00NR012773]; Clinical and Translational Science Award (CTSA) program through NIH National Center for Advancing Translational Sciences [UL1TR000427] FX The project described was supported by award number R00NR012773 (Brain Alterations and Cognitive Impairment in Older Adults with Heart Failure) from the National Institute of Nursing Research and the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences, grant UL1TR000427. NR 81 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0887-6274 EI 1538-9782 J9 CLIN NURSE SPEC JI Clin. Nurse Spec. PD NOV-DEC PY 2016 VL 30 IS 6 BP 347 EP 362 DI 10.1097/NUR.0000000000000247 PG 16 WC Nursing SC Nursing GA EA4IG UT WOS:000386574200011 PM 27753673 ER PT J AU Eren, G Kantarci, A Sculean, A Atilla, G AF Eren, Gulnihal Kantarci, Alpdogan Sculean, Anton Atilla, Gul TI Vascularization after treatment of gingival recession defects with platelet-rich fibrin or connective tissue graft SO CLINICAL ORAL INVESTIGATIONS LA English DT Article DE Subepithelial connective tissue graft; Gingival recession; Platelet-rich fibrin; Histology; Wound healing ID PERIODONTAL PLASTIC-SURGERY; ENDOTHELIAL GROWTH-FACTOR; PLASMA P-PRP; HISTOLOGIC EVALUATION; CLINICAL-EVALUATION; PART 2; COVERAGE; ANGIOGENESIS; REGENERATION; CAPILLARIES AB The aim of this study was to evaluate histologically the following treatment of bilateral localized gingival recessions with coronally advanced flap (CAF) combined with platelet-rich fibrin (PRF) or subepithelial connective tissue graft (SCTG). Tissue samples were harvested from 14 subjects either 1 or 6 months after the surgeries. The 2-mm punch biopsies were obtained from the mid-portion of the grafted sites. Neutral buffered formalin fixed, paraffin-embedded 5-mu m thick tissue sections were stained with hematoxylin eosin and Masson's trichrome in order to analyze the collagen framework, epithelium thickness and rete-peg length. Multiple sequential sections were cut from paraffin-embedded blocks of tissue and immunohistochemically prepared for detection of vascular endothelial growth factor, CD31 and CD34, for the assessment of vascularization. Rete peg formation was significantly increased in the sites treated with PRF compared to the SCTG group after 6 months (p < 0.05). On the contrary, the number of vessels was increased in the SCTG group compared to the PRF group after 6 months (p < 0.05). No statistically significant differences were observed in the collagen density. Staining intensity of CD31 increased in submucosal area of PRF group than SCTG group after 1 month. Higher staining intensity of CD34 was observed in the submucosal area of PRF group compared with SCTG group after 6 months. The results of the present study suggest that in histological evaluation because of its biological compounds, PRF results earlier vessel formation and tissue maturation compared to connective tissue graft. PRF regulated the vascular response associated with an earlier wound healing. C1 [Eren, Gulnihal; Atilla, Gul] Ege Univ, Sch Dent, Dept Periodontol, Bornova, Turkey. [Kantarci, Alpdogan] Forsyth Inst, Dept Appl Oral Sci, Ctr Periodontol, Cambridge, MA 02142 USA. [Sculean, Anton] Univ Bern, Sch Dent Med, Dept Periodontol, Bern, Switzerland. RP Eren, G (reprint author), Ege Univ, Sch Dent, Dept Periodontol, Bornova, Turkey. EM gulnihal_karasu@hotmail.com FU NIH/NIDCR [DE020906]; Scientific Technological Research Council of Turkey (TUBITAK) [BIDEB-2219] FX This work was supported by NIH/NIDCR grant DE020906 and Scientific Technological Research Council of Turkey (TUBITAK) Grant: BIDEB-2219 International Postdoctoral Research Fellowship Programme. NR 46 TC 0 Z9 0 U1 14 U2 14 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1432-6981 EI 1436-3771 J9 CLIN ORAL INVEST JI Clin. Oral Investig. PD NOV PY 2016 VL 20 IS 8 BP 2045 EP 2053 DI 10.1007/s00784-015-1697-8 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EA3KS UT WOS:000386501800022 PM 26696115 ER PT J AU Chou, RC Kane, M Ghimire, S Gautam, S Gui, J AF Chou, Richard C. Kane, Michael Ghimire, Sanjay Gautam, Shiva Gui, Jiang TI Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis SO CNS DRUGS LA English DT Article ID TUMOR-NECROSIS-FACTOR; MILD COGNITIVE IMPAIRMENT; FACTOR-ALPHA; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; VASCULAR DEMENTIA; UNITED-STATES; AMYLOID-BETA; INFLAMMATION AB Introduction It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-alpha, the relationship between AD and RA remains unknown. Objective To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. Methods We performed a nested case-control study of more than 8.5 million commercially insured adults (aged aeyen18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. Result AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. Conclusion There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD. C1 [Chou, Richard C.] Dartmouth Hitchcock Med Ctr, Rheumatol Sect, One Med Ctr Dr, Lebanon, NH 03756 USA. [Chou, Richard C.] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. [Kane, Michael] Massachusetts Gen Hosp, Div Rheumatol, Boston, MA 02114 USA. [Kane, Michael; Gautam, Shiva] Harvard Med Sch, Dept Med, Boston, MA USA. [Ghimire, Sanjay] Verisk Hlth, Waltham, MA USA. [Gautam, Shiva] Beth Israel Deaconess Med Ctr, Harvard CTSC Biostat Program, Boston, MA 02215 USA. [Gui, Jiang] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Gui, Jiang] Geisel Sch Med Dartmouth, Dept Community & Family Med, Lebanon, NH USA. [Gui, Jiang] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. RP Chou, RC (reprint author), Dartmouth Hitchcock Med Ctr, Rheumatol Sect, One Med Ctr Dr, Lebanon, NH 03756 USA.; Chou, RC (reprint author), Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. EM Richard.c.chou@dartmouth.edu FU National Center for Research Resources [UL1 RR025758] FX This work was partially supported by Grant No. UL1 RR025758-Harvard Clinical and Translational Science Center, from the National Center for Research Resources for Shiva Gautam. NR 50 TC 1 Z9 1 U1 6 U2 6 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1172-7047 EI 1179-1934 J9 CNS DRUGS JI CNS Drugs PD NOV PY 2016 VL 30 IS 11 BP 1111 EP 1120 DI 10.1007/s40263-016-0374-z PG 10 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EB0HQ UT WOS:000387025300007 PM 27470609 ER PT J AU Ebrahimiadib, N Modjtahedi, BS Roohipoor, R Anesi, SD Foster, CS AF Ebrahimiadib, Nazanin Modjtahedi, Bobeck S. Roohipoor, Ramak Anesi, Stephen D. Foster, C. Stephen TI Successful Treatment Strategies in Granulomatosis With Polyangiitis-Associated Peripheral Ulcerative Keratitis SO CORNEA LA English DT Article DE cyclophosphamide; granulomatosis with polyangiitis; ocular inflammation; peripheral ulcerative keratitis; rituximab ID ANTIBODY-ASSOCIATED VASCULITIS; ANCA-ASSOCIATED VASCULITIS; WEGENERS-GRANULOMATOSIS; OCULAR MANIFESTATIONS; SYSTEMIC-DISEASE; RITUXIMAB; MAINTENANCE; THERAPY; CYCLOPHOSPHAMIDE; SCLERITIS AB Purpose:Management of granulomatosis with polyangiitis (GPA)-associated peripheral ulcerative keratitis (PUK) is challenging and lacks definite guidelines. We aimed to summarize our treatment and outcome experience with patients with GPA-PUK.Methods:The Massachusetts Eye Research and Surgery Institution patient database was searched from 2005 to 2015 to identify patients with diagnosis of PUK who suffered from GPA. Individual patient histories were examined, and treatment strategies and outcomes were summarized.Results:There were 16 patients who started treatment with a mean duration follow-up of 64 months (range: 12-110 mo). Rituximab and cyclophosphamide, either alone or in combination with other agents, were the most successful agents in controlling inflammation. Rituximab was administered in 11 patients with remission being achieved in all. Cyclophosphamide successfully controlled inflammation in 50% (5/10). Two of the patients (2/5, 40%) who had achieved initial control on cyclophosphamide had flares of their PUK. Two of 11 (18%) patients on rituximab had flares of scleritis and orbital inflammation but not PUK. Two patients, one in each treatment group, stopped treatment after achieving remission after 6 months of therapy but suffered disease recurrence within 2 months of treatment cessation.Conclusions:Rituximab achieved a high rate of disease control in PUK patients with GPA and is the preferred agent in halting disease progression. C1 [Ebrahimiadib, Nazanin; Anesi, Stephen D.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, 1440 Main St,Suite 201, Waltham, MA 02451 USA. [Ebrahimiadib, Nazanin; Anesi, Stephen D.; Foster, C. Stephen] Ocular Immunol & Uveitis Fdn, Waltham, MA USA. [Modjtahedi, Bobeck S.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Roohipoor, Ramak] Univ Tehran Med Sci, Farabi Eye Hosp, Eye Res Ctr, Tehran, Iran. [Foster, C. Stephen] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. RP Foster, CS (reprint author), Massachusetts Eye Res & Surg Inst, 1440 Main St,Suite 201, Waltham, MA 02451 USA. EM sfoster@mersi.com FU Aldeyra Therapeutics (Lexington, MA); Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA); Eyegate Pharma (Waltham, MA); Novartis (Cambridge, MA); pSivida (Watertown, MA) FX C. S. Foster has the following financial relationships to declare: Consultancies with Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Novartis (Cambridge, MA), and pSivida (Watertown, MA). The remaining authors have no conflicts of interest to declare. NR 39 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD NOV PY 2016 VL 35 IS 11 BP 1459 EP 1465 DI 10.1097/ICO.0000000000000919 PG 7 WC Ophthalmology SC Ophthalmology GA EA6FH UT WOS:000386721200019 PM 27362884 ER PT J AU Chan, E Le, QH Codriansky, A Hong, JX Xu, JJ Deng, SX AF Chan, Eric Le, Qihua Codriansky, Andres Hong, Jiaxu Xu, Jianjian Deng, Sophie X. TI Existence of Normal Limbal Epithelium in Eyes With Clinical Signs of Total Limbal Stem Cell Deficiency SO CORNEA LA English DT Article DE limbal stem cell deficiency; in vivo confocal microscopy; limbal stem cell; diagnosis ID VIVO CONFOCAL MICROSCOPY; CORNEAL; SURFACE; KERATOPROSTHESIS; TRANSPLANTATION; MAINTENANCE; MANAGEMENT; DIAGNOSIS AB Purpose:To report the presence of normal limbal epithelium detected by in vivo confocal laser scanning microscopy (IVCM) in 3 cases of clinically diagnosed total limbal stem cell deficiency (LSCD).Methods:This is a retrospective case report consisting of 3 patients who were diagnosed with total LSCD based on clinical examination and/or impression cytology. Clinical data including ocular history, presentation, slit-lamp examination, IVCM, and impression cytology were reviewed.Results:The etiology was chemical burn in 3 cases. One patient had 2 failed penetrating keratoplasties. Another had allogeneic keratolimbal transplantation, but the graft failed 1 year after surgery. The third patient had failed amniotic membrane transplantation. These 3 patients presented with signs of total LSCD including the absence of normal Vogt palisades, complete superficial vascularization of the peripheral cornea, nonhealing epithelial defects, and corneal scarring. Impression cytology was performed in 2 cases to confirm the presence of goblet cells. However, each patient still had distinct areas of corneal and/or limbal epithelial cells detected by IVCM.Conclusions:Residual normal limbal epithelial cells could be present in eyes with clinical features of total LSCD. IVCM seems to be a more accurate method to evaluate the degree of LSCD. C1 [Chan, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Le, Qihua; Xu, Jianjian] Fudan Univ, Shanghai Eye Ear Nose & Throat Hosp, Shanghai, Peoples R China. [Codriansky, Andres; Deng, Sophie X.] Univ Calif Los Angeles, Stein Eye Inst, Cornea Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. [Hong, Jiaxu] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Deng, SX (reprint author), Univ Calif Los Angeles, Stein Eye Inst, Cornea Div, 100 Stein Plaza, Los Angeles, CA 90095 USA.; Xu, JJ (reprint author), Fudan Univ, Shanghai Eye Ear Nose & Throat Hosp, Dept Ophthalmol & Visual Sci, 83 Rd Fenyang, Shanghai 200031, Peoples R China. EM jianjiangxu@126.com; Deng@jsei.ucla.edu FU Research to Prevent Blindness; National Eye Institute [5P30EY000331, 1R01EY021797]; California Institute for Regenerative Medicine [TR2-01768, BF1-01768] FX Supported in part by an unrestricted Grant from Research to Prevent Blindness. S. X. Deng received grant support from the National Eye Institute Grants (5P30EY000331 and 1R01EY021797) and the California Institute for Regenerative Medicine (TR2-01768 and BF1-01768). The other authors have no conflicts of interest to disclose. NR 29 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD NOV PY 2016 VL 35 IS 11 BP 1483 EP 1487 DI 10.1097/ICO.0000000000000914 PG 5 WC Ophthalmology SC Ophthalmology GA EA6FH UT WOS:000386721200023 PM 27362882 ER PT J AU Wojciechowski, D Vincenti, F AF Wojciechowski, David Vincenti, Flavio TI Current status of costimulatory blockade in renal transplantation SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE belatacept; costimulation blockade; kidney transplant ID DONOR-SPECIFIC ANTIBODY; SOLID-ORGAN TRANSPLANTATION; ISLET ALLOGRAFT SURVIVAL; CALCINEURIN INHIBITORS; KIDNEY-TRANSPLANTATION; RANDOMIZED-TRIAL; ACUTE REJECTION; BENEFIT-EXT; PHASE-III; MYCOPHENOLATE-MOFETIL AB Purpose of reviewThe review will focus on the impact and current status of costimulatory blockade in renal transplantation.Recent findingsThe mainstay of immunosuppression in kidney transplantation is calcineurin inhibitors (CNIs) which have reduced acute rejection rates but failed to improve long-term allograft survival. Their cardiometabolic side-effects and nephrotoxicity have shifted the focus of investigation to CNI-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of cytotoxic T-lymphocyte associated protein 4 has emerged as part of a CNI-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing the belatacept regimen is underway. ASKP1240, which blocks the cluster of differentiation 40 (CD40)/CD154 costimulatory pathway, has just completed a phase 2 trial with a CNI-free regimen. CFZ533, an anti-CD40, is also poised to be tested in a phase 2 trial in renal transplantation. Nonagonistic CD28 antibodies have re-emerged with two anti-CD28 candidates in preclinical development.SummaryA reliable, CNI-free regimen that maintains low acute rejection rates and improves long-term renal allograft survival has become an achievable goal with costimulation blockade. The task of clinicians and researchers is to find the optimal combinations to maintain safety and improve efficacy. C1 [Wojciechowski, David] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Vincenti, Flavio] Univ Calif San Francisco, Kidney Transplant Serv, 505 Parnassus Ave,Room 884 M, San Francisco, CA 94143 USA. RP Vincenti, F (reprint author), Univ Calif San Francisco, Kidney Transplant Serv, 505 Parnassus Ave,Room 884 M, San Francisco, CA 94143 USA. EM Flavio.Vincenti@ucsfmedctr.org FU Department of Nephrology at UCSF; MGH FX The work was supported by the Department of Nephrology at UCSF and MGH. NR 66 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD NOV PY 2016 VL 25 IS 6 BP 583 EP 590 DI 10.1097/MNH.0000000000000268 PG 8 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA EA1HB UT WOS:000386342000018 PM 27517137 ER PT J AU Ricordi, C Goldstein, JS Balamurugan, AN Szot, GL Kin, T Liu, CY Czarniecki, CW Barbaro, B Bridges, ND Cano, J Clarke, WR Eggerman, TL Hunsicker, LG Kaufman, DB Khan, A Lafontant, DE Linetsky, E Luo, XR Markmann, JF Naji, A Korsgren, O Oberholzer, J Turgeon, NA Brandhorst, D Friberg, AS Lei, J Wang, LJ Wilhelm, JJ Willits, J Zhang, XM Hering, BJ Posselt, AM Stock, PG Shapiro, AMJ AF Ricordi, Camillo Goldstein, Julia S. Balamurugan, A. N. Szot, Gregory L. Kin, Tatsuya Liu, Chengyang Czarniecki, Christine W. Barbaro, Barbara Bridges, Nancy D. Cano, Jose Clarke, William R. Eggerman, Thomas L. Hunsicker, Lawrence G. Kaufman, Dixon B. Khan, Aisha Lafontant, David-Erick Linetsky, Elina Luo, Xunrong Markmann, James F. Naji, Ali Korsgren, One Oberholzer, Jose Turgeon, Nicole A. Brandhorst, Daniel Friberg, Andrew S. Lei, Ji Wang, Ling-jia Wilhelm, Joshua J. Willits, Jamie Zhang, Xiaomin Hering, Bernhard J. Posselt, Andrew M. Stock, Peter G. Shapiro, A. M. James TI National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities SO DIABETES LA English DT Article ID SINGLE-DONOR; EDMONTON PROTOCOL; CULTURED ISLETS; PANCREAS; PRESERVATION; LANGERHANS; PERFUSION; OUTCOMES; YIELD AB Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed. C1 [Ricordi, Camillo; Khan, Aisha; Linetsky, Elina] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Goldstein, Julia S.; Czarniecki, Christine W.; Bridges, Nancy D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Balamurugan, A. N.; Wilhelm, Joshua J.; Hering, Bernhard J.] Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA. [Balamurugan, A. N.; Wilhelm, Joshua J.; Hering, Bernhard J.] Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. [Szot, Gregory L.; Posselt, Andrew M.; Stock, Peter G.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Kin, Tatsuya; Shapiro, A. M. James] Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada. [Kin, Tatsuya; Shapiro, A. M. James] Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada. [Liu, Chengyang; Naji, Ali] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Liu, Chengyang; Naji, Ali] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Liu, Chengyang; Naji, Ali] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Barbaro, Barbara; Oberholzer, Jose] Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA. [Cano, Jose; Turgeon, Nicole A.] Emory Univ, Dept Surg, Emory Transplant Ctr, Div Transplantat, Atlanta, GA 30322 USA. [Clarke, William R.; Hunsicker, Lawrence G.; Lafontant, David-Erick; Willits, Jamie] Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA. [Eggerman, Thomas L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Kaufman, Dixon B.; Luo, Xunrong; Wang, Ling-jia; Zhang, Xiaomin] Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Markmann, James F.; Lei, Ji] Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA. [Korsgren, One; Friberg, Andrew S.] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Brandhorst, Daniel] Uppsala Univ, Dept Clin Immunol, Rudbeck Lab, Uppsala, Sweden. [Balamurugan, A. N.] Univ Louisville, Dept Surg, Islet Cell Lab, Cardiovasc Innovat Inst, Louisville, KY 40292 USA. [Kaufman, Dixon B.] Univ Wisconsin, Madison, WI USA. RP Ricordi, C (reprint author), Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA.; Goldstein, JS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ricordi@miami.edu; goldsteinj@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institute for Diabetes and Digestive and Kidney Diseases [U01-AI-089317]; Northwestern University (Evanston, IL) [U01-AI-089316]; University of Alberta (Edmonton, Alberta, Canada) [U01-AI-065191]; University of California, San Francisco (San Francisco, CA) [U01-DK-085531]; University of Illinois at Chicago (Chicago, IL) [5U01-DK-070431-10]; University of Iowa (Iowa City, IA) [U01-DK-070431]; University of Miami (Miami, FL) [U01-DK-070460]; University of Minnesota (Minneapolis, MN) [U01-AI-065193]; University of Pennsylvania (Philadelphia, PA) [U01-DK-070430]; Uppsala University (Uppsala, Sweden) [U01-AI-065192]; General Clinical Research Center Awards and Clinical and Translational Science Awards: Emory University [UL1-TR-000454]; Northwestern University [5UL1-RR-025741, 8UL1-TR-000150]; University of California, San Francisco [UL1-TR-000004]; University of Illinois at Chicago [UL1-TR-000050]; University of Miami [1UL1-TR-000460]; University of Minnesota [5M01-RR-000400, UL1-TR-000114]; University of Pennsylvania [M01-RR-00040, UL1-TR-000003] FX This research was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute for Diabetes and Digestive and Kidney Diseases to the following institutions: Emory University (Atlanta, GA), U01-AI-089317; Northwestern University (Evanston, IL), U01-AI-089316; University of Alberta (Edmonton, Alberta, Canada), U01-AI-065191; University of California, San Francisco (San Francisco, CA), U01-DK-085531; University of Illinois at Chicago (Chicago, IL), 5U01-DK-070431-10; University of Iowa (Iowa City, IA), U01-DK-070431; University of Miami (Miami, FL), U01-DK-070460; University of Minnesota (Minneapolis, MN), U01-AI-065193; University of Pennsylvania (Philadelphia, PA), U01-DK-070430; and Uppsala University (Uppsala, Sweden), U01-AI-065192. In addition, the study was supported by the following General Clinical Research Center Awards and Clinical and Translational Science Awards: Emory University, UL1-TR-000454; Northwestern University, 5UL1-RR-025741 and 8UL1-TR-000150; University of California, San Francisco, UL1-TR-000004; University of Illinois at Chicago, UL1-TR-000050; University of Miami, 1UL1-TR-000460; University of Minnesota, 5M01-RR-000400 and UL1-TR-000114; and University of Pennsylvania, M01-RR-00040 and UL1-TR-000003. NR 53 TC 3 Z9 3 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD NOV PY 2016 VL 65 IS 11 BP 3418 EP 3428 DI 10.2337/db16-0234 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA3VX UT WOS:000386538500020 PM 27465220 ER PT J AU Chang, CY Abujaber, S Reynolds, TA Camargo, CA Obermeyer, Z AF Chang, Cindy Y. Abujaber, Samer Reynolds, Teri A. Camargo, Carlos A., Jr. Obermeyer, Ziad TI Burden of emergency conditions and emergency care usage: new estimates from 40 countries SO EMERGENCY MEDICINE JOURNAL LA English DT Article ID MIDDLE-INCOME COUNTRIES; SYSTEMS; AGREEMENT; SERVICES; ACCESS AB Objective To estimate the global and national burden of emergency conditions, and compare them to emergency care usage rates. Methods We coded all 291 Global Burden of Disease 2010 conditions into three categories to estimate emergency burden: conditions that, if not addressed within hours to days of onset, commonly lead to serious disability or death; conditions with common acute decompensations that lead to serious disability or death; and non-emergencies. Emergency care usage rates were obtained from a systematic literature review on emergency care facilities in low-income and middle-income countries (LMICs), supplemented by national health system reports. Findings All 15 leading causes of death and disability-adjusted life years (DALYs) globally were conditions with potential emergent manifestations. We identified 41 facility-based reports in 23 countries, 12 of which were in LMICs; data for 17 additional countries were obtained from national or regional reports on emergency usage. Burden of emergency conditions was the highest in low-income countries, with median DALYs of 47 728 per 100 000 population (IQR 45 253-50 085) in low-income, 25 186 (IQR 21 982-40 480) in middle-income and 15 691 (IQR 14 649-16 382) in high-income countries. Patterns were similar using deaths to measure burden and excluding acute decompensations from the definition of emergency conditions. Conversely, emergency usage rates were the lowest in low-income countries, with median 8 visits per 1000 population (IQR 6-10), 78 (IQR 25-197) in middle-income and 264 (IQR 177-341) in high-income countries. Conclusions Despite higher burden of emergency conditions, emergency usage rates are substantially lower in LMICs, likely due to limited access to emergency care. C1 [Chang, Cindy Y.] Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency Progra, Neville House,10 Vining St, Boston, MA 02115 USA. [Chang, Cindy Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Abujaber, Samer; Obermeyer, Ziad] Brigham & Womens Hosp, Dept Emergency Med, Neville House,10 Vining St, Boston, MA 02115 USA. [Reynolds, Teri A.] WHO, Dept Management Noncommunicable Dis Disabil Viole, Geneva, Switzerland. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.; Obermeyer, Ziad] Harvard Med Sch, Dept Emergency Med, Boston, MA USA. RP Obermeyer, Z (reprint author), Brigham & Womens Hosp, Dept Emergency Med, Neville House,10 Vining St, Boston, MA 02115 USA. EM zobermeyer@partners.org FU NIH Office of the Director grant [DP5 OD012161] FX NIH Office of the Director grant# DP5 OD012161. NR 24 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1472-0205 EI 1472-0213 J9 EMERG MED J JI Emerg. Med. J. PD NOV PY 2016 VL 33 IS 11 BP 794 EP 800 DI 10.1136/emermed-2016-205709 PG 7 WC Emergency Medicine SC Emergency Medicine GA EA9GU UT WOS:000386951400009 PM 27334758 ER PT J AU Sylow, L Long, JZ Lokurkar, IA Zeng, X Richter, EA Spiegelman, BM AF Sylow, Lykke Long, Jonathan Z. Lokurkar, Isha A. Zeng, Xing Richter, Erik A. Spiegelman, Bruce M. TI The Cancer Drug Dasatinib Increases PGC-1 alpha in Adipose Tissue but Has Adverse Effects on Glucose Tolerance in Obese Mice SO ENDOCRINOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; HEPATIC GLUCONEOGENESIS; INSULIN-RESISTANCE; CHRONIC-PHASE; COACTIVATOR PGC-1; FAT; HOMEOSTASIS; METABOLISM; EXPRESSION; IMATINIB AB Dasatinib (Sprycel) is a tyrosine kinase inhibitor approved for treatment of chronic myeloid leukemia. In this study, we identify dasatinib as a potent inducer of Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha mRNA. Dasatinib increased PGC-1 alpha mRNA expression up to 6-fold in 3T3-F442A adipocytes, primary adipocytes, and epididymal white adipose tissue from lean and diet-induced obese mice. Importantly, gene expression translated into increased PGC-1 alpha protein content analyzed in melanoma cells and isolated mitochondria from adipocytes. However, dasatinib treatment had adverse effect on glucose tolerance in diet-induced obese and Ob/Ob mice. This correlated with increased hepatic PGC-1 alpha expression and the gluconeogenesis genes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. In conclusion, we show that dasatinib is a potent inducer of PGC-1 alpha mRNA and protein in adipose tissue. However, despite beneficial effects of increased PGC-1 alpha content in adipose tissue, dasatinib significantly impaired glucose tolerance in obese but not lean mice. As far as we are aware, this is the first study to show that dasatinib regulates PGC-1 alpha and causes glucose intolerance in obese mice. This should be considered in the treatment of chronic myeloid leukemia. C1 [Sylow, Lykke; Richter, Erik A.] Univ Copenhagen, Sect Mol Physiol, Dept Nutr Exercise & Sports, Fac Sci, DK-2100 Copenhagen, Denmark. [Long, Jonathan Z.; Lokurkar, Isha A.; Zeng, Xing; Spiegelman, Bruce M.] Harvard Med Sch, Dept Cell Biol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Med Sch, Dept Cell Biol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu FU National Institutes of Health Grants [DK 54477, DK105203]; Danish Research Council Grant [DFF-4004-00233]; Danish Medical Research Council Grant [0602-02273B]; Lundbeck Foundation Grant [2011-8205] FX This work was supported by National Institutes of Health Grants DK 54477 (to B.M.S.) and DK105203 (to J.L.), the Danish Research Council Grant DFF-4004-00233 (to L.S.), the Danish Medical Research Council Grant 0602-02273B (to E.A.R.), and the Lundbeck Foundation Grant 2011-8205 (to E.A.R.). NR 36 TC 0 Z9 0 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2016 VL 157 IS 11 BP 4184 EP 4191 DI 10.1210/en.2016-1398 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA6YF UT WOS:000386774400010 PM 27589085 ER PT J AU Schilit, SLP Currall, BB Yao, R Hanscom, C Collins, RL Pillalamarri, V Lee, DY Kammin, T Zepeda-Mendoza, CJ Mononen, T Nolan, LS Gusella, JF Talkowski, ME Shen, J Morton, CC AF Schilit, Samantha L. P. Currall, Benjamin B. Yao, Ruen Hanscom, Carrie Collins, Ryan L. Pillalamarri, Vamsee Lee, Dong-Young Kammin, Tammy Zepeda-Mendoza, Cinthya J. Mononen, Tarja Nolan, Lisa S. Gusella, James F. Talkowski, Michael E. Shen, Jun Morton, Cynthia C. TI Estrogen-related receptor gamma implicated in a phenotype including hearing loss and mild developmental delay SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CHROMOSOME REARRANGEMENTS; PROJECT AB Analysis of chromosomal rearrangements has been highly successful in identifying genes involved in many congenital abnormalities including hearing loss. Herein, we report a subject, designated DGAP242, with congenital hearing loss (HL) and a de novo balanced translocation 46,XX,t(1;5)(q32;q15)dn. Using multiple next-generation sequencing techniques, we obtained high resolution of the breakpoints. This revealed disruption of the orphan receptor ESRRG on chromosome 1, which is differentially expressed in inner ear hair cells and has previously been implicated in HL, and disruption of KIAA0825 on chromosome 5. Given the translocation breakpoints and supporting literature, disruption of ESRRG is the most likely cause for DGAP242's phenotype and implicates ESRRG in a monogenic form of congenital HL, although a putative contributory role for KIAA0825 in the subject's disorder cannot be excluded. C1 [Schilit, Samantha L. P.; Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Currall, Benjamin B.; Kammin, Tammy; Zepeda-Mendoza, Cinthya J.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. [Currall, Benjamin B.; Zepeda-Mendoza, Cinthya J.; Gusella, James F.; Talkowski, Michael E.; Shen, Jun; Morton, Cynthia C.] Harvard Med Sch, Boston, MA USA. [Yao, Ruen] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai, Peoples R China. [Hanscom, Carrie; Collins, Ryan L.; Pillalamarri, Vamsee; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Lee, Dong-Young; Shen, Jun; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Pathol, New Res Bldg,Rm 160D,77 Ave Louis Pasteur, Boston, MA 02115 USA. [Mononen, Tarja] Kuopio Univ Hosp, Dept Clin Genet, Kuopio, Finland. [Nolan, Lisa S.] UCL, UCL Ear Inst, London, England. [Gusella, James F.; Talkowski, Michael E.; Morton, Cynthia C.] Broad Inst, Med & Populat Genet Program, Cambridge, MA USA. [Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shen, Jun] Partners HealthCare, Partners Personalized Med, Lab Mol Med, Cambridge, MA USA. [Morton, Cynthia C.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. RP Morton, CC (reprint author), Brigham & Womens Hosp, Dept Pathol, New Res Bldg,Rm 160D,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cmorton@partners.org OI Collins, Ryan/0000-0003-1268-9995 FU National Institute of General Medical Sciences [GM061354]; National Institute of Mental Health [MH095867]; National Institute on Deafness and Other Communication Disorders [R03DC013866, F32DC012466]; National Science Foundation [DGE1144152]; Wellcome Trust FX We thank the patient and her family for their participation in our study. This research was supported by the National Institute of General Medical Sciences GM061354 (CCM, JFG), the National Institute of Mental Health MH095867 (MET), the National Institute on Deafness and Other Communication Disorders R03DC013866 (JS) and F32DC012466 (BBC) and the National Science Foundation DGE1144152 (SLPS). Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding institutions. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the DECIPHER data is available from http://decipher.sanger.ac.uk and via E-mail from decipher@sanger.ac.uk. Funding for DECIPHER was provided by the Wellcome Trust. NR 20 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD NOV PY 2016 VL 24 IS 11 BP 1622 EP 1626 DI 10.1038/ejhg.2016.64 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EA5UX UT WOS:000386690500021 PM 27381092 ER PT J AU Thompson, LA Haburcakova, C Lewis, RF AF Thompson, Lara A. Haburcakova, Csilla Lewis, Richard F. TI Vestibular ablation and a semicircular canal prosthesis affect postural stability during head turns SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Vestibular; Posture; Balance; Prosthesis; Implant ID ELECTRICAL-STIMULATION; GAZE SHIFTS; RHESUS-MONKEYS; EYE; COORDINATION; SYSTEM; MOVEMENTS; RESPONSES; BALANCE; TRANSFORMATION AB In our study, we examined postural stability during head turns for two rhesus monkeys: one animal study contrasted normal and mild bilateral vestibular ablation and a second animal study contrasted severe bilateral vestibular ablation with and without prosthetic stimulation. The monkeys freely stood, unrestrained on a balance platform and made voluntary head turns between visual targets. To quantify each animals' posture, motions of the head and trunk, as well as torque about the body's center of mass, were measured. In the mildly ablated animal, we observed less foretrunk sway in comparison with the normal state. When the canal prosthesis provided electric stimulation to the severely ablated animal, it showed a decrease in trunk sway during head turns. Because the rhesus monkey with severe bilateral vestibular loss exhibited a decrease in trunk sway when receiving vestibular prosthetic stimulation, we propose that the prosthetic electrical stimulation partially restored head velocity information. Our results provide an indication that a semicircular canal prosthesis may be an effective way to improve postural stability in patients with severe peripheral vestibular dysfunction. C1 [Haburcakova, Csilla; Lewis, Richard F.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Lewis, Richard F.] Harvard Med Sch, Dept Neurol, Boston, MA USA. [Thompson, Lara A.; Haburcakova, Csilla; Lewis, Richard F.] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. [Thompson, Lara A.; Lewis, Richard F.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Thompson, Lara A.] Univ Dist Columbia, Sch Engn & Appl Sci, Washington, DC 20008 USA. RP Thompson, LA (reprint author), Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA.; Thompson, LA (reprint author), Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA.; Thompson, LA (reprint author), Univ Dist Columbia, Sch Engn & Appl Sci, Washington, DC 20008 USA. EM lthomps@alum.mit.edu FU National Institutes of Health (NIH) [DC8362]; NIH [T32 DC00038] FX We thank Dr. Conrad Wall for advice on experimental design and James Lackner. This work was supported by the National Institutes of Health (NIH) grant DC8362 to R.F. Lewis and by NIH Grant T32 DC00038 which supported L.A. Thompson. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. NR 36 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD NOV PY 2016 VL 234 IS 11 BP 3245 EP 3257 DI 10.1007/s00221-016-4722-5 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EA4TO UT WOS:000386607900016 PM 27405997 ER PT J AU Varraso, R Camargo, CA AF Varraso, Raphaelle Camargo, Carlos A., Jr. TI Diet and asthma: need to account for asthma type and level of prevention SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Editorial Material DE Dietary intake; asthma incidence; asthma control; epidemiology; primary prevention; secondary prevention; asthma heterogeneity ID MEDITERRANEAN DIET; DISEASE; SYMPTOMS; PATTERNS; IMPACT C1 [Varraso, Raphaelle] INSERM U1168, VIMA Aging & Chron Dis Epidemiol & Publ Hlth Appr, Villejuif, France. [Varraso, Raphaelle] Univ Versailles St Quentin En Yvelines, UVSQ, UMR S 1168, Versailles, France. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Varraso, R (reprint author), INSERM U1168, VIMA Aging & Chron Dis Epidemiol & Publ Hlth Appr, Villejuif, France.; Varraso, R (reprint author), Univ Versailles St Quentin En Yvelines, UVSQ, UMR S 1168, Versailles, France. EM raphaelle.varraso@inserm.fr RI Varraso, Raphaelle/R-8740-2016 OI Varraso, Raphaelle/0000-0002-3338-7825 NR 28 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD NOV PY 2016 VL 10 IS 11 BP 1147 EP 1150 DI 10.1080/17476348.2016.1240033 PG 4 WC Respiratory System SC Respiratory System GA EB0MO UT WOS:000387038100001 ER PT J AU Duprey, MS Al-Qadheeb, N Roberts, R Skrobik, Y Schumaker, G Devlin, JW AF Duprey, Matthew S. Al-Qadheeb, Nada Roberts, Russel Skrobik, Yoanna Schumaker, Greg Devlin, John W. TI The use of low-dose IV haloperidol is not associated with QTc prolongation: post hoc analysis of a randomized, placebo-controlled trial SO INTENSIVE CARE MEDICINE LA English DT Letter ID CRITICALLY-ILL PATIENTS; TORSADES-DE-POINTES; INTRAVENOUS-HALOPERIDOL; DELIRIUM C1 [Duprey, Matthew S.; Devlin, John W.] Northeastern Univ, Sch Pharm, 360 Huntington Ave,TF R218, Boston, MA 02115 USA. [Al-Qadheeb, Nada] Hafer Albatin Cent Hosp, Dept Crit Care, Riyadh, Saudi Arabia. [Roberts, Russel] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Skrobik, Yoanna] McGill Univ, Div Crit Care, Ctr Hlth, Montreal, PQ, Canada. [Schumaker, Greg; Devlin, John W.] Tufts Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA USA. RP Devlin, JW (reprint author), Northeastern Univ, Sch Pharm, 360 Huntington Ave,TF R218, Boston, MA 02115 USA. EM j.devlin@neu.edu FU NIA NIH HHS [R15 AG034915] NR 5 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2016 VL 42 IS 11 BP 1818 EP 1819 DI 10.1007/s00134-016-4512-3 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EA4EI UT WOS:000386561900031 PM 27637718 ER PT J AU Zhu, ZH Zhang, RY Liang, LM Su, L Lu, Q Baccarelli, AA Bajwa, EK Thompson, BT Christiani, DC AF Zhu, Zhaozhong Zhang, Ruyang Liang, Liming Su, Li Lu, Quan Baccarelli, Andrea A. Bajwa, Ednan K. Thompson, B. Taylor Christiani, David C. TI Whole blood microRNAs as a prognostic classifier for acute respiratory distress syndrome 28-day mortality SO INTENSIVE CARE MEDICINE LA English DT Letter C1 [Zhu, Zhaozhong; Zhang, Ruyang; Su, Li; Lu, Quan; Baccarelli, Andrea A.; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Zhang, Ruyang] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat,Dept Environm Hlth, Minist Educ,Key Lab Modern Toxicol, Nanjing, Jiangsu, Peoples R China. [Liang, Liming] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liang, Liming] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bajwa, Ednan K.; Thompson, B. Taylor; Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Bajwa, Ednan K.; Thompson, B. Taylor; Christiani, David C.] Harvard Med Sch, Boston, MA USA. RP Christiani, DC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu NR 5 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2016 VL 42 IS 11 BP 1824 EP 1825 DI 10.1007/s00134-016-4462-9 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EA4EI UT WOS:000386561900034 PM 27506755 ER PT J AU Kassis, EB Loring, SH Talmor, D AF Kassis, Elias Baedorf Loring, Stephen H. Talmor, Daniel TI Is transpulmonary pressure-guided PEEP titration really optimal? Response to Yamaga et al. SO INTENSIVE CARE MEDICINE LA English DT Letter ID ESOPHAGEAL PRESSURE; MECHANICS; ARDS C1 [Kassis, Elias Baedorf] Harvard Med Sch, Div Pulm & Crit Care, Beth Israel Deaconess Med Ctr, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. [Kassis, Elias Baedorf] Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. [Loring, Stephen H.; Talmor, Daniel] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA. [Loring, Stephen H.; Talmor, Daniel] Harvard Med Sch, Boston, MA USA. RP Kassis, EB (reprint author), Harvard Med Sch, Div Pulm & Crit Care, Beth Israel Deaconess Med Ctr, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA.; Kassis, EB (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. EM ekassis@partners.org NR 5 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2016 VL 42 IS 11 BP 1847 EP 1848 DI 10.1007/s00134-016-4545-7 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA EA4EI UT WOS:000386561900048 PM 27647330 ER PT J AU Natarajan, A Pendleton, AA Nelson, BD Ahn, R Oguttu, M Dulo, L Eckardt, MJ Burke, TF AF Natarajan, Abirami Pendleton, Anna Alaska Nelson, Brett D. Ahn, Roy Oguttu, Monica Dulo, Lidu Eckardt, Melody J. Burke, Thomas F. TI Provider experiences with improvised uterine balloon tamponade for the management of uncontrolled postpartum hemorrhage in Kenya SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Kenya; Maternal health; Maternal hemorrhage; Maternal mortality; Postpartum hemorrhage; Uterine balloon tamponade ID MATERNAL DEATH AB Objective: To understand healthcare providers' experiences with improvised uterine balloon tamponade (UBT) for the management of uncontrolled postpartum hemorrhage (PPH). Methods: In a qualitative descriptive study, in-depth semi-structured interviews were conducted between November 2014 and June 2015 among Kenyan healthcare providers who had previous experience with improvising a UBT device. Interviews were conducted, audio-recorded, and transcribed. Results: Overall, 29 healthcare providers (14 nurse-midwifes, 7 medical officers, 7 obstetricians, and 1 clinical officer) were interviewed. Providers perceived improvised UBT as valuable for managing uncontrolled PPH. Reported benefits included effectiveness in arresting hemorrhage and averting hysterectomy, and ease of use by providers of all levels of training. Providers used various materials to construct an improvised UBT. Challenges to improvising UBT-e.g. searching for materials during an emergency, procuring male condoms, and inserting fluid via a small syringe were reported to lead to delays in care. Providers described their introduction to improvised UBT through both formal and informal sources. There was universal enthusiasm for widespread standardized training. Conclusion: Improvised UBT seems to be a valuable second line treatment for uncontrolled PPH that can be used by providers of all levels. UBT might be optimized by integrating a standard package across the health system. (C) 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. C1 [Natarajan, Abirami; Pendleton, Anna Alaska; Nelson, Brett D.; Ahn, Roy; Eckardt, Melody J.; Burke, Thomas F.] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. [Natarajan, Abirami; Pendleton, Anna Alaska; Nelson, Brett D.; Burke, Thomas F.] Harvard Med Sch, Boston, MA USA. [Oguttu, Monica; Dulo, Lidu] Kisumu Med Educ Trust, Kisumu, Kenya. RP Natarajan, A (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. EM abirami_natarajan@hms.harvard.edu OI Nelson, Brett/0000-0002-5049-1798 FU Izumi Foundation; Ujenzi Charitable Trust; Harvard Medical School; Saving Lives at Birth (United States Agency for International Development); Saving Lives at Birth (Government of Norway); Saving Lives at Birth (Bill & Melinda Gates Foundation); Saving Lives at Birth (Grand Challenges Canada); Saving Lives at Birth (UK Government) FX Funding was provided by the Izumi Foundation, the Ujenzi Charitable Trust, Harvard Medical School, and partners of Saving Lives at Birth (the United States Agency for International Development, the Government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Government). The manuscript was written by the authors and does not necessarily reflect the views of the funding partners. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD NOV PY 2016 VL 135 IS 2 BP 210 EP 213 DI 10.1016/j.ijgo.2016.05.006 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EA5EW UT WOS:000386643200019 PM 27530220 ER PT J AU Rosati, CM Ekser, B Kaafarani, HMA Gaudino, M Koniaris, LG AF Rosati, Carlo Maria Ekser, Burcin Kaafarani, Haytham M. A. Gaudino, Mario Koniaris, Leonidas G. TI International medical graduates among top US transplant surgeons SO INTERNATIONAL JOURNAL OF SURGERY LA English DT Letter DE International medical graduates; Transplant surgery; Academic surgery C1 [Rosati, Carlo Maria; Ekser, Burcin; Koniaris, Leonidas G.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA. [Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Gaudino, Mario] Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY USA. RP Rosati, CM (reprint author), Emerson Hall,545 Barnhill Dr, Indianapolis, IN 46202 USA. EM carlo.m.rosati@gmail.com NR 5 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1743-9191 EI 1743-9159 J9 INT J SURG JI Int. J. Surg. PD NOV PY 2016 VL 35 BP 19 EP 20 DI 10.1016/j.ijsu.2016.09.005 PG 2 WC Surgery SC Surgery GA EA8QQ UT WOS:000386903200004 PM 27619016 ER PT J AU Yende, S Thompson, BT AF Yende, Sachin Thompson, B. Taylor TI Evaluating Glucocorticoids for Sepsis Time to Change Course SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID SEPTIC SHOCK; TRIAL C1 [Yende, Sachin] Univ Pittsburgh, Dept Crit Care Med, Clin Res Invest & Syst Modeling Acute Illness CRI, Pittsburgh, PA USA. [Yende, Sachin] VA Pittsburgh Healthcare Syst, Univ Dr C,Room 2A124, Pittsburgh, PA 15240 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Thompson, B. Taylor] Harvard Med Sch, Boston, MA USA. RP Yende, S (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr C,Room 2A124, Pittsburgh, PA 15240 USA. EM yendes@upmc.edu NR 9 TC 1 Z9 1 U1 6 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 1 PY 2016 VL 316 IS 17 BP 1769 EP 1770 DI 10.1001/jama.2016.13904 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EA4GP UT WOS:000386569300014 PM 27695850 ER PT J AU Ekhlaspour, L Baskaran, C Campoverde, KJ Sokoloff, NC Neumeyer, AM Misra, M AF Ekhlaspour, Laya Baskaran, Charumathi Campoverde, Karen Joanie Sokoloff, Natalia Cano Neumeyer, Ann M. Misra, Madhusmita TI Bone Density in Adolescents and Young Adults with Autism Spectrum Disorders SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism spectrum disorder; Bone mineral density; Adolescent; Dual energy X-ray absorptiometry; Body mass index ID MINERAL DENSITY; ANTIEPILEPTIC DRUGS; PHYSICAL-ACTIVITY; VALPROIC ACID; CHILDREN; BOYS; MASS; CARBAMAZEPINE; MONOTHERAPY; METAANALYSIS AB Patients with autism spectrum disorder (ASD) are at increased risk for fracture, and peri-pubertal boys with ASD have lower bone mineral density (BMD) than controls. Data are lacking regarding BMD in older adolescents with ASD. We compared BMD using dual-energy X-ray absorptiometry in 9 adolescents/young adults with ASD against 9 typically developing matched controls. Patients with ASD and controls were excluded if they had other underlying conditions that may affect bone. Compared to controls, patients with ASD had (i) lower femoral neck and hip BMD Z-scores, and (ii) lower spine, femoral neck and hip height adjusted BMD Z-scores even after controlling for BMI. Understanding the underlying pathophysiology will be key to developing therapies to improve BMD and reduce fracture risk. C1 [Ekhlaspour, Laya; Baskaran, Charumathi; Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, 55 Fruit St,Yawkey 6c, Boston, MA 02114 USA. [Ekhlaspour, Laya; Baskaran, Charumathi; Misra, Madhusmita] Harvard Med Sch, 55 Fruit St,Yawkey 6c, Boston, MA 02114 USA. [Campoverde, Karen Joanie; Sokoloff, Natalia Cano] Massachusetts Gen Hosp, Neuroendocrine Unit, 101 Merrimac St,6th Floor,Off 615, Boston, MA 02114 USA. [Neumeyer, Ann M.] Massachusetts Gen Hosp, Lurie Ctr Autism, One Maguire Rd, Lexington, MA 02421 USA. [Neumeyer, Ann M.] Harvard Med Sch, One Maguire Rd, Lexington, MA 02421 USA. RP Ekhlaspour, L (reprint author), Massachusetts Gen Hosp Children, Pediat Endocrine Unit, 55 Fruit St,Yawkey 6c, Boston, MA 02114 USA.; Ekhlaspour, L (reprint author), Harvard Med Sch, 55 Fruit St,Yawkey 6c, Boston, MA 02114 USA. EM lekhlaspour@mgh.harvard.edu; cbaskaran@mgh.harvard.edu; kcampoverdereyes@partners.org; natalia.cano@gmail.com; aneumeyer@mgh.harvard.edu; mmisra@partners.org FU NICHD NIH HHS [K24 HD071843] NR 31 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD NOV PY 2016 VL 46 IS 11 BP 3387 EP 3391 DI 10.1007/s10803-016-2871-9 PG 5 WC Psychology, Developmental SC Psychology GA EA7BI UT WOS:000386782700001 PM 27491424 ER PT J AU Hundley, RJ Shui, A Malow, BA AF Hundley, Rachel J. Shui, Amy Malow, Beth A. TI Relationship Between Subtypes of Restricted and Repetitive Behaviors and Sleep Disturbance in Autism Spectrum Disorder SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Sleep; Repetitive behavior; Repetitive sensory motor; Insistence on sameness ID PERVASIVE DEVELOPMENTAL DISORDERS; HABITS QUESTIONNAIRE; DIAGNOSTIC INTERVIEW; CHILDREN; ANXIETY; INDIVIDUALS; PREVALENCE; VALIDATION; INTERESTS; SYMPTOMS AB We examined the association of two types of restricted and repetitive behaviors, repetitive sensory motor (RSM) and insistence on sameness (IS), with sleep problems in children with autism spectrum disorder (ASD). Participants included 532 children (aged 2-17) who participated in the Autism Speaks Autism Treatment Network research registry. Confirmatory factor analysis of the Autism Diagnostic Interview-Revised detected the presence of RSM and IS. RSM behaviors were positively associated with parent-reported sleep problems, and this relationship remained significant after controlling for anxiety symptoms. IS was not significantly associated with sleep problems. Better understanding of the relationship between specific types of repetitive behaviors and sleep problems may allow providers to tailor interventions to the individual presentations of their patients with ASD. C1 [Hundley, Rachel J.] Vanderbilt Univ, Sch Med, Dept Pediat, Div Dev Med, 11101 Doctors Off Tower, Nashville, TN 37232 USA. [Shui, Amy] Massachusetts Gen Hosp, Ctr Biostat, 50 Staniford St,Suite 560, Boston, MA 02114 USA. [Malow, Beth A.] Vanderbilt Univ, Med Ctr, Sch Med, Sleep Disorders Div,Dept Neurol, A-0118 MCN, Nashville, TN 37232 USA. RP Hundley, RJ (reprint author), Vanderbilt Univ, Sch Med, Dept Pediat, Div Dev Med, 11101 Doctors Off Tower, Nashville, TN 37232 USA. EM Rachel.j.hundley@vanderbilt.edu FU Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) [UA3 MC11054] FX This project is/was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under cooperative agreement UA3 MC11054-Autism Intervention Research Network on Physical Health. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. This work was conducted through the Autism Speaks Autism Treatment Network serving as the autism intervention research network on physical health. NR 49 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD NOV PY 2016 VL 46 IS 11 BP 3448 EP 3457 DI 10.1007/s10803-016-2884-4 PG 10 WC Psychology, Developmental SC Psychology GA EA7BI UT WOS:000386782700006 PM 27511195 ER PT J AU Eichler, FS Cox, TM Crombez, E Christine i Dali Kohlschutter, A AF Eichler, Florian S. Cox, Timothy M. Crombez, Eric Christine i Dali Kohlschuetter, Alfried TI Metachromatic Leukodystrophy: An Assessment of Disease Burden SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE metachromatic leukodystrophy; burden of illness; quality of life; caregivers; survey ID LIFE-LIMITING CONDITIONS; CHILDREN; FAMILIES AB Metachromatic leukodystrophy is accompanied by severe motor and cognitive dysfunction. This is the first survey of metachromatic leukodystrophy caregiver perspectives to identify relevant clinical/quality-of-life outcomes for patients/caregivers. Interviews and 1 focus group were conducted with 30 caregivers representing 23 patients. Caregivers were asked about their experiences, including diagnostic process, signs/symptoms, symptoms affecting caregivers' and patients' lives, and treatment priorities. Caregivers reported loss of physical autonomy, weight loss, limited social relationships, frequent crying, and challenging sibling relationships. Most troublesome symptoms were immobility (9/30) and respiratory difficulties (6/30). Health care visits were frequent: 8/22 patients had experienced 11 hospitalizations since diagnosis, and 14/22 caregivers reported that these lasted 4 days. Caregivers also experienced work problems, feelings of fear/sadness, and loss of social relationships. Caregivers/physicians consider a therapy that could improve decline in mobility, pain, cognitive ability, communication, or food intake as conferring the greatest benefit. In conclusion, a so-far-unreported physical/economic burden in these families is presented. C1 [Eichler, Florian S.] Massachusetts Gen Hosp, Dept Neurol, Ste 820,165 Cambridge St, Boston, MA 02114 USA. [Cox, Timothy M.] Univ Cambridge, Addenbrookes Cambridge Univ Hosp, Dept Med, Cambridge, England. [Crombez, Eric] Shire, Lexington, MA USA. [Christine i Dali] Rigshosp, Dept Clin Genet, Copenhagen, Denmark. [Kohlschuetter, Alfried] Univ Hosp Hamburg Eppendorf, Dept Pediat, Hamburg, Germany. RP Eichler, FS (reprint author), Massachusetts Gen Hosp, Dept Neurol, Ste 820,165 Cambridge St, Boston, MA 02114 USA. EM feichler@partners.org FU Shire FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This survey was funded by Shire. NR 14 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2016 VL 31 IS 13 BP 1457 EP 1463 DI 10.1177/0883073816656401 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DZ3KQ UT WOS:000385745900002 PM 27389394 ER PT J AU Massaad, MJ Zhou, J Tsuchimoto, D Chou, J Jabara, H Janssen, E Glauzy, S Olson, BG Morbach, H Ohsumi, TK Schmitz, K Kyriacos, M Kane, J Torisu, K Nakabeppu, Y Notarangelo, LD Chouery, E Megarbane, A Kang, PB Al-Idrissi, E Aldhekri, H Meffre, E Mizui, M Tsokos, GC Manis, JP Al-Herz, W Wallace, SS Geha, RS AF Massaad, Michel J. Zhou, Jia Tsuchimoto, Daisuke Chou, Janet Jabara, Haifa Janssen, Erin Glauzy, Salome Olson, Brennan G. Morbach, Henner Ohsumi, Toshiro K. Schmitz, Klaus Kyriacos, Markianos Kane, Jennifer Torisu, Kumiko Nakabeppu, Yusaku Notarangelo, Luigi D. Chouery, Eliane Megarbane, Andre Kang, Peter B. Al-Idrissi, Eman Aldhekri, Hasan Meffre, Eric Mizui, Masayuki Tsokos, George C. Manis, John P. Al-Herz, Waleed Wallace, Susan S. Geha, Raif S. TI Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID AUTOREACTIVE B-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLI ENDONUCLEASE III; DNA GLYCOSYLASE NEIL1; DOUBLE-STRANDED-RNA; REGULATORY T-CELLS; LRBA DEFICIENCY; HUMAN HOMOLOG; OGG1 GENE; IMMUNE DYSREGULATION AB Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3(-/-) mice. Although Neil3(-/-) mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3(-/-) mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity. C1 [Massaad, Michel J.; Chou, Janet; Jabara, Haifa; Janssen, Erin; Kane, Jennifer; Notarangelo, Luigi D.; Geha, Raif S.] Boston Childrens Hosp, Div Immunol, Karp Family Res Bldg,One Blackfan Circle, Boston, MA 02115 USA. [Massaad, Michel J.; Chou, Janet; Jabara, Haifa; Janssen, Erin; Kane, Jennifer; Notarangelo, Luigi D.; Geha, Raif S.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Zhou, Jia; Wallace, Susan S.] Univ Vermont, Dept Microbiol & Mol Genet, Burlington, VT 05405 USA. [Tsuchimoto, Daisuke; Torisu, Kumiko; Nakabeppu, Yusaku] Kyushu Univ, Med Inst Biaregulat, Div Neurofunct Gen, Fukuoka, Japan. [Glauzy, Salome; Olson, Brennan G.; Morbach, Henner; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Ohsumi, Toshiro K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Schmitz, Klaus; Kyriacos, Markianos] Boston Childrens Hosp, Dept Genet, Boston, MA USA. [Chouery, Eliane; Megarbane, Andre] Univ St Joseph, Fac Med, Unite Genet Med, Beirut, Lebanon. [Kang, Peter B.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Kang, Peter B.] Harvard Med Sch, Boston, MA USA. [Al-Idrissi, Eman] King Fahad Med City, Dept Pediat, Riyadh, Saudi Arabia. [Aldhekri, Hasan] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh, Saudi Arabia. [Tsokos, George C.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Manis, John P.] Boston Childrens Hosp, Dept Pathol, Div Transfus Med, Boston, MA USA. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Al-Herz, Waleed] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait, Kuwait. RP Geha, RS (reprint author), Boston Childrens Hosp, Div Immunol, Karp Family Res Bldg,One Blackfan Circle, Boston, MA 02115 USA. EM raif.geha@childrens.harvard.edu RI Nakabeppu, Yusaku/A-8902-2011; Zhou, Jia/C-5940-2017; OI Zhou, Jia/0000-0002-2156-0483; Mizui, Masayuki/0000-0003-2543-8108 FU Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010]; Boston Children's Hospital Investigatorship Award; Perkins Fund; Dubai-Harvard Foundation for Medical research; Kuwait Foundation for the Advancement of Sciences [2010-1302-05]; NIH National Cancer Institute [P01098993]; Japan Society for the Promotion of Science [22221004]; National Institute of Allergy and Infectious Diseases (NIAID) [AI061093] FX We thank the patients, their families, and all blood donors for their cooperation. The authors thank those involved with the NHLBI GO Exome Sequencing Project, the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), the Heart GO Sequencing Project (HL-103010), the Exome Aggregation Consortium, and the groups that provided exome variant data for comparison (http://exac.broadinstitute.org/about). This work was supported by a Boston Children's Hospital Investigatorship Award (to MJM), grants from the Perkins Fund and the Dubai-Harvard Foundation for Medical research (to RSG), the Kuwait Foundation for the Advancement of Sciences (2010-1302-05 to WAH), the NIH National Cancer Institute (P01098993 to SSW), the Japan Society for the Promotion of Science (22221004 to YN), and the National Institute of Allergy and Infectious Diseases (NIAID) (AI061093 to EM). NR 82 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2016 VL 126 IS 11 BP 4219 EP 4236 DI 10.1172/JCI85647 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EA9VN UT WOS:000386992900015 PM 27760045 ER PT J AU Miraflor, AP LeBoit, PE Hirschman, SA AF Miraflor, Allen P. LeBoit, Philip E. Hirschman, Scott A. TI Intraepidermal Merkel cell carcinoma with pagetoid Bowen's disease SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Editorial Material DE cutaneous neoplasm; squamous cell carcinoma in-situ; non-melanoma skin cancer; skin tumors; UV stress ID IN-SITU; NEUROENDOCRINE CARCINOMA; POLYOMAVIRUS; SKIN C1 [Miraflor, Allen P.] Dartmouth Hitchcock Med Ctr, Dept Pathol, 1 Med Ctr Dr, Lebanon, NH 03766 USA. [LeBoit, Philip E.] Univ Calif San Francisco, Dept Dermatopathol, 1701 Divisadero St,Suite 280, San Francisco, CA 94115 USA. [Hirschman, Scott A.] US Dept Vet Affairs, Dept Pathol, 215 N Main St, White River Jct, VT 05009 USA. RP Hirschman, SA (reprint author), US Dept Vet Affairs, Dept Pathol, 215 N Main St, White River Jct, VT 05009 USA. EM Scott.Hirschman@va.gov NR 26 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6987 EI 1600-0560 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD NOV PY 2016 VL 43 IS 11 BP 921 EP 926 DI 10.1111/cup.12813 PG 6 WC Dermatology; Pathology SC Dermatology; Pathology GA EA7AC UT WOS:000386779400001 PM 27758029 ER PT J AU Clark, SL Tse, JY Fisher, DC LeBeouf, NR Murphy, GF Kupper, TS Clark, RA Lian, CG AF Clark, Stacie L. Tse, Julie Y. Fisher, David C. LeBeouf, Nicole R. Murphy, George F. Kupper, Thomas S. Clark, Rachael A. Lian, Christine G. TI Histopathologic spectrum of hypersensitivity reactions associated with anti-CD52 therapy (alemtuzumab) SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article DE alemtuzumab; CD52; CLL; CTCL; hypersensitivity ID T-CELL; MALIGNANCIES; SKIN AB BackgroundAlemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface antigen on B and T lymphocytes, and used to treat B-cell chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Skin rash is a common adverse reaction following treatment with alemtuzumab. However, the clinicopathologic features and immunologic basis for the reaction have not been previously reported. MethodsOur hospital's electronic pathology database was searched for cases with documentation of alemtuzumab' or anti-CD52' in the clinical history provided by either the ordering physician or the pathologist. Clinical and histopathologic review of the cases was performed. ResultsFive patients with cutaneous T-cell lymphoma (CTCL) or chronic lymphocytic leukemia (CLL) were treated with alemtuzumab, and developed pruritic, erythematous papules and plaques. Histopathology of the skin lesions revealed subacute spongiotic dermatitis with multifocal parakeratosis, endothelial activation and perivascular lymphocytic infiltrate. Eosinophils were not a prominent feature. ConclusionsWe describe the clinicopathologic features of a novel hypersensitivity reaction to alemtuzumb, and hypothesize it may be due to an immunologic response precipitated by the persistence of resident memory T-cells (T-RM) in the skin. Our findings raise awareness for a novel reaction pattern and guide the histopathologic interpretation of lesions which may clinically mimic residual or recurrent cutaneous lymphoproliferative disorders. C1 [Clark, Stacie L.; Murphy, George F.; Lian, Christine G.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Program Dermatopathol, Boston, MA USA. [Clark, Stacie L.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. [Tse, Julie Y.] Tufts Sch Med, Dept Pathol, Tufts Med Ctr, Boston, MA USA. [Fisher, David C.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [LeBeouf, Nicole R.; Kupper, Thomas S.; Clark, Rachael A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA. RP Lian, CG (reprint author), Brigham & Womens Hosp, 221 Longwood Ave,EBRC 401, Boston, MA 02115 USA. EM cglian@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6987 EI 1600-0560 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD NOV PY 2016 VL 43 IS 11 BP 989 EP 993 DI 10.1111/cup.12800 PG 5 WC Dermatology; Pathology SC Dermatology; Pathology GA EA7AC UT WOS:000386779400010 PM 27531597 ER PT J AU Alqaderi, H Tavares, M Hartman, M Goodson, JM AF Alqaderi, H. Tavares, M. Hartman, M. Goodson, J. M. TI Effect of Sleep and Salivary Glucose on Gingivitis in Children SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE salivary physiology; epidemiology; pediatrics; inflammation; lifestyle; oral-systemic disease ID PERIODONTAL-DISEASE; ORAL HYGIENE; SHIFT WORK; RISK; ADOLESCENTS; DURATION; OBESITY; INDEXES; NIGHT; EPIDEMIOLOGY AB It has been shown that inadequate sleep has deleterious effects on health by suppressing immunity and promoting inflammation. The aim of this study was to investigate the effect of sleep and salivary glucose levels on the development of gingivitis in a prospective longitudinal study of Kuwaiti children. Data were collected from 10-y-old children (N = 6,316) in 2012 and again in 2014. Children were approximately equally distributed from 138 elementary schools representing the 6 governorates of Kuwait. Calibrated examiners conducted oral examination, self-reported sleep evaluation interviews, anthropomorphic measurements, and unstimulated whole saliva sample collection. Salivary glucose levels were measured by a florescent glucose oxidase method; values of salivary glucose 1.13 mg/dL were defined as high glucose levels. A multilevel random intercept and slope analysis was conducted to determine the relationship between sleep duration and gingivitis on 3 levels: within schools, among children, and over time. The outcome was the progression of the extent of gingival inflammation in children over time. The main independent variables were the number of daily sleep hours and salivary glucose levels. Other explanatory variables and confounders assessed were governorate, dental caries and restorations, and obesity by waist circumference (adjusted for snacking and sex). Gingivitis increased over time in children who had shorter sleep duration (P < 0.05). Salivary glucose levels >1.13 mg/dL predicted gingivitis (P < 0.05). Children who had more decayed or filled teeth had more gingivitis (P < 0.05). No significant association was found between gingivitis and obesity. The level of gingivitis was different among the 6 governorates of Kuwait. Additionally, there was a strong clustering effect of the observations within schools and among children across time. Longitudinal analysis of 6,316 Kuwaiti children revealed that shorter sleep duration and higher salivary glucose levels were both associated with increased gingival inflammation. C1 [Alqaderi, H.; Tavares, M.] Harvard Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. [Tavares, M.; Hartman, M.; Goodson, J. M.] Forsyth Res Inst, Dept Appl Oral Sci, Cambridge, MA USA. RP Alqaderi, H (reprint author), Harvard Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. EM dr.hend.q@gmail.com FU Dasman Diabetes Institute in Kuwait [RA/065/2011, RA/005/2011] FX The present study was funded by the Dasman Diabetes Institute in Kuwait (RA/065/2011 and RA/005/2011). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 43 TC 0 Z9 0 U1 6 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2016 VL 95 IS 12 BP 1387 EP 1393 DI 10.1177/0022034516661509 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EA8UR UT WOS:000386915100010 PM 27470068 ER PT J AU Dawson, AL Tinker, SC Jamieson, DJ Hobbs, CA Berry, RJ Rasmussen, SA Anderka, M Keppler-Noreuil, KM Lin, AE Reefhuis, J AF Dawson, April L. Tinker, Sarah C. Jamieson, Denise J. Hobbs, Charlotte A. Berry, R. J. Rasmussen, Sonja A. Anderka, Marlene Keppler-Noreuil, Kim M. Lin, Angela E. Reefhuis, Jennita CA Natl Birth Defects Prevention TI Twinning and major birth defects, National Birth Defects Prevention Study, 1997-2007 SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID ASSISTED REPRODUCTIVE TECHNOLOGY; MULTIPLE BIRTHS; INCREASED RISK; UNITED-STATES; MATERNAL AGE; YOUNG TWINS; QUESTIONNAIRE; EPIDEMIOLOGY; ASSOCIATION; ANOMALIES AB Background Twinning has been associated with many types of birth defects, although previous studies have had inconsistent findings. Many studies lack information about potential confounders, particularly use of fertility treatment. Our objective was to assess the association between twinning and birth defects in the National Birth Defects Prevention Study (NBDPS). Methods We used data from the NBDPS, a population-based, case-control study of major birth defects in the USA, to evaluate associations between twinning and birth defects. The study population included mothers of twin and singleton controls (live-born infants without major birth defects), and cases (fetuses or infants with a major birth defect) born October 1997-December 2007. Adjusted ORs and 95% CIs were estimated using multivariable logistic regression stratified by use of fertility treatment. Twin sex-pairing data and a simulation approach were used to estimate the zygosity of twins. Results In the unassisted conception stratum, we observed significant positive associations between twinning and 29 of 45 defect groups. The largest effect estimates were observed for multiple ventricular septal defects and cloacal exstrophy. Among mothers reporting any use of fertility treatments, we observed a significant association with twinning for 5 of 25 defect groups, with the largest effect estimates for hypoplastic left heart syndrome and omphalocele. OR estimates in the estimated monozygotic stratum were generally further from the null than in the dizygotic stratum. Conclusions Compared with singletons, a wide range of birth defects are significantly more common among twins. Birth defect risk in twins may be differential by use of fertility treatment. C1 [Dawson, April L.; Tinker, Sarah C.; Berry, R. J.; Reefhuis, Jennita] CDC, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd,MS-E86, Atlanta, GA 30333 USA. [Jamieson, Denise J.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Hobbs, Charlotte A.] Univ Arkansas Med Sci, Coll Med, Fayetteville, AR USA. [Rasmussen, Sonja A.] CDC, Off Infect Dis, Atlanta, GA 30333 USA. [Anderka, Marlene; Lin, Angela E.] Massachusetts Ctr Birth Defects Res & Prevent, Boston, MA USA. [Keppler-Noreuil, Kim M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. RP Dawson, AL (reprint author), CDC, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd,MS-E86, Atlanta, GA 30333 USA. EM isp3@cdc.gov FU Intramural CDC HHS [CC999999] NR 27 TC 0 Z9 0 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD NOV PY 2016 VL 70 IS 11 BP 1114 EP 1121 DI 10.1136/jech-2015-206302 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EA3PP UT WOS:000386516300009 PM 27325867 ER PT J AU Herzig, SJ Schnipper, JL Doctoroff, L Kim, CS Flanders, SA Robinson, EJ Ruhnke, GW Thomas, L Kripalani, S Lindenauer, PK Williams, MV Metlay, JP Auerbach, AD AF Herzig, Shoshana J. Schnipper, Jeffrey L. Doctoroff, Lauren Kim, Christopher S. Flanders, Scott A. Robinson, Edmondo J. Ruhnke, Gregory W. Thomas, Larissa Kripalani, Sunil Lindenauer, Peter K. Williams, Mark V. Metlay, Joshua P. Auerbach, Andrew D. TI Physician Perspectives on Factors Contributing to Readmissions and Potential Prevention Strategies: A Multicenter Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE readmissions; physician opinion; survey; causes; prevention ID HOSPITAL READMISSIONS; PATIENT ACTIVATION; TRANSITIONAL CARE; KAPPA; INTERVENTIONS; HOME AB The transition out of the hospital is a vulnerable time for patients, relying heavily on communication and coordination of resources across care settings. Understanding the perspectives of inpatient and outpatient physicians regarding factors contributing to readmission and potential preventive strategies is crucial in designing appropriately targeted readmission prevention efforts. To examine and compare inpatient and outpatient physician opinions regarding reasons for readmission and interventions that might have prevented readmission. Cross-sectional multicenter study. We identified patients readmitted to general medicine services within 30 days of discharge at 12 US academic medical centers, and surveyed the primary care physician (PCP), discharging physician from the index admission, and admitting physician from the readmission regarding their endorsement of pre-specified factors contributing to the readmission and potential preventive strategies. We calculated kappa statistics to gauge agreement between physician dyads (PCP-discharging physician, PCP-admitting physician, and admitting-discharging physician). We evaluated 993 readmission events, which generated responses from 356 PCPs (36 % of readmissions), 675 discharging physicians (68 % of readmissions), and 737 admitting physicians (74 % of readmissions). The most commonly endorsed contributing factors by both PCPs and inpatient physicians related to patient understanding and ability to self-manage. The most commonly endorsed preventive strategies involved providing patients with enhanced post-discharge instructions and/or support. Although PCPs and inpatient physicians endorsed contributing factors and potential preventive strategies with similar frequencies, agreement among the three physicians on the specific factors and/or strategies that applied to individual readmission events was poor (maximum kappa 0.30). Differing opinions among physicians on factors contributing to individual readmissions highlights the importance of communication between inpatient and outpatient providers at discharge to share their different perspectives, and suggests that multi-faceted, broadly applied interventions may be more successful than those that rely on individual providers choosing specific services based on perceived risk factors. C1 [Herzig, Shoshana J.; Doctoroff, Lauren] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. [Herzig, Shoshana J.; Schnipper, Jeffrey L.; Doctoroff, Lauren] Harvard Med Sch, Boston, MA USA. [Schnipper, Jeffrey L.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Hospitalist Serv, 75 Francis St, Boston, MA 02115 USA. [Kim, Christopher S.; Flanders, Scott A.] Univ Michigan, Sch Med, Div Gen Med, Ann Arbor, MI USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Value Inst, Wilmington, DE USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Dept Med, Wilmington, DE USA. [Ruhnke, Gregory W.] Univ Chicago, Dept Med, Sect Hosp Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Thomas, Larissa] San Francisco Gen Hosp, Div Hosp Med, San Francisco, CA 94110 USA. [Thomas, Larissa] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kripalani, Sunil] Vanderbilt Univ, Sect Hosp Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Kripalani, Sunil] Vanderbilt Univ, Ctr Clin Qual & Implementat Res, 221 Kirkland Hall, Nashville, TN 37235 USA. [Lindenauer, Peter K.] Baystate Med Ctr, Ctr Qual Care Res, Springfield, MA USA. [Lindenauer, Peter K.] Baystate Med Ctr, Dept Med, Springfield, MA 01199 USA. [Williams, Mark V.] Univ Kentucky, Ctr Hlth Serv Res, Lexington, KY USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Auerbach, Andrew D.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. RP Herzig, SJ (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM sherzig@bidmc.harvard.edu OI Robinson, Edmondo/0000-0001-9625-6235 FU American Association of Medical Colleges; National Center for Advancing Translational Sciences [2 UL1 TR000445-06]; NHLBI [K24HL098372]; NIA [K23AG042459] FX The study was funded through an unrestricted research grant from the American Association of Medical Colleges, and in part by 2 UL1 TR000445-06 from the National Center for Advancing Translational Sciences. Dr. Auerbach was supported by NHLBI K24HL098372, and Dr. Herzig was supported by NIA K23AG042459. The funding organizations had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. NR 20 TC 4 Z9 4 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1287 EP 1293 DI 10.1007/s11606-016-3764-5 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200010 PM 27282857 ER PT J AU Axon, RN Gebregziabher, M Dismuke, CE Hunt, KJ Yeager, D Ana, EJS Egede, LE AF Axon, R. Neal Gebregziabher, Mulugeta Dismuke, Clara E. Hunt, Kelly J. Yeager, Derik Ana, Elizabeth J. Santa Egede, Leonard E. TI Differential Impact of Homelessness on Glycemic Control in Veterans with Type 2 Diabetes Mellitus SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE diabetes mellitus; homelessness; healthcare disparities; access to care; Veterans ID EMERGENCY-DEPARTMENTS; HEALTH SYSTEM; LOS-ANGELES; ADULTS; CARE; INDIVIDUALS; PREVALENCE; DISEASE AB Veterans with evidence of homelessness have high rates of mental health and substance abuse disorders, but chronic medical conditions such as diabetes are also prevalent. We aimed to determine the impact of homelessness on glycemic control in patients with type 2 diabetes mellitus. Longitudinal analysis of a retrospective cohort. A national cohort of 1,263,906 Veterans with type 2 diabetes. Subjects with evidence of homelessness were identified using a combination of diagnostic and administrative codes. Odds for poor glycemic control using hemoglobin A1C (HbA1C) cutoff values of 8 % and 9 %. Homeless defined as a score based on the number of indicator variables for homelessness within a veterans chart. Veterans with evidence of homelessness had a significantly greater annual mean HbA1C aeyen 8 (32.6 % vs. 20.43 %) and HbA1C aeyen 9 (21.4 % vs. 9.9 %), tended to be younger (58 vs. 67 years), were more likely to be non-Hispanic black (39.1 %), divorced (43 %) or never married (34 %), to be urban dwelling (88.8 %), and to have comorbid substance abuse (46.7 %), depression (42.3 %), psychoses (39.7 %), liver disease (18.8 %), and fluid/electrolyte disorders (20.4 %), relative to non-homeless veterans (all p < 0.0001). Homelessness was modeled as an ordinal variable that scored the number of times a homelessness indicator was found in the Veterans medical record. We observed a significant interaction between homelessness and race/ethnicity on the odds of poor glycemic control. Homelessness, across all racial-ethnic groups, was associated with increased odds of uncontrolled diabetes at a cut-point of 8 % and 9 % for hemoglobin A1C ; however, the magnitude of the association was greater in non-Hispanic whites [8 %, OR 1.55 (1.47;1.63)] and Hispanics [8 %, OR 2.11 (1.78;2.51)] than in non-Hispanic blacks [8 %, OR 1.22 (1.15;1.28)]. Homelessness is a significant risk factor for uncontrolled diabetes in Veterans, especially among non-Hispanic white and Hispanic patients. While efforts to engage homeless patients in primary care services have had some success in recent years, these data suggest that broader efforts targeting management of diabetes and other chronic medical conditions remain warranted. C1 [Axon, R. Neal; Gebregziabher, Mulugeta; Dismuke, Clara E.; Hunt, Kelly J.; Yeager, Derik; Ana, Elizabeth J. Santa; Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Charleston Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. [Axon, R. Neal; Dismuke, Clara E.] Med Univ South Carolina, Div Gen Internal Med, Dept Med, Charleston, SC USA. [Gebregziabher, Mulugeta; Hunt, Kelly J.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Ana, Elizabeth J. Santa] Med Univ South Carolina, Dept Psychiat, Charleston, SC USA. [Egede, Leonard E.] Med Univ South Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,MSC 593, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ South Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,MSC 593, Charleston, SC 29425 USA. EM egedel@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU VHA Health Services Research and Development (HSRD) program [IIR-06-219] FX This study was supported by grant #IIR-06-219 funded by the VHA Health Services Research and Development (HSR&D) program (PI: Leonard Egede). The funding agency did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The manuscript represents the views of the authors and not those of the VA or HSR&D. NR 45 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1331 EP 1337 DI 10.1007/s11606-016-3786-z PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200016 PM 27418346 ER PT J AU Jacobs, EA Walker, CM Miller, T Fletcher, KE Ganschow, PS Imbert, D O'Connell, M Neuner, JM Schapira, MM AF Jacobs, Elizabeth A. Walker, Cindy M. Miller, Tamara Fletcher, Kathlyn E. Ganschow, Pamela S. Imbert, Diana O'Connell, Maria Neuner, Joan M. Schapira, Marilyn M. TI Development and Validation of the Spanish Numeracy Understanding in Medicine Instrument SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cross cultural research; health numeracy; health literacy; measurement; Spanish language ID FUNCTIONAL HEALTH LITERACY; ITEM RESPONSE THEORY; RISK COMMUNICATIONS; PRIMARY-CARE; SCALE; INFORMATION; FRAMEWORK; SKILLS; COMPREHENSION; ASSOCIATION AB The Spanish-speaking population in the U.S. is large and growing and is known to have lower health literacy than the English-speaking population. Less is known about the health numeracy of this population due to a lack of health numeracy measures in Spanish. we aimed to develop and validate a short and easy to use measure of health numeracy for Spanish-speaking adults: the Spanish Numeracy Understanding in Medicine Instrument (Spanish-NUMi). Items were generated based on qualitative studies in English- and Spanish-speaking adults and translated into Spanish using a group translation and consensus process. Candidate items for the Spanish NUMi were selected from an eight-item validated English Short NUMi. Differential Item Functioning (DIF) was conducted to evaluate equivalence between English and Spanish items. Cronbach's alpha was computed as a measure of reliability and a Pearson's correlation was used to evaluate the association between test scores and the Spanish Test of Functional Health Literacy (S-TOFHLA) and education level. Two-hundred and thirty-two Spanish-speaking Chicago residents were included in the study. The study population was diverse in age, gender, and level of education and 70 % reported Mexico as their country of origin. Two items of the English eight-item Short NUMi demonstrated DIF and were dropped. The resulting six-item test had a Cronbach's alpha of 0.72, a range of difficulty using classical test statistics (percent correct: 0.48 to 0.86), and adequate discrimination (item-total score correlation: 0.34-0.49). Scores were positively correlated with print literacy as measured by the S- TOFHLA (r = 0.67; p < 0.001) and varied as predicted across grade level; mean scores for up to eighth grade, ninth through twelfth grade, and some college experience or more, respectively, were 2.48 (SD +/- 1.64), 4.15 (SD +/- 1.45), and 4.82 (SD +/- 0.37). The Spanish NUMi is a reliable and valid measure of important numerical concepts used in communicating health information. C1 [Jacobs, Elizabeth A.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Walker, Cindy M.; Miller, Tamara] Univ Wisconsin, Dept Educ Psychol, Milwaukee, WI 53201 USA. [Fletcher, Kathlyn E.; Neuner, Joan M.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Fletcher, Kathlyn E.; Neuner, Joan M.] Zablocki VA Med Ctr, Milwaukee, WI USA. [Ganschow, Pamela S.; O'Connell, Maria] Rush Univ, Sch Med, Dept Med, Chicago, IL 60612 USA. [Imbert, Diana; Schapira, Marilyn M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res Program, Philadelphia, PA USA. RP Jacobs, EA (reprint author), Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 USA. EM eajacobs@medicine.wisc.edu RI imbert, daniel/H-7850-2014 FU National Cancer Institute of the National Institutes of Health [NC1R01CA115954]; American Cancer Society [121158-RSG-11-104-01-CPPB] FX This work was supported by grants from the National Cancer Institute of the National Institutes of Health NC1R01CA115954 and the American Cancer Society 121158-RSG-11-104-01-CPPB. NR 48 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1345 EP 1352 DI 10.1007/s11606-016-3759-2 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200018 PM 27312095 ER PT J AU McNamara, M Batur, P Walsh, JME Johnson, KM AF McNamara, Megan Batur, Pelin Walsh, Judith M. E. Johnson, Kay M. TI HPV Update: Vaccination, Screening, and Associated Disease SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE HPV; vaccination; screening; cervical cancer; prevention ID HUMAN-PAPILLOMAVIRUS INFECTION; CERVICAL-CANCER; INTRAEPITHELIAL NEOPLASIA; UNITED-STATES; WOMEN; METAANALYSIS; PREVALENCE; GUIDELINES; RECOMMENDATIONS; PREDICTORS AB Human papillomavirus (HPV) infection is the causative agent in cervical cancer, and is associated with numerous other genital cancers, including vulvar, vaginal, and anal cancer. Primary prevention with HPV vaccination is safe and efficacious, and a recently approved HPV vaccine will provide even more extensive protection against several oncogenic HPV strains. Screening strategies for HPV are rapidly evolving, reflecting the essential role that HPV infection plays in cervical cancer. This article highlights new evidence regarding the efficacy of the recently approved 9-valent HPV (9vHPV) vaccine and the use of primary high-risk HPV testing in cervical cancer screening. We consider the utility of urinary HPV testing in routine clinical practice and review current guidelines regarding anal HPV screening. C1 [McNamara, Megan] Case Western Reserve Univ, Sch Med, Dept Med, 10701 East Blvd, Cleveland, OH 44106 USA. [McNamara, Megan] Louis Stokes Cleveland Vet Affairs Med Ctr, 10701 East Blvd, Cleveland, OH 44106 USA. [Batur, Pelin] Cleveland Clin, Dept Med & Primary Care Womens Hlth, Cleveland, OH 44106 USA. [Walsh, Judith M. E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Walsh, Judith M. E.] Univ Calif San Francisco, Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA. [Johnson, Kay M.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Johnson, Kay M.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP McNamara, M (reprint author), Case Western Reserve Univ, Sch Med, Dept Med, 10701 East Blvd, Cleveland, OH 44106 USA.; McNamara, M (reprint author), Louis Stokes Cleveland Vet Affairs Med Ctr, 10701 East Blvd, Cleveland, OH 44106 USA. EM megan.mcnamara@va.gov NR 32 TC 0 Z9 0 U1 17 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1360 EP 1366 DI 10.1007/s11606-016-3725-z PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200026 PM 27184752 ER PT J AU Blackburn, R Estrada, CA McCollum, D AF Blackburn, Reaford, Jr. Estrada, Carlos A. McCollum, David TI Empathy as a Diagnostic Tool in a 33-Year-Old Man with Eye Pain and Vision Loss: Exercises in Clinical Reasoning SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE clinical reasoning; empathy; uveitis; syphilis; HIV infection ID CARE; SPECTRUM; MEDICINE; SYPHILIS; ERRORS C1 [Blackburn, Reaford, Jr.] Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, Birmingham, AL USA. [Estrada, Carlos A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.; McCollum, David] Univ Alabama Birmingham, 720 Fac Off Tower,510 20th St South, Birmingham, AL 35294 USA. RP Estrada, CA (reprint author), Univ Alabama Birmingham, 720 Fac Off Tower,510 20th St South, Birmingham, AL 35294 USA. EM cestrada@uabmc.edu NR 13 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1389 EP 1392 DI 10.1007/s11606-016-3797-9 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200031 PM 27456235 ER PT J AU Mihara, K AF Mihara, Kip TI Omphalolith: An Umbilical Concretion to Recognize SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE clinical image; dermatology; dementia C1 [Mihara, Kip] San Francisco VA Med Ctr, Emergency Dept, 4150 Clement St,Mail Code 111A3, San Francisco, CA 94121 USA. [Mihara, Kip] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. RP Mihara, K (reprint author), San Francisco VA Med Ctr, Emergency Dept, 4150 Clement St,Mail Code 111A3, San Francisco, CA 94121 USA. EM kip.mihara@va.gov NR 3 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2016 VL 31 IS 11 BP 1396 EP 1396 DI 10.1007/s11606-016-3708-0 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EA5SL UT WOS:000386683200034 PM 27114363 ER PT J AU Xu, S Allred, J Kirsch, B Raff, A Anderson, RR Ju, W AF Xu, Shuai Allred, James Kirsch, Brandon Raff, Adam Anderson, R. Rox Ju, William TI Training the Next Generation of Innovators in Dermatology SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID MEDICAL INNOVATION; ENTREPRENEURSHIP C1 [Xu, Shuai] Northwestern Univ, Mcgaw Med Ctr, Dept Dermatol, 676 N St Clair St,Suite 1600, Chicago, IL 60611 USA. [Xu, Shuai; Allred, James; Kirsch, Brandon; Raff, Adam; Ju, William] Advancing Innovat Dermatol, Mendham, NJ USA. [Allred, James] Graves Gilbert Clin, Dept Dermatol, Bowling Green, KY USA. [Kirsch, Brandon] Univ North Carolina Chapel Hill, Dept Dermatol, Chapel Hill, NC USA. [Raff, Adam] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Raff, Adam; Anderson, R. Rox] Harvard Med Sch, Boston, MA USA. [Anderson, R. Rox] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Xu, S (reprint author), Northwestern Univ, Mcgaw Med Ctr, Dept Dermatol, 676 N St Clair St,Suite 1600, Chicago, IL 60611 USA. EM stevexu@northwestern.edu NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2016 VL 136 IS 11 BP 2113 EP 2115 DI 10.1016/j.jid.2016.08.028 PG 3 WC Dermatology SC Dermatology GA EB0CS UT WOS:000387011600004 PM 27772542 ER PT J AU Asgari, MM AF Asgari, Maryam M. TI Utility and Limitations of Large Population-Based Data for Skin Cancer Outcomes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID MULTIPLE PRIMARY RULES; MELANOMA; REGISTRIES; TRENDS AB Large population-based studies are useful for determining cancer outcomes, but interpreting their findings requires understanding their limitations. Youlden et al. highlight the utility of using a large dataset for studying melanoma survival, whereas Gimotty et al. point out the limitations of such datasets in miscoding thickness, a key prognostic variable. Awareness of limitations of population-based registry data can help to inform their interpretations and clinical implications. C1 [Asgari, Maryam M.] Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 230A, Boston, MA 02114 USA. [Asgari, Maryam M.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. RP Asgari, MM (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 230A, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 10 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2016 VL 136 IS 11 BP 2128 EP 2130 DI 10.1016/j.jid.2016.07.031 PG 3 WC Dermatology SC Dermatology GA EB0CS UT WOS:000387011600009 PM 27772547 ER PT J AU Wang, J Li, PY Wu, MX AF Wang, Ji Li, Peiyu Wu, Mei X. TI Natural STING Agonist as an "Ideal" Adjuvant for Cutaneous Vaccination SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CYCLIC GMP-AMP; C-DI-GMP; CYTOSOLIC DNA; INTRADERMAL DELIVERY; ANTIVIRAL DEFENSE; MUCOSAL ADJUVANT; CLASS-II; VACCINES; POTENT; 2ND-MESSENGER AB A potent adjuvant that induces strong protective immunity without incurring any significant skin reactogenicity is urgently needed for cutaneous vaccination. Here, we report that a natural agonist of stimulator of interferon genes (STING), 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), robustly augmented and prolonged the cellular and humoral immune responses provoked by H5N1 and 2009 H1N1 pandemic influenza vaccines after a single dose of intradermal, but not intramuscular, immunization. The potency of cGAMP for cutaneous vaccination was ascribed to a large number of antigen-presenting cells resident in the skin and ready for immediate activation when cGAMP was injected. However, its potency was severely compromised in the muscle, because antigen-presenting cells could not be promptly recruited to the injection site before the injected cGAMP was diffused out. The superior adjuvant effect and safety of cGAMP were also confirmed in a more clinically relevant swine model of skin. The vigorous immune responses elicited by cGAMP with no overt skin irritation was attributable to its stay in the skin, which was brief but sufficient to activate dermal dendritic cells. This small and well-characterized self-molecule holds great promise as an ideal adjuvant for cutaneous vaccination. C1 [Wang, Ji; Li, Peiyu; Wu, Mei X.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA USA. [Wu, Mei X.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Li, Peiyu] Fudan Univ, Key Lab Med Mol Virol, Sch Basic Med Sci, Minist Educ, Shanghai, Peoples R China. [Li, Peiyu] Fudan Univ, Key Lab Med Mol Virol, Sch Basic Med Sci, Minist Hlth, Shanghai, Peoples R China. [Li, Peiyu] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St,Edwards 222, Boston, MA 02114 USA. EM mwu5@mgh.harvard.edu NR 33 TC 2 Z9 2 U1 9 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2016 VL 136 IS 11 BP 2183 EP 2191 DI 10.1016/j.jid.2016.05.105 PG 9 WC Dermatology SC Dermatology GA EB0CS UT WOS:000387011600017 PM 27287182 ER PT J AU Golberg, A Villiger, M Khan, S Quinn, KP Lo, WCY Bouma, BE Mihm, MC Austen, WG Yarmush, ML AF Golberg, Alexander Villiger, Martin Khan, Saiqa Quinn, Kyle P. Lo, William C. Y. Bouma, Brett E. Mihm, Martin C., Jr. Austen, William G., Jr. Yarmush, Martin L. TI Preventing Scars after Injury with Partial Irreversible Electroporation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PULSED ELECTRIC-FIELDS; HYPERTROPHIC SCARS; BURN SCARS; ABLATION; KELOIDS; MODEL AB Preventing the formation of hypertrophic scars, especially those that are a result of major trauma or burns, would have enormous impact in the fields of regenerative and trauma medicine. In this report, we introduce a noninvasive method to prevent scarring based on nonthermal partial irreversible electroporation. Contact burn injuries in rats were treated with varying treatment parameters to optimize the treatment protocol. Scar surface area and structural properties of the scar were assessed with histology and non-invasive, longitudinal imaging with polarization-sensitive optical coherence tomography. We found that partial irreversible electroporation using 200 pulses of 250 V and 70 ms duration, delivered at 3 Hz every 20 days during a total of five therapy sessions after the initial burn injury, resulted in a 57.9% reduction of the scar area compared with untreated scars and structural features approaching those of normal skin. Unlike humans, rats do not develop hypertrophic scars. Therefore, the use of a rat animal model is the limiting factor of this work. C1 [Golberg, Alexander; Yarmush, Martin L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Ctr Engn Med, Boston, MA 02115 USA. [Golberg, Alexander; Yarmush, Martin L.] Shriners Burns Hosp, Boston, MA 02114 USA. [Golberg, Alexander] Tel Aviv Univ, Porter Sch Environm Studies, Tel Aviv, Israel. [Villiger, Martin; Lo, William C. Y.; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Villiger, Martin; Lo, William C. Y.; Bouma, Brett E.] Harvard Med Sch, 50 Blossom St, Boston, MA USA. [Khan, Saiqa; Austen, William G., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Dept Surg, Boston, MA USA. [Quinn, Kyle P.] Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA. [Lo, William C. Y.; Bouma, Brett E.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Mihm, Martin C., Jr.] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Golberg, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Ctr Engn Med, Boston, MA 02115 USA.; Golberg, A (reprint author), Shriners Burns Hosp, Boston, MA 02114 USA.; Golberg, A (reprint author), Tel Aviv Univ, Porter Sch Environm Studies, Tel Aviv, Israel. EM agolberg@tauex.tau.ac.il OI Lo, William Chun Yip/0000-0002-6562-088X NR 41 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2016 VL 136 IS 11 BP 2297 EP 2304 DI 10.1016/j.jid.2016.06.620 PG 8 WC Dermatology SC Dermatology GA EB0CS UT WOS:000387011600029 PM 27393126 ER PT J AU Podbielska, M Das, A Smith, AW Chauhan, A Ray, SK Inoue, J Azuma, M Nozaki, K Hogan, EL Banik, NL AF Podbielska, Maria Das, Arabinda Smith, Amena W. Chauhan, Ashok Ray, Swapan K. Inoue, Jun Azuma, Mitsuyoshi Nozaki, Kenkichi Hogan, Edward L. Banik, Naren L. TI Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE calpain; microglia; microgliosis; multiple sclerosis; neurodegeneration; neurons ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFLAMMATION-MEDIATED NEURODEGENERATION; PROVIDES FUNCTIONAL NEUROPROTECTION; MULTIPLE-SCLEROSIS; PARKINSONS-DISEASE; INTERFERON-GAMMA; REACTIVE MICROGLIOSIS; CYTOKINE PROFILE; OPTIC NEURITIS; AXONAL INJURY AB Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again. Thus, inflammation, neuronal damage, and microglia activation, i. e., bi-directional interaction between neurons and microglia, may be involved in the progressive neurodegeneration. We tested this hypothesis using two in vitro models: (i) the effects of soluble factors from damaged primary cortical neurons upon primary rat neurons and microglia and (ii) soluble factors released from CD3/CD28 activated peripheral blood mononuclear cells of MS patients on primary human neurons and microglia. The first model indicated that neurons due to injury with pro-inflammatory agents (IFN-c) release soluble neurotoxic factors, including COX-2, reactive oxygen species, and calpain, thus activating microglia, which in turn released neurotoxic factors as well. This repeated microglial activation leads to persistent inflammation and neurodegeneration. The released calpain from neurons and microglia was confirmed by the use of calpain inhibitor calpeptin or SNJ-1945 as well as mu- and m-calpain knock down using the small interfering RNA (siRNA) technology. Our second model using activated peripheral blood mononuclear cells, a source of proinflammatory Th1/Th17 cytokines and calpain released from auto-reactive T cells, corroborated similar results in human primary cell cultures and confirmed calpain to be involved in progressive MS. These insights into reciprocal paracrine regulation of cell injury and calpain activation in the progressive phase of MS, Parkinson's disease, and other neurodegenerative diseases suggest potentially beneficial preventive and therapeutic strategies, including calpain inhibition. C1 [Podbielska, Maria; Das, Arabinda; Smith, Amena W.; Hogan, Edward L.; Banik, Naren L.] Med Univ South Carolina, Dept Neurol & Neurosurg, 96 Jonathan Lucas St,309 CSB, Charleston, SC 29425 USA. [Podbielska, Maria; Banik, Naren L.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Podbielska, Maria] Polish Acad Sci, Ludwik Hirszfeld Inst Immunol & Expt Therapy, Lab Signaling Prot, Wroclaw, Poland. [Chauhan, Ashok; Ray, Swapan K.] Univ South Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC USA. [Azuma, Mitsuyoshi] Senju Pharmaceut Co LTD, Kobe, Hyogo, Japan. [Nozaki, Kenkichi] Univ Alabama Birmingham, Sch Med, Dept Neurol, Birmingham, AL USA. RP Banik, NL (reprint author), Med Univ South Carolina, Dept Neurol & Neurosurg, 96 Jonathan Lucas St,309 CSB, Charleston, SC 29425 USA. EM baniknl@musc.edu FU National Institute of Neurological Disorders - National Institutes of Health, Bethesda, MD, USA [NS-41088, NS-56176, NS-65456]; Veterans Affairs [5I01BX002349-02]; Kosciuszko Foundation; Polish-U.S Fulbright Commission FX We gratefully acknowledge the funding support in part by the R01 grants from the National Institute of Neurological Disorders - National Institutes of Health, Bethesda, MD, USA (NS-41088, NS-56176 and NS-65456); non-HHS Research Project (101) award from Veterans Affairs (5I01BX002349-02) for the work to NLB. Special thanks are to the Kosciuszko Foundation for the fellowship 2014/15 and to the Polish-U.S Fulbright Commission (2015/16 Senior Award Grant) to MP. The authors also thank Mrs. Katarzyna Izydorczyk for her excellent graphic skills in rendering the diagrams of the cell treatments and the Figure 8 depicting the mechanisms proposed for microglia-neuron interactions to drive progressive MS. We also thank Ms. Denise Matzelle for editorial assistance in the manuscript. The authors have no conflicting financial interests. Calpain inhibitor SNJ-1945 was obtained from Senju Pharmaceuticals, Kobe, Japan. NR 71 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2016 VL 139 IS 3 BP 440 EP 455 DI 10.1111/jnc.13774 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EB0ZO UT WOS:000387076000009 PM 27529445 ER PT J AU Cheng, LS Schwartz, DM Hotta, R Graham, HK Goldstein, AM AF Cheng, Lily S. Schwartz, Dana M. Hotta, Ryo Graham, Hannah K. Goldstein, Allan M. TI Bowel dysfunction following pullthrough surgery is associated with an overabundance of nitrergic neurons in Hirschsprung disease SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Hirschsprung disease; Constipation; Enteric nervous system; Myenteric plexus; Nitric oxide synthase; Calretinin ID QUALITY-OF-LIFE; NEUROTRANSMITTER EXPRESSION; MYENTERIC NEURONS; NITRIC-OXIDE; RISK-FACTORS; CHILDHOOD; MUSCLE; MICE AB Purpose: Recent evidence suggests that patients with Hirschsprung disease (HD) have abnormal neurotransmitter expression in the ganglionated proximal colon. These alterations may cause persistent bowel dysfunction even after pullthrough surgery. We sought to quantify the proportion of nitrergic neurons in the ganglionic colon of HD patients and relate these findings to functional outcome. Methods: The proximal resection margin from 17 patients with colonic HD who underwent a pullthrough procedure and colorectal tissue from 4 age-matched controls were immunohistochemically examined to quantify the proportion of nitrergic neurons. The incidence of constipation, incontinence, and enterocolitis in HD patients was assessed retrospectively and correlated with the proportion of nitric oxide synthase (NOS) expressing neurons. Neuronal subtypes in the ganglionic colon of the Edrnb(-/-) mouse model of HD were also studied. Results: Mice with HD had a significantly higher proportion of NOS+ neurons in ganglionic colon than normal littermates (32.0 +/- 5.6% vs. 19.8 +/- 1.2%, p < 0.01). Patients with HD also had significantly more NOS+ neurons than controls (18.4 +/- 4.6% vs. 13.1 +/- 1.9%, p < 0.01). Patients who experienced constipation or enterocolitis post-operatively tended toward a higher proportion of NOS+ neurons (21.4 +/- 3.9% vs. 17.1 +/- 4.1%, p = 0.06). Furthermore, patients with a proportion of NOS+ neurons above the median of all HD patients (18.3%) were significantly more likely to have constipation than those below the median (75% vs. 14%, p < 0.05). Conclusion: An overabundance of nitrergic neurons in the proximal resection margin is associated with HD and may predict bowel dysfunction following pullthrough surgery. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cheng, Lily S.; Schwartz, Dana M.; Hotta, Ryo; Graham, Hannah K.; Goldstein, Allan M.] Massachusetts Gen Hosp, Dept Surg, Div Pediat Surg, 55 Fruit St, Boston, MA 02114 USA. [Cheng, Lily S.] Univ Calif San Francisco, Dept Surg, 500 Parnassus Ave, San Francisco, CA 94143 USA. RP Goldstein, AM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM agoldstein@partners.org FU National Institutes of Health [R01DK103785]; Society of University Surgeons Resident Research Award FX This work was supported by the National Institutes of Health (R01DK103785 to A.M.G.) and the Society of University Surgeons Resident Research Award (to L.S.C.). NR 24 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 EI 1531-5037 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD NOV PY 2016 VL 51 IS 11 BP 1834 EP 1838 DI 10.1016/j.jpedsurg.2016.08.001 PG 5 WC Pediatrics; Surgery SC Pediatrics; Surgery GA EA4NH UT WOS:000386588900018 PM 27570241 ER PT J AU Farris, SG Metrik, J Bonn-Miller, MO Kahler, CW Zvolensky, MJ AF Farris, Samantha G. Metrik, Jane Bonn-Miller, Marcel O. Kahler, Christopher W. Zvolensky, Michael J. TI Anxiety Sensitivity and Distress Intolerance as Predictors of Cannabis Dependence Symptoms, Problems, and Craving: The Mediating Role of Coping Motives SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID MARIJUANA USE MOTIVES; COGNITIVE-BEHAVIORAL THERAPY; BREATH-HOLDING DURATION; EARLY SMOKING LAPSE; USE DISORDERS; INCREMENTAL VALIDITY; TOLERANCE TREATMENT; YOUNG-ADULTS; VALIDATION; ALCOHOL AB Objective: The tendency to react with fear to anxiety related sensations (anxiety sensitivity) and the inability to tolerate distressing psychological or physiological states (distress intolerance) are implicated in the comorbidity between affective psychopathology and cannabis use disorders. Emotionally vulnerable cannabis users may be particularly apt to use cannabis to cope with distress, which may both lead to and maintain its problematic use (e.g., dependence, craving). The current study tested a comprehensive model of anxiety sensitivity and distress intolerance as predictors of the number of cannabis dependence symptoms and problems, and severity of cannabis craving following deprivation from cannabis, and the mediating role of cannabis coping motives. Method: Participants (n = 103; mean age = 21.2 years, SD = 4.3; 35.9% female) were non treatment-seeking frequent cannabis users. Data were cross-sectional in nature. Anxiety sensitivity was assessed via self-report, and distress intolerance was assessed via both self-report and breath-holding duration. Results: Greater perceived distress intolerance, but not breath-holding duration or anxiety sensitivity, was associated with a greater number of cannabis dependence symptoms and problems and elevated cannabis craving. These relations were mediated by cannabis coping motives. Conclusions: Findings provide specificity for the etiologic mechanisms related to emotional vulnerability and maintenance of cannabis problems. Perceived distress intolerance appears to be uniquely related to maladaptive coping motives for cannabis use, which could be meaningfully targeted in interventions for emotionally vulnerable cannabis users. C1 [Farris, Samantha G.; Zvolensky, Michael J.] Univ Houston, Dept Psychol, Houston, TX USA. [Farris, Samantha G.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Metrik, Jane] Providence Vet Affairs Med Ctr, Providence, RI USA. [Metrik, Jane; Kahler, Christopher W.] Brown Univ, Sch Publ Hlth, Ctr Alcohol & Addict Studies, Box G-S121-4, Providence, RI 02912 USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Bonn-Miller, Marcel O.] Philadelphia VA Med Ctr, Ctr Excellence Subst Abuse Treatment & Educ, Philadelphia, PA USA. [Bonn-Miller, Marcel O.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. RP Metrik, J (reprint author), Brown Univ, Sch Publ Hlth, Ctr Alcohol & Addict Studies, Box G-S121-4, Providence, RI 02912 USA. EM Jane_Metrik@brown.edu FU National Institute on Drug Abuse [R03 DA027484, F31-DA035564-03]; Veterans Affairs Center of Excellence in Substance Abuse Treatment and Education FX This study was funded by National Institute on Drug Abuse Grant R03 DA027484, awarded to Jane Metrik and Valerie S. Knopik. Marcel O. Bonn Miller's work on this project was supported by the Veterans Affairs Center of Excellence in Substance Abuse Treatment and Education. Samantha G. Farris is supported by a pre-doctoral National Research Service Award from the National Institute on Drug Abuse (F31-DA035564-03). The funding sources had no role other than financial support. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 70 TC 0 Z9 0 U1 6 U2 6 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD NOV PY 2016 VL 77 IS 6 BP 889 EP 897 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA EA9TC UT WOS:000386986600006 PM 27797690 ER PT J AU Hill, MK Pishkenari, AK Braunberger, TL Armstrong, AW Dunnick, CA AF Hill, Mary K. Pishkenari, Azin Kheirandish Braunberger, Taylor L. Armstrong, April W. Dunnick, Cory A. TI Recent trends in disease severity and quality of life instruments for patients with atopic dermatitis: A systematic review SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review ID RANDOMIZED-CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; LACTOBACILLUS-ACIDOPHILUS L-92; MULTICENTER CLINICAL-TRIAL; VITAMIN-D SUPPLEMENTATION; LOW-DOSE CYCLOSPORINE; DOUBLE-BLIND; OUTCOME MEASURES; ADULT PATIENTS; TACROLIMUS OINTMENT AB Background: A significant number of instruments exist that are aimed at quantifying atopic dermatitis (AD) outcomes. Objective: We sought to assess recent trends in the use of disease severity and quality of life (QOL) outcome instruments in randomized controlled trials (RCTs) conducted on patients with AD between July 2010 and July 2015. Methods: A total of 540 nonduplicate records were identified through searches of Scopus and Ovid MEDLINE. Included studies were RCTs conducted on humans with AD that were published in English between July 2010 and July 2015 and that reported the results of disease severity or QOL outcome measures. Results: All of the 135 included studies assessed disease severity. Only 45 studies assessed QOL. Sixty-two disease severity measures and 28 QOL scales were identified. Limitations: This study was limited by its timeframe of 5 years and by the exclusion of non-RCTs and gray literature. Conclusion: Disease severity and QOL outcome measures are instrumental in evaluating AD treatment efficacy. The number of such tools used in RCTs on patients with AD continues to rise. Standardization of outcomes instruments is essential for comparability among studies and improved quality of evidence. C1 [Hill, Mary K.; Pishkenari, Azin Kheirandish] Univ Colorado, Sch Med, Aurora, CO USA. [Braunberger, Taylor L.] Univ North Dakota, Sch Med, Grand Forks, ND USA. [Armstrong, April W.] Univ Southern Calif, Dept Dermatol, Los Angeles, CA USA. [Dunnick, Cory A.] Univ Colorado Denver, Dept Dermatol, 1665 Aurora Ct,MS 703, Aurora, CO 80045 USA. [Dunnick, Cory A.] US Dept Vet Affairs, Eastern Colorado Hlth Care Syst, Denver, CO USA. RP Dunnick, CA (reprint author), Univ Colorado Denver, Dept Dermatol, 1665 Aurora Ct,MS 703, Aurora, CO 80045 USA. EM cory.dunnick@ucdenver.edu NR 160 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD NOV PY 2016 VL 75 IS 5 BP 906 EP 917 DI 10.1016/j.jaad.2016.07.002 PG 12 WC Dermatology SC Dermatology GA EA6WJ UT WOS:000386769500017 PM 27615798 ER PT J AU Shishehbor, MH White, CJ Gray, BH Menard, MT Lookstein, R Rosenfield, K Jaff, MR AF Shishehbor, Mehdi H. White, Christopher J. Gray, Bruce H. Menard, Matthew T. Lookstein, Robert Rosenfield, Kenneth Jaff, Michael R. TI Critical Limb Ischemia An Expert Statement SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE amputation; endovascular; open bypass; peripheral artery disease ID PERIPHERAL ARTERIAL-DISEASE; INTERMITTENT PNEUMATIC COMPRESSION; DRUG-ELUTING STENTS; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; LOWER-EXTREMITY AMPUTATION; BELOW-THE-KNEE; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; ANTEGRADE-RETROGRADE INTERVENTION; FOOT ULCER CLASSIFICATION; INTER-SOCIETY CONSENSUS AB Critical limb ischemia (CLI), the most advanced form of peripheral artery disease, is associated with significant morbidity, mortality, and health care resource utilization. It is also associated with physical, as well as psychosocial, consequences such as amputation and depression. Importantly, after a major amputation, patients are at heightened risk of amputation on the contralateral leg. However, despite the technological advances to manage CLI with minimally invasive technologies, this condition often remains untreated, with significant disparities in revascularization and amputation rates according to race, socioeconomic status, and geographic region. Care remains disparate across medical specialties in this rapidly evolving field. Many challenges persist, including appropriate reimbursement for treating complex patients with difficult anatomy. This paper provides a comprehensive summary that includes diagnostic assessment and analysis, endovascular versus open surgical treatment, regenerative and adjunctive therapies, and other important aspects of CLI. (C) 2016 by the American College of Cardiology Foundation. C1 [Shishehbor, Mehdi H.] Cleveland Clin, Cleveland, OH 44106 USA. [White, Christopher J.] Univ Queensland, Ochsner Clin Sch, New Orleans, LA USA. [Gray, Bruce H.] Greenville Hlth Syst, Greenville, SC USA. [Menard, Matthew T.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Lookstein, Robert] Mt Sinai Med Ctr, New York, NY 10029 USA. [Rosenfield, Kenneth; Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Shishehbor, MH (reprint author), Cleveland Clin, Inst Heart & Vasc, 9500 Euclid Ave,J3-5, Cleveland, OH 44195 USA. EM shishem@ccf.org FU National Institutes of Health; AstraZeneca; Luna; Venite; Boston Scientific; Spectranetics; Philips Healthcare; Abbott Vascular; Atrium; Lutonix-Bard; Cardinal Health; Volcano Corporation FX Dr. Shishehbor has served as a noncompensated advisor and educator for Medtronic, Boston Scientific, Abbott Vascular, Spectranetics, Cardiovascular Systems, Inc., Cook Medical, Merck, and Terumo; and has received research grants from the National Institutes of Health, AstraZeneca, and Luna. Dr. White is a member of the NCDR-PVI registry. Dr. Gray has served as a consultant and researcher for Medtronic, Abbott, and W.L. Gore; is a steering committee member for the NCDR-PVI registry; and is a board member of the American Board of Vascular Medicine. Dr. Menard is a member of the scientific advisory boards for Merck and Proteon; and has served as a national Principal Investigator for the BEST-CLI trial. Dr. Lookstein has served as a consultant for Boston Scientific, Bayer HealthCare, and The Medicines Company; has received research support from Venite, Boston Scientific, Spectranetics, and Philips Healthcare; and is a member of the clinical events committee for Shockwave. Dr. Rosenfield has served as a consultant/scientific advisory board member for Abbott Vascular, Cardinal Health, Inari Medical, InspireMD, Surmodics, and Volcano/Philips; has served as a consultant/scientific advisory board member with equity or stock options for Capture Vascular, Contego, CRUZAR Systems, Endospan, Eximo, MD Insider, Micell, Shockwave, Silk Road Medical, and Valcare; has personal equity in CardioMEMs, Contego, CRUZAR Systems, Embolitech, Icon, Janacare, MD Insider, Primacea, and PQ Bypass; has received research or fellowship support from Abbott Vascular, Atrium, the National Institutes of Health, and Lutonix-Bard; and is a board member of VIVA Physicians. Dr. Jaff has served as a noncompensated advisor for Abbott Vascular, Boston Scientific, Cordis, and Medtronic; has served as a paid consultant for Cardinal Health and Volcano Corporation; is an equity shareholder in PQ Bypass and Primacea; is a board member of VIVA Physicians (a 501[c][3] not-for-profit education and research organization) and the Society for Cardiovascular Angiography and Intervention; has served as a scientific advisor for the American Orthotics and Prosthetics Association; and is an equity shareholder in Embolitech and Vascular Therapies. Donald Cutlip, MD, served as Guest Editor for this paper. NR 117 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 1 PY 2016 VL 68 IS 18 BP 2002 EP 2015 DI 10.1016/j.jacc.2016.04.071 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA7QZ UT WOS:000386828100011 PM 27692726 ER PT J AU Kraemer, K Cohen, ME Liu, YM Barnhart, DC Rangel, SJ Saito, JM Bilimoria, KY Ko, CY Hall, BL AF Kraemer, Kari Cohen, Mark E. Liu, Yaoming Barnhart, Douglas C. Rangel, Shawn J. Saito, Jacqueline M. Bilimoria, Karl Y. Ko, Clifford Y. Hall, Bruce L. TI Development and Evaluation of the American College of Surgeons NSQIP Pediatric Surgical Risk Calculator SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID SHARED DECISION-MAKING; MORTALITY; ADJUSTMENT; PREDICTION; VALIDATION; CHILDREN; QUALITY AB BACKGROUND: There is an increased desire among patients and families to be involved in the surgical decision-making process. A surgeon's ability to provide patients and families with patient-specific estimates of postoperative complications is critical for shared decision making and informed consent. Surgeons can also use patient-specific risk estimates to decide whether or not to operate and what options to offer patients. Our objective was to develop and evaluate a publicly available risk estimation tool that would cover many common pediatric surgical procedures across all specialties. STUDY DESIGN: American College of Surgeons NSQIP Pediatric standardized data from 67 hospitals were used to develop a risk estimation tool. Surgeons enter 18 preoperative variables (demographics, comorbidities, procedure) that are used in a logistic regression model to predict 9 postoperative outcomes. A surgeon adjustment score is also incorporated to adjust for any additional risk not accounted for in the 18 risk factors. RESULTS: A pediatric surgical risk calculator was developed based on 181,353 cases covering 382 CPT codes across all specialties. It had excellent discrimination for mortality (c-statistic = 0.98), morbidity (c-statistic = 0.81), and 7 additional complications (c-statistic > 0.77). The Hosmer-Lemeshow statistic and graphic representations also showed excellent calibration. CONCLUSIONS: The ACS NSQIP Pediatric Surgical Risk Calculator was developed using standardized and audited multi-institutional data from the ACS NSQIP Pediatric, and it provides empirically derived, patient-specific postoperative risks. It can be used as a tool in the shared decision-making process by providing clinicians, families, and patients with useful information for many of the most common operations performed on pediatric patients in the US. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.) C1 [Kraemer, Kari; Cohen, Mark E.; Liu, Yaoming; Ko, Clifford Y.; Hall, Bruce L.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Dept Surg, SOQIC, Chicago, IL 60611 USA. [Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Ctr Healthcare Studies, Chicago, IL 60611 USA. [Bilimoria, Karl Y.] Northwestern Univ, Northwestern Med, Chicago, IL 60611 USA. [Barnhart, Douglas C.] Univ Utah, Div Pediat Surg, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Rangel, Shawn J.] Harvard Med Sch, Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Saito, Jacqueline M.; Hall, Bruce L.] Washington Univ, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce L.] BJC Healthcare, St Louis, MO USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Kraemer, K (reprint author), Amer Coll Surg, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM kkraemer@facs.org NR 18 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD NOV PY 2016 VL 223 IS 5 BP 685 EP 693 DI 10.1016/j.jamcollsurg.2016.08.542 PG 9 WC Surgery SC Surgery GA EA6TO UT WOS:000386762100002 PM 27666656 ER PT J AU Jovanovich, A Chonchol, M AF Jovanovich, Anna Chonchol, Michel TI Calcific Uremic Arteriolopathy Revisited SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID CALCIPHYLAXIS C1 [Jovanovich, Anna] Denver Vet Affairs Med Ctr, Renal Sect, Denver, CO USA. [Jovanovich, Anna; Chonchol, Michel] Univ Colorado, Div Renal Dis & Hypertens, Aurora, CO USA. RP Jovanovich, A (reprint author), 13199 East Montview Blvd,Suite 495, Aurora, CO 80045 USA. EM michel.chonchol@ucdenver.edu NR 12 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2016 VL 27 IS 11 BP 3233 EP 3235 DI 10.1681/ASN.2016040480 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EA3VV UT WOS:000386538300003 PM 27225039 ER PT J AU Trepiccione, F Gerber, SD Grahammer, F Lopez-Cayuqueo, KI Baudrie, V Paunescu, TG Capen, DE Picard, N Alexander, RT Huber, TB Chambrey, R Brown, D Houillier, P Eladari, D Simons, M AF Trepiccione, Francesco Gerber, Simon D. Grahammer, Florian Lopez-Cayuqueo, Karen I. Baudrie, Veronique Paunescu, Teodor G. Capen, Diane E. Picard, Nicolas Alexander, R. Todd Huber, Tobias B. Chambrey, Regine Brown, Dennis Houillier, Pascal Eladari, Dominique Simons, Matias TI Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID (PRO)RENIN RECEPTOR; PRORENIN RECEPTOR; AUTOPHAGY; CELLS; MICE; EXPRESSION; MEMBRANE; NEPHRON; ACIDIFICATION; HYPERTENSION AB ATPase H+-transporting lysosomal accessory protein 2 (Atp6ap2), also known as the (pro)renin receptor, is a type 1 transmembrane protein and an accessory subunit of the vacuolar H+-ATPase (V-ATPase) that may also function within the renin-angiotensin system. However, the contribution of Atp6ap2 to renin-angiotensin-dependent functions remains unconfirmed. Using mice with an inducible conditional deletion of Atp6ap2 in mouse renal epithelial cells, we found that decreased V-ATPase expression and activity in the intercalated cells of the collecting duct impaired acid-base regulation by the kidney. In addition, these mice suffered from marked polyuria resistant to desmopressin administration. Immunoblotting revealed downregulation of the medullary Na+-K(+)2Cl(-) cotransporter NKCC2 in these mice compared with wild-type mice, an effect accompanied by a hypotonic medullary interstitium and impaired countercurrent multiplication. This phenotype correlated with strong autophagic defects in epithelial cells of medullary tubules. Notably, cells with high accumulation of the autophagosomal substrate p62 displayed the strongest reduction of NKCC2 expression. Finally, nephron-specific Atp6ap2 depletion did not affect angiotensin II production, angiotensin II-dependent BP regulation, or sodium handling in the kidney. Taken together, our results show that nephron-specific deletion of Atp6ap2 does not affect the renin-angiotensin system but causes a combination of renal concentration defects and distal renal tubular acidosis as a result of impaired V-ATPase activity. C1 [Trepiccione, Francesco; Lopez-Cayuqueo, Karen I.; Baudrie, Veronique; Chambrey, Regine; Eladari, Dominique] Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Paris Ctr Rech Cardiovasc, INSERM,Unite Mixte Rech S970, Paris, France. [Trepiccione, Francesco] Univ Naples 2, Dept Cardiothorac & Resp Sci, Caserta, Italy. [Gerber, Simon D.; Simons, Matias] Paris Descartes Univ, Sorbonne Paris Cite, Imagine Inst, 24 Blvd Montparnasse, F-75015 Paris, France. [Grahammer, Florian; Paunescu, Teodor G.; Capen, Diane E.; Brown, Dennis; Houillier, Pascal] Univ Med Ctr Freiburg, Renal Div, Freiburg, Germany. [Lopez-Cayuqueo, Karen I.] Ctr Estudios Cient, Valdivia, Chile. [Paunescu, Teodor G.; Capen, Diane E.; Brown, Dennis; Houillier, Pascal] Harvard Med Sch, Massachusetts Gen Hosp, Program Membrane Biol, Div Nephrol, Boston, MA USA. [Picard, Nicolas] Univ Paris 06, CNRS, INSERM, Unite Mixte Rech S1138,Ctr Rech Cordeliers,Equipe, Paris, France. [Alexander, R. Todd] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. [Huber, Tobias B.] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, Freiburg, Germany. RP Simons, M (reprint author), Paris Descartes Univ, Sorbonne Paris Cite, Imagine Inst, 24 Blvd Montparnasse, F-75015 Paris, France.; Eladari, D (reprint author), Hop Europeen Georges Pompidou, Paris Ctr Rech Cardiovasc, 56 Rue Leblanc, F-75737 Paris, France. EM dominique.eladari@inserm.fr; matias.simons@institutimagine.org RI Picard, Nicolas/B-6677-2012 OI Picard, Nicolas/0000-0002-1695-3389 FU Fondation Bettencourt-Schuller; Deutsche Forschungsgemeinschaft Emmy-Noether grant [SI1303/2-1]; Action Thematique et Incitative sur Programme-Avenir grant; l'Agence Nationale de la Recherche (ANR) [ANR BLANC 2012-R13011KK, ANR BLANC 14-CE12-0013-01/HYPERSCREEN]; CHLORBLOCK from the Initiative d'excellence Sorbonne Paris Cite; Comision Nacional de Investigacion Cientifica y Tecnologica; European Renal Association - European Dialysis and Translpantation Association [LTF141-2013]; Excellence Initiative of the German Federal and State Governments [EXC 294]; National Institutes of Health [DK042956]; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Massachussets General Hospital Center for the Study of Inflammatory Bowel Disease [DK43351] FX The work has been supported by the Fondation Bettencourt-Schuller, a Deutsche Forschungsgemeinschaft Emmy-Noether grant (SI1303/2-1) and an Action Thematique et Incitative sur Programme-Avenir grant to M.S., as well as grants from l'Agence Nationale de la Recherche (ANR; ANR BLANC 2012-R13011KK to R.C., and ANR BLANC 14-CE12-0013-01/HYPERSCREEN to D.E.). D.E. is also funded by grant CHLORBLOCK from the Initiative d'excellence Sorbonne Paris Cite. K.I.L. received a fellowship from the Comision Nacional de Investigacion Cientifica y Tecnologica. F.T. received a fellowship from the European Renal Association - European Dialysis and Translpantation Association (LTF141-2013). T.B.H. is supported by the Excellence Initiative of the German Federal and State Governments (EXC 294). D.B. and T.G.P. were supported by National Institutes of Health grant DK042956. Additional support for the Program in Membrane Biology Microscopy Core comes from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Massachussets General Hospital Center for the Study of Inflammatory Bowel Disease (DK43351). NR 38 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2016 VL 27 IS 11 BP 3320 EP 3330 DI 10.1681/ASN.2015080915 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA EA3VV UT WOS:000386538300014 PM 27044666 ER PT J AU Nigwekar, SU Zhao, S Wenger, J Hynnes, JL Maddux, FW Thadhani, RI Chan, KE AF Nigwekar, Sagar U. Zhao, Sophia Wenger, Julia Hynnes, Jeffrey L. Maddux, Franklin W. Thadhani, Ravi I. Chan, Kevin E. TI A Nationally Representative Study of Calcific Uremic Arteriolopathy Risk Factors SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; DIABETIC HEMODIALYSIS-PATIENTS; PROXIMAL CALCIPHYLAXIS; SODIUM THIOSULFATE; CONTROLLED-TRIALS; CINACALCET; THERAPY; ESRD AB Accurate identification of risk factors for calcific uremic arteriolopathy (CUA) is necessary to develop preventive strategies for this morbid disease. We investigated whether baseline factors recorded at hemodialysis initiation would identify patients at risk for future CUA in a matched case-control study using data from a large dialysis organization. Hemodialysis patients with newly diagnosed CUA (n=1030) between January 1, 2010, and December 31, 2014, were matched by age, sex, and race in a 1:2 ratio to hemodialysis patients without CUA (n=2060). Mean ages for patients and controls were 54 and 55 years, respectively; 67% of participants were women and 49% were white. Median duration between hemodialysis initiation and subsequent CUA development was 925 days (interquartile range, 273-2185 days). In multivariable conditional logistic regression analyses, diabetes mellitus; higher body mass index; higher levels of serum calcium, phosphorous, and parathyroid hormone; and nutritional vitamin D, cinacalcet, and warfarin treatments were associated with increased odds of subsequent CUA development. Compared with patients with diabetes receiving no insulin injections, those receiving insulin injections had a dose response increase in the odds of CUA involving lower abdomen and/or upper thigh areas (odds ratio, 1.49; 95% confidence interval, 1.03 to 2.51 for one or two injections per day; odds ratio, 1.88; 95% confidence interval, 1.30 to 3.43 for 3 injections per day; odds ratio, 3.74; 95% confidence interval, 2.28 to 6.25 for more than three injections per day), suggesting a dose-effect relationship between recurrent skin trauma and CUA risk. The presence of risk factors months to years before CUA development observed in this study will direct the design of preventive strategies and inform CUA pathobiology. C1 [Nigwekar, Sagar U.; Zhao, Sophia; Thadhani, Ravi I.; Chan, Kevin E.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Wenger, Julia] Univ N Carolina, Kidney Ctr, Div Nephrol, Chapel Hill, NC USA. [Hynnes, Jeffrey L.; Maddux, Franklin W.; Chan, Kevin E.] Fresenius Med Care North Amer, Med Off, Waltham, MA USA. RP Nigwekar, SU (reprint author), 165 Cambridge St,Suite 302, Boston, MA 02114 USA. EM snigwekar@mgh.harvard.edu FU KL2/Catalyst Medical Research Investigator Training award; Harvard Catalyst; Harvard Clinical and Translational Science Center (National Center for Research Resources [NCRP]; National Center for Advancing Translational Sciences; National Institutes of Health (NIH) [KL2 TR001100]; National Kidney Foundation's Young Investigator Award; Fund for Medical Discovery Award from Massachusetts General Hospital's Executive Committee on Research [R00000000007190]; American Heart Association's NCRP Summer Mentored Clinical and Population Research Award [15CRP22900008]; American Heart Association's NCRP Winter Fellow-to-Faculty Transition Award [15FTF25980003]; NIH [DK094872, DK094486] FX This work was conducted with the support of a KL2/Catalyst Medical Research Investigator Training award to S.U.N. (an appointed KL2 award) from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources [NCRP] and the National Center for Advancing Translational Sciences, he National Institutes of Health (NIH) Award KL2 TR001100). S.U.N. is also supported by National Kidney Foundation's Young Investigator Award, Fund for Medical Discovery Award from Massachusetts General Hospital's Executive Committee on Research (R00000000007190), American Heart Association's NCRP Summer 2014 Mentored Clinical and Population Research Award (15CRP22900008), and by American Heart Association's NCRP Winter 2015 Fellow-to-Faculty Transition Award (15FTF25980003). R.I.T. is supported by NIH grants DK094872 and DK094486. NR 33 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2016 VL 27 IS 11 BP 3421 EP 3429 DI 10.1681/ASN.2015091065 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EA3VV UT WOS:000386538300023 PM 27080977 ER PT J AU Fischer, MJ Hsu, JY Lora, CM Ricardo, AC Anderson, AH Bazzano, L Cuevas, MM Hsu, CY Kusek, JW Renteria, A Ojo, AO Raj, DS Rosas, SE Pan, Q Yaffe, K Go, AS Lash, JP AF Fischer, Michael J. Hsu, Jesse Y. Lora, Claudia M. Ricardo, Ana C. Anderson, Amanda H. Bazzano, Lydia Cuevas, Magdalena M. Hsu, Chi-yuan Kusek, John W. Renteria, Amada Ojo, Akinlolu O. Raj, Dominic S. Rosas, Sylvia E. Pan, Qiang Yaffe, Kristine Go, Alan S. Lash, James P. CA Chronic Renal Insufficiency Cohort TI CKD Progression and Mortality among Hispanics and Non-Hispanics SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; RENAL-INSUFFICIENCY COHORT; NUTRITION EXAMINATION SURVEY; BASE-LINE CHARACTERISTICS; EVALUATION PROGRAM KEEP; 3RD NATIONAL-HEALTH; ETHNIC-DIFFERENCES; RACIAL-DIFFERENCES; CARDIOVASCULAR-DISEASE; DIABETIC-NEPHROPATHY AB Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes. C1 [Fischer, Michael J.; Lora, Claudia M.; Ricardo, Ana C.; Renteria, Amada; Lash, James P.] Univ Illinois, Dept Med, Chicago, IL USA. [Fischer, Michael J.] Jesse Brown VA Med Ctr, Med Serv, Chicago, IL USA. [Fischer, Michael J.] Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Healthcare, Res Serv, Hines, IL USA. [Hsu, Jesse Y.; Anderson, Amanda H.; Cuevas, Magdalena M.; Pan, Qiang] Univ Penn, Dept Epidemiol & Biostat, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Bazzano, Lydia] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Hsu, Chi-yuan; Go, Alan S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Ojo, Akinlolu O.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Raj, Dominic S.] George Washington Univ, Dept Med, Washington, DC USA. [Rosas, Sylvia E.] Harvard Med Sch, Joslin Diabet Ctr, Kidney & Hypertens Unit, Boston, MA USA. [Rosas, Sylvia E.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Nephrol Sect, Boston, MA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Fischer, MJ (reprint author), Hines VA Hosp, Ctr Innovat Complex Chron Healthcare, 5000 S 5th Ave 151H, Hines, IL 60141 USA. EM fischerm@uic.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U0IDK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award; National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) [UL1 TR-000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland General Clinical Research Center [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; NCATS component of the NIH [UL1 TR-000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1 TR-000433]; University of Illinois at Chicago Clinical and Translational Science Award [UL1 RR-029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GMI03337]; Kaiser Permanente NIH/National Center for Research Resources, University of California-San Francisco Clinical & Translational Science Institute [UL1 RR-024131]; National Center for Minority Health and Health Disparities; NIH; Department of Veterans Affairs Health Services Research and Development Service; NIH/NIDDK [K24-DK092290, K23 DK091313, K23 DK094829] FX Funding for the Chronic Renal Insufficiency Cohort Study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U0IDK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award and the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (UL1 TR-000003), Johns Hopkins University (UL1 TR-000424), University of Maryland General Clinical Research Center (M01 RR-16500), Clinical and Translational Science Collaborative of Cleveland, UL1 TR-000439 from the NCATS component of the NIH and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (UL1 TR-000433), University of Illinois at Chicago Clinical and Translational Science Award (UL1 RR-029879), Tulane University Translational Research in Hypertension and Renal Biology (P30GMI03337), and Kaiser Permanente NIH/National Center for Research Resources, University of California-San Francisco Clinical & Translational Science Institute (UL1 RR-024131). Additional support was provided by the National Center for Minority Health and Health Disparities, the NIH, and Department of Veterans Affairs Health Services Research and Development Service (to M.J.F.). Support was provided from NIH/NIDDK K24-DK092290 (to J.P.L.), K23 DK091313 (to C.M.L.), K23 DK094829 (to A.C.R.). NR 43 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2016 VL 27 IS 11 BP 3488 EP 3497 DI 10.1681/ASN.2015050570 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EA3VV UT WOS:000386538300030 PM 27151925 ER PT J AU Danesh, MJ Koo, EB Kimball, AB AF Danesh, M. J. Koo, E. B. Kimball, A. B. TI Effects of TNF-alpha antagonism in patients with metabolic syndrome and psoriasis SO JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY LA English DT Letter ID REACTIVE PROTEIN-LEVELS; ETANERCEPT; MARKERS C1 [Danesh, M. J.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Koo, E. B.] Harvard Med Sch, Boston, MA USA. [Kimball, A. B.] Mass Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Kimball, AB (reprint author), Mass Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 10 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0926-9959 EI 1468-3083 J9 J EUR ACAD DERMATOL JI J. Eur. Acad. Dermatol. Venereol. PD NOV PY 2016 VL 30 IS 11 BP E152 EP E154 DI 10.1111/jdv.13461 PG 3 WC Dermatology SC Dermatology GA EA9DL UT WOS:000386941300028 PM 26558474 ER PT J AU VanderWalde, N Jagsi, R Dotan, E Baumgartner, J Browner, IS Burhenn, P Cohen, HJ Edil, BH Edwards, B Extermann, M Ganti, AKP Gross, C Hubbard, J Keating, NL Korc-Grodzicki, B Mckoy, JM Medeiros, BC Mrozek, E O'Connor, T Rugo, HS Rupper, RW Shepard, D Silliman, RA Stirewalt, DL Tew, WP Walter, LC Wildes, T Bergman, MA Sundar, H Hurria, A AF VanderWalde, Noam Jagsi, Reshma Dotan, Efrat Baumgartner, Joel Browner, Ilene S. Burhenn, Peggy Cohen, Harvey Jay Edil, Barish H. Edwards, Beatrice Extermann, Martine Ganti, Apar Kishor P. Gross, Cary Hubbard, Joleen Keating, Nancy L. Korc-Grodzicki, Beatriz Mckoy, June M. Medeiros, Bruno C. Mrozek, Ewa O'Connor, Tracey Rugo, Hope S. Rupper, Randall W. Shepard, Dale Silliman, Rebecca A. Stirewalt, Derek L. Tew, William P. Walter, Louise C. Wildes, Tanya Bergman, Mary Anne Sundar, Hema Hurria, Arti TI NCCN Guidelines (R) Insights Older Adult Oncology, Version 2.2016 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID CELL LUNG-CANCER; STEREOTACTIC BODY RADIOTHERAPY; PROPHYLACTIC CRANIAL IRRADIATION; EARLY BREAST-CANCER; NEOADJUVANT ANDROGEN DEPRIVATION; PRIMARY HEPATOCELLULAR-CARCINOMA; LUMPECTOMY PLUS TAMOXIFEN; ADVANCED PROSTATE-CANCER; PATIENTS AGED 90; QUALITY-OF-LIFE AB Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer. C1 [VanderWalde, Noam] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Jagsi, Reshma] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA. [Dotan, Efrat] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Baumgartner, Joel] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA USA. [Browner, Ilene S.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Burhenn, Peggy; Hurria, Arti] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Cohen, Harvey Jay] Duke Canc Inst, Durham, NC USA. [Edil, Barish H.] Univ Colorado, Canc Ctr, Boulder, CO 80309 USA. [Edwards, Beatrice] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Extermann, Martine] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Ganti, Apar Kishor P.] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Gross, Cary] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT USA. [Hubbard, Joleen] Mayo Clin, Canc Ctr, Rochester, MN USA. [Hubbard, Joleen] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Korc-Grodzicki, Beatriz; Tew, William P.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Mckoy, June M.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Medeiros, Bruno C.] Stanford Canc Inst, Stanford, CA USA. [Mrozek, Ewa] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Mrozek, Ewa] Solove Res Inst, Columbus, OH USA. [O'Connor, Tracey] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Rugo, Hope S.; Walter, Louise C.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Rupper, Randall W.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Shepard, Dale] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Center, Cleveland, OH USA. [Shepard, Dale] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Stirewalt, Derek L.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. [Wildes, Tanya] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Wildes, Tanya] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Bergman, Mary Anne; Sundar, Hema] Natl Comprehens Canc Network, Ft Washington, PA USA. RP VanderWalde, N (reprint author), Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. FU AstraZeneca; Bayer Healthcare Pharmaceuticals Inc.; Bristol-Myers Squibb; Clovis Oncology; Foundation Medicine; Genentech; Novartis Oncology; Otsuka America Pharmaceutical, Inc.; Seattle Genetics, Inc.; Takeda Oncology; Actelion Pharmaceuticals US, Inc.; Astellas; Medivation, Inc. FX This activity is supported by educational grants from AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Clovis Oncology, Foundation Medicine, Genentech, Novartis Oncology, Otsuka America Pharmaceutical, Inc., Seattle Genetics, Inc., and Takeda Oncology; support provided by Actelion Pharmaceuticals US, Inc.; and by an independent educational grant from Astellas and Medivation, Inc. NR 57 TC 0 Z9 0 U1 3 U2 3 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV 1 PY 2016 VL 14 IS 11 BP 1357 EP 1370 PG 14 WC Oncology SC Oncology GA EA8JE UT WOS:000386880300007 PM 27799507 ER PT J AU Shields, PG Herbst, RS Arenberg, D Benowitz, NL Bierut, L Luckart, JB Cinciripini, P Collins, B David, S Davis, J Hitsman, B Hyland, A Lang, M Leischow, S Park, ER Purcell, WT Selzle, J Silber, A Spencer, S Tanvetyanon, T Tiep, B Tindle, HA Tucker-Seeley, R Urbanic, J Hooper, MW Weksler, B Whitlock, CW Wood, DE Burns, J Scavone, J AF Shields, Peter G. Herbst, Roy S. Arenberg, Douglas Benowitz, Neal L. Bierut, Laura Luckart, Julie Bylund Cinciripini, Paul Collins, Bradley David, Sean Davis, James Hitsman, Brian Hyland, Andrew Lang, Margaret Leischow, Scott Park, Elyse R. Purcell, W. Thomas Selzle, Jill Silber, Andrea Spencer, Sharon Tanvetyanon, Tawee Tiep, Brian Tindle, Hilary A. Tucker-Seeley, Reginald Urbanic, James Hooper, Monica Webb Weksler, Benny Whitlock, C. Will Wood, Douglas E. Burns, Jennifer Scavone, Jillian TI Smoking Cessation, Version 1.2016 Clinical Practice Guidelines in Oncology SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID NICOTINE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; NECK-CANCER PATIENTS; SUSTAINED-RELEASE BUPROPION; PLACEBO-CONTROLLED-TRIAL; CELL LUNG-CANCER; QUALITY-OF-LIFE; RECEPTOR PARTIAL AGONIST; ELECTRONIC CIGARETTE USE; HELPING SMOKERS QUIT AB Cigarette smoking has been implicated in causing many cancers and cancer deaths. There is mounting evidence indicating that smoking negatively impacts cancer treatment efficacy and overall survival. The NCCN Guidelines for Smoking Cessation have been created to emphasize the importance of smoking cessation and establish an evidence-based standard of care in all patients with cancer. These guidelines provide recommendations to address smoking in patients and outlines behavioral and pharmacologic interventions for smoking cessation throughout the continuum of oncology care. C1 [Shields, Peter G.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Shields, Peter G.] Solove Res Inst, Columbus, OH 43210 USA. [Herbst, Roy S.; Silber, Andrea] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT USA. [Arenberg, Douglas] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Benowitz, Neal L.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bierut, Laura] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Bierut, Laura] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Luckart, Julie Bylund] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Cinciripini, Paul] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Collins, Bradley] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [David, Sean] Stanford Canc Inst, Stanford, CA USA. [Davis, James] Duke Canc Inst, Durham, NC USA. [Hitsman, Brian] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Hyland, Andrew] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Lang, Margaret] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Leischow, Scott] Mayo Clin, Ctr Canc, Rochester, MN USA. [Park, Elyse R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Purcell, W. Thomas] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Selzle, Jill] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Spencer, Sharon] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Tanvetyanon, Tawee] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Tiep, Brian] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Tindle, Hilary A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Tucker-Seeley, Reginald] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Urbanic, James] UC San Diego Moores Canc Ctr, San Diego, CA USA. [Hooper, Monica Webb] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Hooper, Monica Webb] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Weksler, Benny] Univ Tennessee, St Jude Childrens Res Hosp, Hlth Sci Ctr, Knoxville, TN 37996 USA. [Whitlock, C. Will] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Wood, Douglas E.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. [Burns, Jennifer; Scavone, Jillian] NCCN, Ft Washington, PA USA. RP Shields, PG (reprint author), Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA.; Shields, PG (reprint author), Solove Res Inst, Columbus, OH 43210 USA. NR 260 TC 0 Z9 0 U1 7 U2 7 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV 1 PY 2016 VL 14 IS 11 BP 1430 EP 1468 PG 39 WC Oncology SC Oncology GA EA8JE UT WOS:000386880300013 PM 27799513 ER PT J AU Hanudel, M Juppner, H Salusky, IB AF Hanudel, Mark Juppner, Harald Salusky, Isidro B. TI Fibroblast growth factor 23: fueling the fire SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID LEFT-VENTRICULAR HYPERTROPHY; CHRONIC KIDNEY-DISEASE; MORTALITY; CKD AB In chronic kidney disease, systemic inflammation is common and associated with mortality. The present study demonstrates that fibroblast growth factor 23 (FGF23) contributes to uremic inflammation by increasing hepatic expression and secretion of inflammatory cytokines. FGF23 binds to hepatic FGFR4, inducing calcineurin/nuclear factor of activated T-cell signaling, resulting in increased expression of interleukin 6 and C-reactive protein. The proinflammatory effects of FGF23 are inhibited by an isoform-specific FGFR4 blocking antibody and by cyclosporine, a calcineurin inhibitor. Copyright (C) 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved. C1 [Hanudel, Mark; Salusky, Isidro B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pediat Nephrol, 10833 LeConte Ave, Los Angeles, CA 90095 USA. [Juppner, Harald] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. [Juppner, Harald] Harvard Med Sch, Massachusetts Gen Hosp, Div Pediat Nephrol, Boston, MA USA. RP Salusky, IB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Pediat Nephrol, 10833 LeConte Ave, Los Angeles, CA 90095 USA. EM isalusky@mednet.ucla.edu NR 9 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2016 VL 90 IS 5 BP 928 EP 930 DI 10.1016/j.kint.2016.08.013 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EA3ZF UT WOS:000386547100004 PM 27742194 ER PT J AU Liu, WJ Yang, YP Liu, YM Lu, XL Guo, SZ Wu, M Wang, M Yan, LL Wang, QH Zhao, XL Tong, X Hu, J Li, YM Hu, RM Stanton, RC Zhang, ZY AF Liu, Wenjuan Yang, Yeping Liu, Yemei Lu, Xiaolan Guo, Shizhe Wu, Meng Wang, Meng Yan, Linling Wang, Qinghua Zhao, Xiaolong Tong, Xian Hu, Ji Li, Yiming Hu, Renming Stanton, Robert C. Zhang, Zhaoyun TI Exogenous kallikrein protects against diabetic nephropathy SO KIDNEY INTERNATIONAL LA English DT Article DE diabetic nephropathy; fibrosis; inflammation; oxidative stress ID RECEPTOR GENE-EXPRESSION; HUMAN LUNG FIBROBLASTS; OXIDATIVE STRESS; KININ SYSTEM; KIDNEY-DISEASE; HIGH GLUCOSE; B2-KININ RECEPTOR; BRADYKININ B1; DB/DB MICE; CELLS AB The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db + kallikrein, streptozotocin + kallikrein) or saline (db/db + saline, streptozotocin + saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin' + kallikrein, streptozotocin' + saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased, the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system. C1 [Liu, Wenjuan; Yang, Yeping; Liu, Yemei; Guo, Shizhe; Wang, Qinghua; Zhao, Xiaolong; Li, Yiming; Hu, Renming; Zhang, Zhaoyun] Fudan Univ, Huashan Hosp, Div Endocrinol & Metab, 12 Wulumuqi Rd, Shanghai 200040, Peoples R China. [Wu, Meng; Wang, Meng; Hu, Ji] Soochow Univ, Affiliated Hosp 2, Dept Endocrinol, Suzhou, Jiangsu, Peoples R China. [Wang, Qinghua; Li, Yiming; Hu, Renming; Zhang, Zhaoyun] Fudan Univ, Inst Endocrinol & Diabetol, Shanghai, Peoples R China. [Liu, Yemei] Second Peoples Hosp, Dept Endocrinol, Wuhu, Anhui, Peoples R China. [Lu, Xiaolan] High Tech Dist Peoples Hosp, Dept Endocrinol, Suzhou, Jiangsu, Peoples R China. [Yan, Linling] First Peoples Hosp Taichang, Dept Endocrinol, Taichang, Jiangsu, Peoples R China. [Wang, Qinghua] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Div Endocrinol & Metab, Toronto, ON, Canada. [Wang, Qinghua] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Tong, Xian] Jiangsu Qianhong Engn Res Ctr Innovat Biol Drugs, Changzhou, Jiangsu, Peoples R China. [Stanton, Robert C.] Joslin Diabet Ctr, Renal Div, Boston, MA 02215 USA. RP Zhang, ZY (reprint author), Fudan Univ, Huashan Hosp, Div Endocrinol & Metab, 12 Wulumuqi Rd, Shanghai 200040, Peoples R China. EM zhaoyunzhang@fudan.edu.cn FU Natural Science Foundation of China [81370938, 81471041]; Shanghai Municipal Commission of Health and Family Planning [XYQ2011002]; Shanghai Science and Technology Commission [11PJ1402000]; Sheng Kang Hospital Development Center [SHDC12012220]; Shanghai Committee of Science and Technology [12431900205] FX This study was supported by grants from the Natural Science Foundation of China (81370938 and 81471041), Shanghai Municipal Commission of Health and Family Planning (XYQ2011002), Shanghai Science and Technology Commission (11PJ1402000), Sheng Kang Hospital Development Center (SHDC12012220), and Shanghai Committee of Science and Technology (12431900205). NR 45 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2016 VL 90 IS 5 BP 1023 EP 1036 DI 10.1016/j.kint.2016.06.018 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA EA3ZF UT WOS:000386547100017 PM 27546607 ER PT J AU Camp, KM Krotoski, D Parisi, MA Gwinn, KA Cohen, BH Cox, CS Enns, GM Falk, MJ Goldstein, AC Gopal-Srivastava, R Gorman, GS Hersh, SP Hirano, M Hoffman, FA Karaa, A MacLeod, EL McFarland, R Mohan, C Mulberg, AE Odenkirchen, JC Parikh, S Rutherford, PJ Suggs-Anderson, SK Tang, WHW Vockley, J Wolfe, LA Yannicelli, S Yeske, PE Coates, PM AF Camp, Kathryn M. Krotoski, Danuta Parisi, Melissa A. Gwinn, Katrina A. Cohen, Bruce H. Cox, Christine S. Enns, Gregory M. Falk, Marni J. Goldstein, Amy C. Gopal-Srivastava, Rashmi Gorman, Grainne S. Hersh, Stephen P. Hirano, Michio Hoffman, Freddie Ann Karaa, Amel MacLeod, Erin L. McFarland, Robert Mohan, Charles Mulberg, Andrew E. Odenkirchen, Joanne C. Parikh, Sumit Rutherford, Patricia J. Suggs-Anderson, Shawne K. Tang, W. H. Wilson Vockley, Jerry Wolfe, Lynne A. Yannicelli, Steven Yeske, Philip E. Coates, Paul M. TI Nutritional interventions in primary mitochondrial disorders: Developing an evidence base SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Primary mitochondrial disorders; Mitochondrial disease; Nutritional interventions; Dietary supplements; Medical foods; OXPHOS ID RESPIRATORY-CHAIN DEFECTS; COMPLEX-I-DEFICIENCY; KETOGENIC DIET; METHYLMALONIC ACIDEMIA; CARDIOVASCULAR-DISEASE; PRACTICE PATTERNS; INBORN-ERRORS; C. ELEGANS; CHILDREN; EPILEPSY AB In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Camp, Kathryn M.; Coates, Paul M.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Krotoski, Danuta; Parisi, Melissa A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Gwinn, Katrina A.; Odenkirchen, Joanne C.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cohen, Bruce H.] Akron Childrens Hosp, Dept Pediat, Akron, OH 44308 USA. [Cox, Christine S.] MitoAction, Boston, MA 02205 USA. [Enns, Gregory M.] Stanford Univ, Div Med Genet, Stanford, CA 94305 USA. [Falk, Marni J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Falk, Marni J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Goldstein, Amy C.] Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA 15224 USA. [Gopal-Srivastava, Rashmi] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Gorman, Grainne S.; McFarland, Robert] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Hersh, Stephen P.] J Willard & Alice S Marriott Fdn, Bethesda, MD 20817 USA. [Hirano, Michio] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Hoffman, Freddie Ann] HeteroGeneity LLC, Washington, DC 20011 USA. [Karaa, Amel] Massachusetts Gen Hosp, Genet Unit, Boston, MA 02114 USA. [MacLeod, Erin L.] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC 20010 USA. [Mohan, Charles; Yeske, Philip E.] United Mitochondrial Dis Fdn, Pittsburgh, PA 15239 USA. [Mulberg, Andrew E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20903 USA. [Parikh, Sumit] Cleveland Clin, Neurosci, Cleveland, OH 44195 USA. [Rutherford, Patricia J.] Vitaflo Int Ltd, Liverpool L3 4BQ, Merseyside, England. [Suggs-Anderson, Shawne K.] US FDA, Off Nutr & Food Labeling, College Pk, MD 20740 USA. [Tang, W. H. Wilson] Cleveland Clin, Ctr Clin Genom, Cleveland, OH 44195 USA. [Vockley, Jerry] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15224 USA. [Wolfe, Lynne A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Yannicelli, Steven] Nutricia North Amer, Med & Sci Affairs, Rockville, MD 20850 USA. [Mulberg, Andrew E.] US FDA, Rockville, MD 20857 USA. RP Camp, KM (reprint author), 6100 Execut Blvd, Rockville, MD 20892 USA. EM campkm@od.nih.gov; krotoskd@mail.nih.gov; parisima@mail.nih.gov; gwinnk@ninds.nih.gov; bcohen@chmca.org; outreach@mitoaction.org; genns@stanford.edu; falkm@email.chop.edu; amy.goldstein@chp.edu; rashmi.gopal-srivastava@nih.gov; grainne.gorman@newcastle.ac.uk; hershs@starpower.net; mh29@cumc.columbia.edu; fhoffman@heterogeneity-LLC.com; akaraa@mgh.harvard.edu; emacleod@childrensnational.org; robert.mcfarland@newcastle.ac.uk; chuckm@umdf.org; amulberg@amicusrx.com; jo21x@nih.gov; parikhs@ccf.org; triciarutherford@vitaflo.co.uk; shawne.suggs-anderson@fda.hhs.gov; tangw@ccf.org; gerard.vockley@chp.edu; lynne.wolfe@nih.gov; steven.yannicelli@nutricia.com; philip.yeske@umdf.org; coatesp@od.nih.gov OI Gwinn, Katrina/0000-0002-8277-651X FU Edison; Raptor; Reata Pharmaceutical companies; Stealth Peptides; Raptor Pharmaceuticals; Vitaflo; NIH; Neurovive; Stealth Biopeptides; Muscular Dystrophy Association; Santhera Pharmaceuticals; Edison Pharmaceuticals; BioMarin; Medical Research Council; Wellcome Trust; Ryan Stanford Appeal; Lily Foundation; International Foundation for CDKL5 Research (IFCR); Edison Pharmaceutical company; Reata Pharmaceutical company FX The following authors declared financial relationships: B.H. Cohen receives research funding from Edison, Raptor, and Reata Pharmaceutical companies, research funding from and consults to Stealth Peptides, was a consultant to Transgenomic labs and on the speakers board for Courtagen labs; G.M. Enns was a consultant to Mitobridge and runs clinical trials for Edison and Raptor Pharmaceutical companies; M.J. Falk consults to MitoBridge and the KC Group, receives or received research funding from Raptor Pharmaceuticals, Vitaflo, NIH, Neurovive, and Stealth Biopeptides, and has stock options from Perlstein Labs, Inc., LLC; A.C. Goldstein was a consultant to Stealth Biotherapeutics; M. Hirano has been a consultant to MitoBridge, Raptor, Stealth Biopeptides Pharmaceuticals and has received research funding from NIH, Muscular Dystrophy Association, Santhera Pharmaceuticals and Edison Pharmaceuticals; A. Karaa is on the advisory board of Stealth Biotherapeutics and consults to and is on the advisory board of Genzyme; E.L. MacLeod is on the advisory board for Nutricia North America, receives honoraria from Nutricia North America and Cambrooke Therapeutics, and research funding from BioMarin; R. McFarland receives research funding from the Medical Research Council, the Wellcome Trust, the Ryan Stanford Appeal, and the Lily Foundation; S. Parikh receives research funding from NIH, Edison Pharmaceuticals, and International Foundation for CDKL5 Research (IFCR); P.J. Rutherford is employed by VitaFlo Intl, LTD.; W.H. Wilson Tang receives research funding from NIH; J. Vockley participates in clinical trials sponsored by Edison and Reata Pharmaceutical companies, and Stealth Peptides; S. Yannicelli is employed by and owns stock in Nutricia North America. NR 108 TC 1 Z9 1 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2016 VL 119 IS 3 BP 187 EP 206 DI 10.1016/j.ymgme.2016.09.002 PG 20 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EA9TH UT WOS:000386987100001 PM 27665271 ER PT J AU Gunn, BM Schneider, JR Shansab, M Bastian, AR Fahrbach, KM Smith, AD Mahan, AE Karim, MM Licht, AF Zvonar, I Tedesco, J Anderson, MR Chapel, A Suscovich, TJ Malaspina, DC Streeck, H Walker, BD Kim, A Lauer, G Altfeld, M Pillai, S Szleifer, I Kelleher, NL Kiser, PF Hope, TJ Alter, G AF Gunn, B. M. Schneider, J. R. Shansab, M. Bastian, A. R. Fahrbach, K. M. Smith, A. D. Mahan, A. E. Karim, M. M. Licht, A. F. Zvonar, I. Tedesco, J. Anderson, M. R. Chapel, A. Suscovich, T. J. Malaspina, D. C. Streeck, H. Walker, B. D. Kim, A. Lauer, G. Altfeld, M. Pillai, S. Szleifer, I. Kelleher, N. L. Kiser, P. F. Hope, T. J. Alter, G. TI Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16 SO MUCOSAL IMMUNOLOGY LA English DT Article ID FC-GAMMA-RIII; VIRION CAPTURE; IGG-FC; GLYCOSYLATION; SURFACE; IMMUNOGLOBULIN; GLYCOFORMS; EXPRESSION; RESPONSES; ANTIGEN AB Transmission of HIV across mucosal barriers accounts for the majority of HIV infections worldwide. Thus, efforts aimed at enhancing protective immunity at these sites are a top priority, including increasing virus-specific antibodies (Abs) and antiviral activity at mucosal sites. Mucin proteins, including the largest cell-associated mucin, mucin 16 (MUC16), help form mucus to provide a physical barrier to incoming pathogens. Here, we describe a natural interaction between Abs and MUC16 that is enhanced in specific disease settings such as chronic HIV infection. Binding to MUC16 was independent of IgG subclass, but strongly associated with shorter Ab glycan profiles, with agalactosylated (G0) Abs demonstrating the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding. Further, agalactosylated VRC01 captured HIV more efficiently in MUC16. These data point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement and sequestering the virus far from the epithelial border. Thus, next-generation vaccines or monoclonal therapeutics may enhance protective immunity by tuning Ab glycosylation to promote the enrichment of Abs at mucosal barriers. C1 [Gunn, B. M.; Shansab, M.; Mahan, A. E.; Karim, M. M.; Licht, A. F.; Zvonar, I.; Tedesco, J.; Chapel, A.; Suscovich, T. J.; Walker, B. D.; Altfeld, M.; Pillai, S.; Alter, G.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Schneider, J. R.; Fahrbach, K. M.; Anderson, M. R.; Hope, T. J.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Shansab, M.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Bastian, A. R.; Malaspina, D. C.; Szleifer, I.; Kiser, P. F.; Hope, T. J.] Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA. [Smith, A. D.; Kelleher, N. L.] Northwestern Univ, Prote Ctr Excellence, Evanston, IL USA. [Chapel, A.; Altfeld, M.] Heinrich Pette Inst, Dept Virus Immunol, Hamburg, Germany. [Streeck, H.] Mil HIV Res Program, Bethesda, MD USA. [Kim, A.; Lauer, G.; Pillai, S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Szleifer, I.; Kelleher, N. L.; Kiser, P. F.; Hope, T. J.] Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA. [Szleifer, I.; Kelleher, N. L.] Northwestern Univ, Dept Chem, Evanston, IL USA. [Kelleher, N. L.] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. [Kiser, P. F.; Hope, T. J.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. RP Alter, G (reprint author), Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA.; Hope, TJ (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA.; Hope, TJ (reprint author), Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA.; Hope, TJ (reprint author), Northwestern Univ, Chem Life Proc Inst, Evanston, IL 60208 USA.; Hope, TJ (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. EM thope@northwestern.edu; galter@mgh.harvard.edu FU Bill and Melinda Gates Foundation (BMGF) [OPP1031734]; NIH [P30 AI 117943]; NIAID; NHLBI; NIA; NIMHD; NIMH FX This work was supported by the Bill and Melinda Gates Foundation (BMGF) OPP1031734 (TJH). HIV + samples were collected under the BMGF OPP1066973 (B.D.W.). Ab glycan analysis was developed under the BMGF OPP1114729 (G.A.). HCV samples were collected under the NIH U19 A166345 (G.L.). Co-first authors contributed equally to this work including the identification of the Ab-MUC16 interaction (M.S.), performance of experiments (B.G./J.S./M.S.), and all figure and paper preparation (B.G./J.S.). We would like to thank Daniel Stieh for helpful advice pertaining to experimental design. We appreciate services and infrastructure support from Third Coast Center for AIDS Research (CFAR), an NIH funded center (P30 AI 117943) supported by NIAID, NHLBI, NIA, NIMHD, and NIMH. NR 52 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD NOV PY 2016 VL 9 IS 6 BP 1549 EP 1558 DI 10.1038/mi.2016.8 PG 10 WC Immunology SC Immunology GA EA6XZ UT WOS:000386773800019 PM 26960182 ER PT J AU Agnihotri, S Jalali, S Wilson, MR Danesh, A Lil, M Klironomos, G Krieger, JR Mansouri, A Khan, O Mamatjan, Y Landon-Brace, N Tung, T Dowar, M Li, TT Bruce, JP Burrell, KE Tonge, PD Alamsahebpour, A Krischek, B Agarwalla, PK Bi, WL Dunn, IF Beroukhim, R Fehlings, MG Bril, V Pagnotta, SM Iavarone, A Pugh, TJ Aldape, KD Zadeh, G AF Agnihotri, Sameer Jalali, Shahrzad Wilson, Mark R. Danesh, Arnavaz Li, Mira Klironomos, George Krieger, Jonathan R. Mansouri, Alireza Khan, Osaama Mamatjan, Yasin Landon-Brace, Natalie Tung, Takyee Dowar, Mark Li, Tiantian Bruce, Jeffrey P. Burrell, Kelly E. Tonge, Peter D. Alamsahebpour, Amir Krischek, Boris Agarwalla, Pankaj Kumar Bi, Wenya Linda Dunn, Ian F. Beroukhim, Rameen Fehlings, Michael G. Bril, Vera Pagnotta, Stefano M. Iavarone, Antonio Pugh, Trevor J. Aldape, Kenneth D. Zadeh, Gelareh TI The genomic landscape of schwannoma SO NATURE GENETICS LA English DT Article ID NERVE-SHEATH TUMORS; PROSTATE-CANCER CELLS; VESTIBULAR SCHWANNOMAS; NEUROFIBROMATOSIS TYPE-2; LUNG ADENOCARCINOMA; DRIVER MUTATIONS; GENE-EXPRESSION; CLASSIFICATION; RESISTANCE; INHIBITORS AB Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors. C1 [Agnihotri, Sameer; Jalali, Shahrzad; Wilson, Mark R.; Li, Mira; Klironomos, George; Mansouri, Alireza; Khan, Osaama; Mamatjan, Yasin; Landon-Brace, Natalie; Tung, Takyee; Burrell, Kelly E.; Tonge, Peter D.; Alamsahebpour, Amir; Aldape, Kenneth D.; Zadeh, Gelareh] Univ Hlth Network, Princess Margaret Canc Ctr, MacFeeters Hamilton Ctr Neurooncol Res, Toronto, ON, Canada. [Danesh, Arnavaz; Dowar, Mark; Li, Tiantian; Bruce, Jeffrey P.; Pugh, Trevor J.; Aldape, Kenneth D.; Zadeh, Gelareh] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Krieger, Jonathan R.] Hosp Sick Children, SPARC Bioctr, Toronto, ON, Canada. [Krischek, Boris] Univ Hosp Cologne, Dept Neurosurg, Cologne, Germany. [Agarwalla, Pankaj Kumar; Bi, Wenya Linda; Dunn, Ian F.; Beroukhim, Rameen] Harvard Med Sch, Boston, MA USA. [Agarwalla, Pankaj Kumar; Bi, Wenya Linda; Beroukhim, Rameen] Broad Inst MIT & Harvard, Cambridge, MA USA. [Agarwalla, Pankaj Kumar] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Agarwalla, Pankaj Kumar; Bi, Wenya Linda; Beroukhim, Rameen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bi, Wenya Linda; Dunn, Ian F.; Beroukhim, Rameen] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fehlings, Michael G.; Zadeh, Gelareh] Univ Hlth Network, Dept Neurosurg, Toronto, ON, Canada. [Bril, Vera] Univ Toronto, Dept Med Neurol, Toronto, ON, Canada. [Bril, Vera] Univ Toronto, Elizabeth Raab Neurofibromatosis Program, Toronto, ON, Canada. [Pagnotta, Stefano M.] Univ Sannio, Dept Sci & Technol, Benevento, Italy. [Pagnotta, Stefano M.; Iavarone, Antonio] Columbia Univ, Dept Pathol & Cell Biol & Neurol, New York, NY USA. [Pugh, Trevor J.; Aldape, Kenneth D.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Aldape, Kenneth D.] Maryland Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Aldape, Kenneth D.] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. RP Aldape, KD; Zadeh, G (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, MacFeeters Hamilton Ctr Neurooncol Res, Toronto, ON, Canada.; Aldape, KD; Zadeh, G (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.; Zadeh, G (reprint author), Univ Hlth Network, Dept Neurosurg, Toronto, ON, Canada.; Aldape, KD (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada.; Aldape, KD (reprint author), Maryland Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.; Aldape, KD (reprint author), Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. EM kaldape@uhnresearch.ca; gelareh.zadeh@uhn.ca FU Canadian Institute of Health Research (CIHR); Princess Margaret Cancer Foundation; Wilkins Family Chair in Brain Tumor Research; CIHR; Terry Fox Research Institute; MacFeeters-Hamilton Neuro-Oncology Research Program FX This work was supported by the Canadian Institute of Health Research (CIHR) post-doctoral fellowship (S.A.). The contributions of T.J.P., K.D.A. and G.Z. to this project were supported by the Princess Margaret Cancer Foundation. We thank the staff of the Princess Margaret Genomics Centre (N. Winegarden, J. Tsao and N. Khuu) and Bioinformatics Services (C. Virtanen and Z. Lu) for their expertise in generating the sequencing data used in this study. G.Z. is supported by the Wilkins Family Chair in Brain Tumor Research, CIHR grants, and The Terry Fox Research Institute. K.D.A. is supported by funding from the MacFeeters-Hamilton Neuro-Oncology Research Program. The human immortalized Schwann cells were a gift from A. Hoke (The Johns Hopkins School of Medicine, Baltimore, Maryland, USA). NR 58 TC 2 Z9 2 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2016 VL 48 IS 11 BP 1339 EP 1348 DI 10.1038/ng.3688 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EA3XU UT WOS:000386543400010 PM 27723760 ER PT J AU Bonder, MJ Kurilshikov, A Tigchelaar, EF Mujagic, Z Imhann, F Vila, AV Deelen, P Vatanen, T Schirmer, M Smeekens, SP Zhernakova, DV Jankipersadsing, SA Jaeger, M Oosting, M Cenit, MC Masclee, AAM Swertz, MA Li, Y Kumar, V Joosten, L Harmsen, H Weersma, RK Franke, L Hofker, MH Xavier, RJ Jonkers, D Netea, MG Wijmenga, C Fu, JY Zhernakova, A AF Bonder, Marc Jan Kurilshikov, Alexander Tigchelaar, Ettje F. Mujagic, Zlatan Imhann, Floris Vila, Arnau Vich Deelen, Patrick Vatanen, Tommi Schirmer, Melanie Smeekens, Sanne P. Zhernakova, Dania V. Jankipersadsing, Soesma A. Jaeger, Martin Oosting, Marije Cenit, Maria Carmen Masclee, Ad A. M. Swertz, Morris A. Li, Yang Kumar, Vinod Joosten, Leo Harmsen, Hermie Weersma, Rinse K. Franke, Lude Hofker, Marten H. Xavier, Ramnik J. Jonkers, Daisy Netea, Mihai G. Wijmenga, Cisca Fu, Jingyuan Zhernakova, Alexandra TI The effect of host genetics on the gut microbiome SO NATURE GENETICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; LACTASE PERSISTENCE; COLORECTAL-CANCER; RECEPTOR; EXPRESSION; DIVERSITY; VARIANTS; OBESITY AB The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 x 10(-8). Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 x 10(-6). Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 x 10(-8)) and provide evidence of a gene-diet interaction in the regulation of Bifidobacterium abundance. Our, results demonstrate the importance of understanding host-microbe interactions to gain better insight into human health. C1 [Bonder, Marc Jan; Kurilshikov, Alexander; Tigchelaar, Ettje F.; Deelen, Patrick; Zhernakova, Dania V.; Jankipersadsing, Soesma A.; Cenit, Maria Carmen; Swertz, Morris A.; Li, Yang; Kumar, Vinod; Franke, Lude; Wijmenga, Cisca; Fu, Jingyuan; Zhernakova, Alexandra] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Kurilshikov, Alexander] RAS, Inst Chem Biol & Fundamental Med, SB, Novosibirsk, Russia. [Kurilshikov, Alexander] Novosibirsk State Univ, Dept Nat Sci, Novosibirsk, Russia. [Tigchelaar, Ettje F.; Mujagic, Zlatan; Zhernakova, Alexandra] Top Inst Food & Nutr, Wageningen, Netherlands. [Mujagic, Zlatan; Masclee, Ad A. M.; Jonkers, Daisy] Maastricht Univ, NUTRIM Sch Nutr & Translat Res Metab, Div Gastroenterol Hepatol, Dept Internal Med Med Ctr, Maastricht, Netherlands. [Imhann, Floris; Vila, Arnau Vich; Weersma, Rinse K.] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands. [Deelen, Patrick; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Groningen, Netherlands. [Vatanen, Tommi; Schirmer, Melanie; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Vatanen, Tommi] Aalto Univ, Dept Comp Sci, Sch Sci, Espoo, Finland. [Schirmer, Melanie] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smeekens, Sanne P.; Jaeger, Martin; Oosting, Marije; Joosten, Leo; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands. [Smeekens, Sanne P.; Jaeger, Martin; Oosting, Marije; Joosten, Leo; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Nijmegen, Netherlands. [Jankipersadsing, Soesma A.; Hofker, Marten H.; Fu, Jingyuan] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands. [Harmsen, Hermie] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, Groningen, Netherlands. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Cenit, Maria Carmen] Dr Peset Univ Hosp, Dept Pediat, Valencia, Spain. RP Wijmenga, C; Fu, JY; Zhernakova, A (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.; Zhernakova, A (reprint author), Top Inst Food & Nutr, Wageningen, Netherlands.; Fu, JY (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands. EM c.wijmenga@umcg.nl; j.fu@umcg.nl; a.zhernakova@umcg.nl RI Oosting, Marije/H-7437-2015; OI Deelen, Patrick/0000-0002-5654-3966; Bonder, Marc Jan/0000-0002-8431-3180 FU Top Institute Food and Nutrition, Wageningen [TiFN GH001]; Netherlands Organization for Scientific Research [NWO-VIDI 864.13.013]; ZonMW-VIDI [917.14.374, 016.136.308]; CardioVasculair Onderzoek Nederland [CVON 2012-03]; University of Groningen; European Research Council under the European Union; ERC [2012-322698]; Spinoza Prize from the Netherlands Organization for Scientific Research; ERC Consolidator Grant [310372, 259867]; ERC Starting Grant [637640]; Netherlands Organization for Scientific Research VENI grant [863.13.011] FX This project was funded by grants from Top Institute Food and Nutrition, Wageningen, to C.W. (TiFN GH001), the Netherlands Organization for Scientific Research to J.F. (NWO-VIDI 864.13.013), L.F. (ZonMW-VIDI 917.14.374) and R.K.W. (ZonMW-VIDI 016.136.308), and CardioVasculair Onderzoek Nederland to M.H.H., M.G.N., A.Z. and J.F. (CVON 2012-03). A.Z. holds a Rosalind Franklin Fellowship (University of Groningen). This research received funding from the European Research Council under the European Union's Seventh Framework Programme: C.W. is supported by FP7/2007-2013/ERC Advanced Grant (agreement 2012-322698) and a Spinoza Prize from the Netherlands Organization for Scientific Research. M.G.N. holds an ERC Consolidator Grant (310372). L.P. has an FP7/2007-2013 grant (agreement 259867) and an ERC Starting Grant (637640, ImmRisk). Y.L. holds a Netherlands Organization for Scientific Research VENI grant (863.13.011). NR 66 TC 10 Z9 10 U1 39 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2016 VL 48 IS 11 BP 1407 EP 1412 DI 10.1038/ng.3663 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EA3XU UT WOS:000386543400017 PM 27694959 ER PT J AU Vutskits, L Xie, ZC AF Vutskits, Laszlo Xie, Zhongcong TI Lasting impact of general anaesthesia on the brain: mechanisms and relevance SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID POSTOPERATIVE COGNITIVE DYSFUNCTION; DEVELOPING RAT-BRAIN; ISOFLURANE INDUCES APOPTOSIS; MEDIAL PREFRONTAL CORTEX; INDUCED CASPASE-3 ACTIVATION; TERM NEUROCOGNITIVE FUNCTION; AMYLOID PRECURSOR PROTEIN; KAPPA-B PATHWAY; ALZHEIMERS-DISEASE; EARLY EXPOSURE AB General anaesthesia is usually considered to safely induce a reversible brain state allowing the performance of surgery under optimal conditions. An increasing number of clinical and experimental observations, however, suggest that anaesthetic drugs, especially when they are administered at the extremes of age, can trigger long-term morphological and functional alterations in the brain. Here, we review available mechanistic data linking general-anaesthesia exposure to impaired cognitive performance in both young and mature nervous systems. We also provide a critical appraisal of the translational value of animal models and highlight the important challenges that need to be addressed to strengthen the link between laboratory work and clinical investigations in the field of anaesthesia-neurotoxicity research. C1 [Vutskits, Laszlo] Univ Hosp Geneva, Dept Anesthesiol Pharmacol & Intens Care, 4 Rue Gabrielle Perret Gentil, CH-1205 Geneva 4, Switzerland. [Vutskits, Laszlo] Univ Geneva, Sch Med, Dept Basic Neurosci, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St,Room 4310, Charlestown, MA 02129 USA. [Xie, Zhongcong] Harvard Med Sch, 149 13th St,Room 4310, Charlestown, MA 02129 USA. RP Vutskits, L (reprint author), Univ Hosp Geneva, Dept Anesthesiol Pharmacol & Intens Care, 4 Rue Gabrielle Perret Gentil, CH-1205 Geneva 4, Switzerland.; Vutskits, L (reprint author), Univ Geneva, Sch Med, Dept Basic Neurosci, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. EM laszlo.vutskits@unige.ch; zxie@mgh.harvard.edu NR 191 TC 3 Z9 3 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2016 VL 17 IS 11 BP 705 EP 717 DI 10.1038/nrn.2016.128 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EA7HA UT WOS:000386800200008 PM 27752068 ER PT J AU Hnilicova, P Povazan, M Strasser, B Andronesi, OC Gajdosik, M Dydak, U Ukropec, J Dobrota, D Trattnig, S Bogner, W AF Hnilicova, Petra Povazan, Michal Strasser, Bernhard Andronesi, Ovidiu C. Gajdosik, Martin Dydak, Ulrike Ukropec, Jozef Dobrota, Dusan Trattnig, Siegfried Bogner, Wolfgang TI Spatial variability and reproducibility of GABA-edited MEGA-LASER 3D-MRSI in the brain at 3T SO NMR IN BIOMEDICINE LA English DT Article DE acquisition methods; MEGA editing; MRS and MRSI methods; neurotransmitters; normal brain; reproducibility ID MAGNETIC-RESONANCE-SPECTROSCOPY; IN-VIVO DETECTION; REAL-TIME MOTION; MR SPECTROSCOPY; REGIONAL-VARIATIONS; GLUTAMATE; AGE; NEUROTRANSMITTERS; SCHIZOPHRENIA; GENDER AB The reproducibility of gamma-aminobutyric acid (GABA) quantification results, obtained with MRSI, was determined on a 3T MR scanner in healthy adults. In this study, a spiral-encoded, GABA-edited, MEGA-LASER MRSI sequence with real-time motion-scanner-instability corrections was applied for robust 3D mapping of neurotransmitters in the brain. In particular, the GABA(+) (i.e. GABA plus macromolecule contamination) and Glx (i.e. glutamate plus glutamine contamination) signal was measured. This sequence enables 3D-MRSI with about 3cm(3) nominal resolution in about 20min. Since reliable quantification of GABA is challenging, the spatial distribution of the inter-subject and intra-subject variability of GABA(+) and Glx levels was studied via test-retest assessment in 14 healthy volunteers (seven men-seven women). For both inter-subject and intra-subject repeated measurement sessions a low coefficient of variation (CV) and a high intraclass correlation coefficient (ICC) were found for GABA(+) and Glx ratios across all evaluated voxels (intra-/inter-subject: GABA(+) ratios, CV similar to 8%-ICC>0.75; Glx ratios, CV similar to 6%-ICC>0.70). The same was found in selected brain regions for Glx ratios versus GABA(+) ratios (CV varied from about 5% versus about 8% in occipital and parietal regions, to about 8% versus about 10% in the frontal area, thalamus, and basal ganglia). These results provide evidence that 3D mapping of GABA(+) and Glx using the described methodology provides high reproducibility for application in clinical and neuroscientific studies. C1 [Hnilicova, Petra] Comenius Univ, Jessenius Fac Med Martin, Biomed Ctr Martin, Div Neurosci, Martin, Slovakia. [Povazan, Michal; Trattnig, Siegfried] Christian Doppler Lab Clin Mol MR Imaging, Vienna, Austria. [Strasser, Bernhard; Gajdosik, Martin; Bogner, Wolfgang] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, High Field MR Ctr, Vienna, Austria. [Andronesi, Ovidiu C.] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA USA. [Dydak, Ulrike] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Dydak, Ulrike] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA. [Ukropec, Jozef] Slovak Acad Sci, Biomed Res Ctr, Inst Expt Endocrinol, Obes Sect,Diabet & Metab Dis Lab, Bratislava, Slovakia. [Dobrota, Dusan] Comenius Univ, Jessenius Fac Med Martin, Dept Med Biochem, Martin, Slovakia. RP Bogner, W (reprint author), Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, High Field MR Ctr, Vienna, Austria. EM wolfgang.bogner@meduniwien.ac.at OI Strasser, Bernhard/0000-0001-9542-3855; Bogner, Wolfgang/0000-0002-0130-3463 FU Austrian Science Fund (FWF) [KLI-61]; FFG Bridge Early Stage Grant [846505]; project SAS-NSC Joint Research Cooperation Grant [2013/17]; project VEGA [2/0191/15]; project "Increasing opportunities for career growth in research and development in the field of medical sciences" [ITMS: 26110230067]; project "Biomedical Center Martin" - EU [ITMS: 26220220187] FX This study was supported by the Austrian Science Fund (FWF), KLI-61, and the FFG Bridge Early Stage Grant 846505, and by the projects SAS-NSC Joint Research Cooperation Grant 2013/17, VEGA 2/0191/15, "Increasing opportunities for career growth in research and development in the field of medical sciences" (ITMS: 26110230067), and "Biomedical Center Martin" (ITMS: 26220220187), co-funded from EU sources. NR 40 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD NOV PY 2016 VL 29 IS 11 BP 1656 EP 1665 DI 10.1002/nbm.3613 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA EA4WR UT WOS:000386617100017 PM 27717093 ER PT J AU Karp, JF McGovern, J Marron, MM Gerszten, P Weiner, DK Okonkwo, D Kanter, AS AF Karp, Jordan F. McGovern, Jonathan Marron, Megan M. Gerszten, Peter Weiner, Debra K. Okonkwo, David Kanter, Adam S. TI Clinical and neuropsychiatric correlates of lumbar spinal surgery in older adults: results of a pilot study SO PAIN MANAGEMENT LA English DT Article DE aging; complications; lumbar spine; predictors; psychiatric; spinal stenosis ID LOW-BACK-PAIN; MINI-MENTAL-STATE; GAIT SPEED; PHYSICAL FUNCTION; ELDERLY-PEOPLE; WALKING SPEED; PRIMARY-CARE; PREDICTORS; STENOSIS; DEPRESSION AB Aim: To improve selection of older lumbar surgical candidates, we surveyed correlates of functioning and satisfaction with surgery. Materials & methods: Prospective sample at lumbar spine surgery clinic. Patients (n = 48) were evaluated before surgery and after 3 months. Dependent variables were functioning and surgical satisfaction. Results: Baseline variables associated with disability at 3 months included cognitive status and widespread pain. There was clinically significant improvement with moderate effects sizes for anxiety and depression at follow-up. Patients with at least a 30% improvement in disability had better physical health-related quality of life and were less likely to report widespread pain before surgery. Conclusion: Although preliminary, two novel potential predictors of lumbar surgery outcome include diminished cognitive functioning and widespread pain. Further study of these variables on post-surgical functioning and satisfaction may improve patient selection. C1 [Karp, Jordan F.; Marron, Megan M.; Weiner, Debra K.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Karp, Jordan F.; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, GRECC, Pittsburgh, PA 15261 USA. [McGovern, Jonathan] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [Gerszten, Peter; Okonkwo, David; Kanter, Adam S.] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15261 USA. [Weiner, Debra K.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. RP Karp, JF (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA.; Karp, JF (reprint author), VA Pittsburgh Healthcare Syst, GRECC, Pittsburgh, PA 15261 USA. EM karpjf@upmc.edu FU NIA NIH HHS [R01 AG033575] NR 42 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-1869 EI 1758-1877 J9 PAIN MANAG JI Pain Manag. PD NOV PY 2016 VL 6 IS 6 BP 543 EP 552 DI 10.2217/pmt.16.9 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EA5WK UT WOS:000386695000005 PM 27102978 ER PT J AU Fernandez-del Castillo, C AF Fernandez-del Castillo, Carlos TI 2016 American Pancreatic Association Presidential Address: Forging Interactions to Advance the Field SO PANCREAS LA English DT Editorial Material C1 [Fernandez-del Castillo, Carlos] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 32 Fruit St, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 32 Fruit St, Boston, MA 02114 USA. EM cfernandez@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1359 EP 1360 DI 10.1097/MPA.0000000000000712 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400001 PM 27748717 ER PT J AU Qian, ZR Li, TT Ter-Minassian, M Yang, JH Chan, JA Brais, LK Masugi, Y Thiaglingam, A Brooks, N Nishihara, R Bonnemarie, M Masuda, A Inamura, K Kim, SA Mima, K Sukawa, Y Dou, RX Lin, XH Christiani, DC Schmidlin, F Fuchs, CS Mahmood, U Ogino, S Kulke, MH AF Qian, Zhi Rong Li, Tingting Ter-Minassian, Monica Yang, Juhong Chan, Jennifer A. Brais, Lauren K. Masugi, Yohei Thiaglingam, Arunthathi Brooks, Nichole Nishihara, Reiko Bonnemarie, Mireille Masuda, Atsuhiro Inamura, Kentaro Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Dou, Ruoxu Lin, Xihong Christiani, David C. Schmidlin, Fabien Fuchs, Charles S. Mahmood, Umar Ogino, Shuji Kulke, Matthew H. TI Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors SO PANCREAS LA English DT Article DE somatostatin receptor; somatostatin analog; prognosis; survival; neuroendocrine tumor ID ENDOCRINE GASTROENTEROPANCREATIC TUMORS; MONOCLONAL-ANTIBODIES; ANALOG OCTREOTIDE; INTERFERON-ALPHA; LANREOTIDE; NEOPLASMS; EFFICACY; SUBTYPES; GROWTH; CELLS AB Objective Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET. Methods Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders. Results High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs. Conclusions Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival. C1 [Qian, Zhi Rong; Li, Tingting; Ter-Minassian, Monica; Yang, Juhong; Chan, Jennifer A.; Brais, Lauren K.; Masugi, Yohei; Brooks, Nichole; Nishihara, Reiko; Masuda, Atsuhiro; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Dou, Ruoxu; Fuchs, Charles S.; Ogino, Shuji; Kulke, Matthew H.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room MA420, Boston, MA 02115 USA. [Li, Tingting] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Gastroenterol, Beijing, Peoples R China. [Ter-Minassian, Monica; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Yang, Juhong] Tianjin Med Univ, Metab Dis Hosp, Minist Hlth, Collaborat Innovat Ctr Tianjin Med Epigenet,Key L, Tianjin, Peoples R China. [Yang, Juhong] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin, Peoples R China. [Thiaglingam, Arunthathi] IPSEN Biosci Inc, Global Drug Discovery Dept, Cambridge, MA USA. [Bonnemarie, Mireille] IPSEN Innovat, Global Drug Discovery Dept, Les Ulis, France. [Lin, Xihong] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Christiani, David C.; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Ogino, Shuji] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. RP Qian, ZR (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room MA420, Boston, MA 02115 USA. EM Zhirong_Qian@dfci.harvard.edu OI Masugi, Yohei/0000-0002-6952-4043 FU Ipsen Pharmaceuticals; US National Institutes of Health [P50 CA127003, R01 CA151532, R01 CA151993, R35 CA197735, R01 CA166582, K07 CA190673] FX This study was funded in part from a grant from Ipsen Pharmaceuticals. This work was also supported by US National Institutes of Health grants P50 CA127003 to C.S.F., R01 CA151532 to M.H.K., R01 CA151993 to S.O., R35 CA197735 to S.O., R01 CA166582 to U.M., and K07 CA190673 to R.N. NR 46 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1386 EP 1393 DI 10.1097/MPA.0000000000000700 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400005 PM 27622342 ER PT J AU Basar, O Yuksel, O Yang, D Samarasena, J DiMaio, CJ Wagh, MS Forcione, DG Ronald, AN Pitman, MB Brugge, WR AF Basar, O. Yuksel, O. Yang, D. Samarasena, J. DiMaio, C. J. Wagh, M. S. Forcione, D. G. Ronald, A. N. Pitman, M. B. Brugge, W. R. TI The Micro-Forceps for Pancreatic Cysts: A Game Changer? SO PANCREAS LA English DT Meeting Abstract C1 [Basar, O.; Yuksel, O.; Forcione, D. G.; Brugge, W. R.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Yang, D.] Univ Florida Hlth Hlth, Gastroenterol, Gainesville, FL USA. [Samarasena, J.] Univ Calif Irvine, Gastroenterol, Irvine, CA USA. [DiMaio, C. J.] Mt Sinai Hosp, Gastroenterol, New York, NY 10029 USA. [Wagh, M. S.] Univ Colorado, Gastroenterol, Denver, CO 80202 USA. [Ronald, A. N.; Pitman, M. B.] Massachusetts Gen Hosp, Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1497 EP 1497 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400034 ER PT J AU Cai, L Michelakos, T Fernandez-Del Castillo, C Mino-Kenudson, M Warshaw, AL Lillemoe, KD Ferrone, S Ferrone, CR AF Cai, L. Michelakos, T. Fernandez-Del Castillo, C. Mino-Kenudson, M. Warshaw, A. L. Lillemoe, K. D. Ferrone, S. Ferrone, C. R. TI Association of High HLA Class I Antigen Expression With Poor Prognosis in Intraductal Papillary Mucinous Neoplasms (IPMN) SO PANCREAS LA English DT Meeting Abstract C1 [Cai, L.; Michelakos, T.; Fernandez-Del Castillo, C.; Warshaw, A. L.; Lillemoe, K. D.; Ferrone, S.; Ferrone, C. R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1499 EP 1499 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400042 ER PT J AU Hollemans, RA Van Brunschot, S Bakker, O Besselink, MG Baron, TH Beger, HG Boermeester, MA Bollen, TL Bruno, MJ Carter, R Charnley, R Coelho, D Dahl, B Dijkgraaf, MG Doctor, N Farkas, G Fagenholz, PJ Fernandez-Del Castillo, C Fockens, P Freeman, ML Gardner, TB Van Goor, H Gooszen, HG Hannink, G Lochan, R Mckay, CJ Peev, MP Neoptolemos, JP Olah, A Parks, RW Raraty, M Rau, B Rosch, T Rovers, M Seifert, H Siriwardena, AK Horvath, KD Van Santvoort, HC AF Hollemans, R. A. Van Brunschot, S. Bakker, O. Besselink, M. G. Baron, T. H. Beger, H. G. Boermeester, M. A. Bollen, T. L. Bruno, M. J. Carter, R. Charnley, R. Coelho, D. Dahl, B. Dijkgraaf, M. G. Doctor, N. Farkas, G. Fagenholz, P. J. Fernandez-Del Castillo, C. Fockens, P. Freeman, M. L. Gardner, T. B. Van Goor, H. Gooszen, H. G. Hannink, G. Lochan, R. Mckay, C. J. Peev, M. P. Neoptolemos, J. P. Olah, A. Parks, R. W. Raraty, M. Rau, B. Roesch, T. Rovers, M. Seifert, H. Siriwardena, A. K. Horvath, K. D. Van Santvoort, H. C. TI Minimally Invasive Versus Open Necrosectomy for Necrotizing Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 [Hollemans, R. A.; Besselink, M. G.; Boermeester, M. A.] Acad Med Ctr, Dept Surg, Amsterdam, Netherlands. [Van Brunschot, S.] Acad Med Ctr, Gastroenterol, Amsterdam, Netherlands. [Bakker, O.] Univ Med Ctr Utrecht, Surg, Utrecht, Netherlands. [Baron, T. H.] Univ N Carolina, Gastroenterol & Hepatol, Chapel Hill, NC USA. [Beger, H. G.] Univ Ulm, Surg, Ulm, Germany. [Bollen, T. L.] St Antonius Hosp, Radiol, Utrecht, Netherlands. [Bruno, M. J.] Erasmus Univ, Gastroenterol & Hepatol, Med Ctr, Rotterdam, Netherlands. [Carter, R.] Glasgow Royal Infirm, Glasgow, Lanark, Scotland. [Charnley, R.] Newcastle Upon Tyne Hosp, Dept HPB Surg, Newcastle Upon Tyne, Tyne & Wear, England. [Coelho, D.] Hosp Clementino Fraga Filho, Rio De Janeiro, Brazil. [Dahl, B.] Oldenburg Municipal Hosp, Dept Internal Med, Oldenburg, Germany. [Dijkgraaf, M. G.] Acad Med Ctr, Clin Res Unit, Amsterdam, Netherlands. [Doctor, N.] Jaslok Hosp & Res Ctr, Surg, Bombay, Maharashtra, India. [Farkas, G.] Univ Szeged, Szeged, Hungary. [Fagenholz, P. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fernandez-Del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Fockens, P.] Acad Med Ctr Amsterdam, Amsterdam, Netherlands. [Freeman, M. L.] Univ Minnesota, Gastroenterol, Minneapolis, MN USA. [Gardner, T. B.] Dartmouth Hitchcock Med Ctr, Gastroenterol & Hepatol, Lebanon, NH 03766 USA. [Van Goor, H.] Radboud Univ Nijmegen, Surg, Med Ctr, Nijmegen, Netherlands. [Gooszen, H. G.] Radboud Univ Nijmegen, Med Ctr, Operating Rooms Evidence Based Surg, Nijmegen, Netherlands. [Hannink, G.; Rovers, M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Lochan, R.] Freeman Rd Hosp, Surg, Newcastle Upon Tyne, Tyne & Wear, England. [Mckay, C. J.] Glasgow Royal Infirm, Surg, Glasgow, Lanark, Scotland. [Peev, M. P.] Massachusetts Gen Hosp, Surg, Boston, MA 02114 USA. [Neoptolemos, J. P.] Royal Liverpool & Broadgreen Univ Hosp, Liverpool Pancreas Biomed Res Unit, Natl Inst Hlth Res, Liverpool, Merseyside, England. [Olah, A.] Petz Aladar Teaching Hosp, Surg, Gyor, Hungary. [Parks, R. W.] Univ Edinburgh, Surg, Edinburgh, Midlothian, Scotland. [Raraty, M.] Royal Liverpool & Broadgreen Univ Hosp, Surg, Liverpool, Merseyside, England. [Rau, B.] Univ Rostock, Surg, Rostock, Germany. [Roesch, T.] Univ Hosp Hamburg Eppendorf, Interdisciplinary Endoscopy, Hamburg, Germany. [Seifert, H.] Oldenburg Municipal Hosp, Internal Med, Oldenburg, Germany. [Siriwardena, A. K.] Manchester Royal Infirm, Surg, Manchester, Lancs, England. [Horvath, K. D.] Univ Washington, Surg, Seattle, WA USA. [Van Santvoort, H. C.] St Antonius Hosp, Surg, Nieuwegein, Netherlands. NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1510 EP 1511 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400090 ER PT J AU Honselmann, KC Pergolini, I Fernandez-Del Castillo, C Warshaw, AL Lillemoe, KD Ferrone, CR AF Honselmann, K. C. Pergolini, I. Fernandez-Del Castillo, C. Warshaw, A. L. Lillemoe, K. D. Ferrone, C. R. TI Node-Negative Disease in Pancreatic Cancer Might Not Present Different Tumor Biology SO PANCREAS LA English DT Meeting Abstract C1 [Honselmann, K. C.; Pergolini, I.; Fernandez-Del Castillo, C.; Warshaw, A. L.; Lillemoe, K. D.; Ferrone, C. R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1511 EP 1511 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400091 ER PT J AU Krishna, SG Brugge, WR Dewitt, JM Kongkam, P Napoleon, B Robles-Medranda, C Tan, D El-Dika, S Hart, P Conwell, DL AF Krishna, S. G. Brugge, W. R. Dewitt, J. M. Kongkam, P. Napoleon, B. Robles-Medranda, C. Tan, D. El-Dika, S. Hart, P. Conwell, D. L. TI An International External Inter-and Intraobserver Variability Study Evaluating Needle Based Confocal Laser Endomicroscopy (nCLE) for Diagnosis of Pancreatic Cystic Lesions (PCLs) SO PANCREAS LA English DT Meeting Abstract C1 [Krishna, S. G.; El-Dika, S.; Hart, P.; Conwell, D. L.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Brugge, W. R.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Dewitt, J. M.] Indiana Univ, Terre Haute, IN USA. [Kongkam, P.] Chulalongkorn Univ, Bangkok, Thailand. [Napoleon, B.] Hop Prive Jean Mermoz, Lyon, France. [Robles-Medranda, C.] Ecuadorian Inst Digest Dis, Guayaquil, Ecuador. [Tan, D.] Singapore Gen Hosp, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1517 EP 1518 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400118 ER PT J AU Elperin, JM Suriany, S Lee, GE French, SW Gukovskaya, AS Gukovsky, I Mareninova, OA AF Elperin, J. M. Suriany, S. Lee, G. E. French, S. W. Gukovskaya, A. S. Gukovsky, I. Mareninova, O. A. TI Downregulation of Atg4B Stimulates Autophagy and Ameliorates Alcohol-Induced Pancreatic Injury SO PANCREAS LA English DT Meeting Abstract C1 [Elperin, J. M.; Suriany, S.; Lee, G. E.; Gukovskaya, A. S.; Gukovsky, I.; Mareninova, O. A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Elperin, J. M.; Suriany, S.; Lee, G. E.; Gukovskaya, A. S.; Gukovsky, I.; Mareninova, O. A.] Univ Calif Los Angeles, Los Angeles, CA USA. [French, S. W.] Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1523 EP 1523 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400141 ER PT J AU Matsuda, Y Furukawa, T Yachida, S Nishimura, M Seki, A Nonaka, K Aida, J Takubo, K Ishiwata, T Kimura, W Arai, T Mino-Kenudson, M AF Matsuda, Y. Furukawa, T. Yachida, S. Nishimura, M. Seki, A. Nonaka, K. Aida, J. Takubo, K. Ishiwata, T. Kimura, W. Arai, T. Mino-Kenudson, M. TI High-Grade PanIN/Carcinoma In Situ of the Pancreas Associated With Cystic Changes and Fibrosis SO PANCREAS LA English DT Meeting Abstract C1 [Matsuda, Y.; Seki, A.; Nonaka, K.; Arai, T.] Tokyo Metropolitan Geriatr Hosp, Dept Pathol, Tokyo, Japan. [Furukawa, T.] Tokyo Womens Med Univ, Inst Integrated Med Sci, Tokyo, Japan. [Yachida, S.] Natl Canc Ctr, Div Canc Genom, Tokyo, Japan. [Nishimura, M.] Tokyo Metropolitan Geriatr Hosp, Dept Endoscopy, Tokyo, Japan. [Aida, J.; Takubo, K.; Ishiwata, T.] Tokyo Metropolitan Inst Gerontol, Res Team Geriatr Pathol, Dept Aging & Carcinogenesis, Tokyo, Japan. [Kimura, W.] Yamagata Univ, Dept Gastroenterol Gen Breast & Thyroid Surg, Yamagata, Japan. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1523 EP 1524 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400143 ER PT J AU Mino-Kenudson, M Morales-Oyarvide, V Date, K Ohtsuka, T Omori, Y Tanino, M Mizukami, Y Hong, SM Hwang, DW Kim, SC Zamboni, G Castelli, P Higuchi, R Yamamoto, M Shimizu, K Nakamura, M Maguchi, H Fernandez-Del Castillo, C Furukawa, T AF Mino-Kenudson, M. Morales-Oyarvide, V. Date, K. Ohtsuka, T. Omori, Y. Tanino, M. Mizukami, Y. Hong, S. -M. Hwang, D. W. Kim, S. C. Zamboni, G. Castelli, P. Higuchi, R. Yamamoto, M. Shimizu, K. Nakamura, M. Maguchi, H. Fernandez-Del Castillo, C. Furukawa, T. TI Invasive Size Predicts Recurrence and Survival of Small Invasive Carcinoma Arising in Intraductal Papillary Mucinous Neoplasm of the Pancreas SO PANCREAS LA English DT Meeting Abstract C1 [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Morales-Oyarvide, V.] Dana Faber Canc Ctr, Boston, MA USA. [Date, K.; Ohtsuka, T.; Nakamura, M.] Kyushu Univ, Dept Surg & Oncol, Fukuoka, Japan. [Omori, Y.] Teine Keijinkai Hosp, Dept Pathol, Sapporo, Hokkaido, Japan. [Tanino, M.] Hokkaido Univ, Dept Canc Pathol, Grad Sch Med, Sapporo, Hokkaido, Japan. [Mizukami, Y.] Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido, Japan. [Hong, S. -M.] Univ Ulsan, Coll Med, Asan Med Ctr, Pathol, Seoul, South Korea. [Hwang, D. W.; Kim, S. C.] Univ Ulsan, Coll Med, Asan Med Ctr, Div Hepatobiliary & Pancreas Surg,Dept Surg, Seoul, South Korea. [Zamboni, G.] Univ Verona, Pathol, Verona, Italy. [Zamboni, G.] Don Calabria Hosp, Verona, Italy. [Castelli, P.] Don Calabria Hosp, Pathol, Negrar, Italy. [Higuchi, R.; Yamamoto, M.] Tokyo Womens Med Univ, Inst Gastroenterol, Surg, Tokyo, Japan. [Shimizu, K.] Tokyo Womens Med Univ, Inst Gastroenterol, Gastroenterol, Tokyo, Japan. [Maguchi, H.] Teine Keijinkai Hosp, Ctr Gastroenterol, Sapporo, Hokkaido, Japan. [Fernandez-Del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Furukawa, T.] Tokyo Womens Med Univ, Inst Integrated Med Sci, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1526 EP 1526 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400151 ER PT J AU Pergolini, I Sahora, K Ferrone, CR Brugge, WR Patino, M Lillemoe, KD Warshaw, AL Fernandez-Del Castillo, C AF Pergolini, I. Sahora, K. Ferrone, C. R. Brugge, W. R. Patino, M. Lillemoe, K. D. Warshaw, A. L. Fernandez-Del Castillo, C. TI Risk of Malignant Transformation in Suspected Branch Duct Intraductal Papillary Mucinous Neoplasms Extends Beyond 5 Years SO PANCREAS LA English DT Meeting Abstract C1 [Pergolini, I.; Sahora, K.; Ferrone, C. R.; Lillemoe, K. D.; Warshaw, A. L.; Fernandez-Del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Brugge, W. R.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Patino, M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1533 EP 1533 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400181 ER PT J AU Takakura, K Mascarinas, E Decant, B Dawson, D Eibl, G Gukovskaya, A Grippo, P AF Takakura, K. Mascarinas, E. Decant, B. Dawson, D. Eibl, G. Gukovskaya, A. Grippo, P. TI Haploinsufficiency of Beclin1 Inhibits PanIN Development in a Kras(G12D) Mouse Model of Pancreatic Tumorigenesis SO PANCREAS LA English DT Meeting Abstract C1 [Takakura, K.; Gukovskaya, A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Takakura, K.; Gukovskaya, A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mascarinas, E.; Decant, B.; Grippo, P.] Univ Illinois, Dept Med, Chicago, IL USA. [Dawson, D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Eibl, G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1541 EP 1541 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400214 ER PT J AU Xourafas, D Fernandez-Del Castillo, C Warshaw, AL Lillemoe, KD Ferrone, CR AF Xourafas, D. Fernandez-Del Castillo, C. Warshaw, A. L. Lillemoe, K. D. Ferrone, C. R. TI Effect of the Medicare Severity-Diagnosis Related Group Classification System on Predicting Hospital Readmission After Distal Pancreatectomy SO PANCREAS LA English DT Meeting Abstract C1 [Xourafas, D.; Fernandez-Del Castillo, C.; Warshaw, A. L.; Lillemoe, K. D.; Ferrone, C. R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1546 EP 1546 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400234 ER PT J AU Yuan, J Qin, Y Malla, SR Geng, M Waldron, RT Mareninova, OA Lugea, A Pandol, SJ Gukovskaya, AS AF Yuan, J. Qin, Y. Malla, S. R. Geng, M. Waldron, R. T. Mareninova, O. A. Lugea, A. Pandol, S. J. Gukovskaya, A. S. TI Genetic Ablation of Mitochondrial Deacetylase Sirtuin 3 Exacerbates Cerulein Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 [Yuan, J.; Qin, Y.; Malla, S. R.; Geng, M.; Waldron, R. T.; Mareninova, O. A.; Lugea, A.; Pandol, S. J.; Gukovskaya, A. S.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Yuan, J.; Qin, Y.; Malla, S. R.; Geng, M.; Waldron, R. T.; Mareninova, O. A.; Lugea, A.; Pandol, S. J.; Gukovskaya, A. S.] Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA. [Qin, Y.] Youjiang Med Univ Nationalities, Div Gastroenterol & Hepatol, Baise, Peoples R China. [Geng, M.] Quinnipiac Univ, Frank Netter H MD Sch Med, North Haven, CT USA. [Waldron, R. T.; Lugea, A.; Pandol, S. J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2016 VL 45 IS 10 BP 1550 EP 1550 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA9QG UT WOS:000386978400249 ER PT J AU Marron, JM DuBois, SG Bender, JG Kim, A Crompton, BD Meyer, SC Janeway, KA Mack, JW AF Marron, Jonathan M. DuBois, Steven G. Bender, Julia Glade Kim, AeRang Crompton, Brian D. Meyer, Stephanie C. Janeway, Katherine A. Mack, Jennifer W. TI Patient/parent perspectives on genomic tumor profiling of pediatric solid tumors: The Individualized Cancer Therapy (iCat) experience SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cancer; genomics; molecular profiling; patient perspectives; pediatric oncology; personalized medicine ID CHILDRENS ONCOLOGY GROUP; CHRONIC MYELOID-LEUKEMIA; INFORMED-CONSENT; INCIDENTAL FINDINGS; POOLED ANALYSIS; CLINICAL TUMOR; BREAST-CANCER; LUNG-CANCER; FOLLOW-UP; PARENTS AB Background: Genomic tumor profiling (GTP) plays an important role in the care of many adult cancer patients. Its role in pediatric oncology is still evolving, with only a subset of patients currently expected to receive clinically significant results. Little is known about perspectives of pediatric oncology patients/parents on GTP. Procedure: We surveyed individuals who previously underwent GTP through the iCat (Individualized Cancer Therapy) pilot study of molecular profiling in children with relapsed, refractory, and high-risk solid tumors at four pediatric cancer centers. Following return of profiling results, a cross-sectional survey was offered to the patient, if he or she was 18 years or older at enrollment, or parent, if he or she was under 18 years of age. Forty-five surveys (85% response) were completed. Results: Eighty-nine percent (39/44) of respondents reported hoping participation would help find cures for future patients, while 59% (26/44) hoped it would increase their/their child's chance of cure. Most had few concerns about GTP, but 12% (5/43) worried they would learn their/their child's cancer was less treatable or more aggressive than previously thought. Sixty-four percent (29/45) reported feeling their participation had helped others and 44% (20/45) felt they had helped themselves/their own child, despite only one substudy subject receiving targeted therapy matched to GTP findings. Fifty-four percent (21/39) wished to receive all available profiling data, including findings unrelated to cancer and of unclear significance. Conclusions: Participants in pediatric GTP research perceive benefits of GTP to themselves and others, but expectations of personal benefits of GTP may exceed actual positive impact. These issues warrant consideration during consent discussions about GTP research participation. C1 [Marron, Jonathan M.; DuBois, Steven G.; Crompton, Brian D.; Meyer, Stephanie C.; Janeway, Katherine A.; Mack, Jennifer W.] Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Boston, MA USA. [Marron, Jonathan M.; DuBois, Steven G.; Crompton, Brian D.; Janeway, Katherine A.; Mack, Jennifer W.] Harvard Med Sch, Boston, MA USA. [Marron, Jonathan M.; Mack, Jennifer W.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Marron, Jonathan M.] Boston Childrens Hosp, Off Eth, Boston, MA USA. [Bender, Julia Glade] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol & Stem Cell Transplantat, New York, NY USA. [Kim, AeRang] Childrens Natl Med Ctr, Dept Pediat Oncol, Washington, DC 20010 USA. RP Marron, JM (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM jonathan_marron@dfci.harvard.edu OI Marron, Jonathan/0000-0001-8935-8524 NR 45 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 IS 11 BP 1974 EP 1982 DI 10.1002/pbc.26137 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EB0HA UT WOS:000387023500018 PM 27429135 ER PT J AU Lu, BY Kojima, L Huang, MS Friedmann, AM Ferry, JA Weinstein, HJ AF Lu, Benjamin Y. Kojima, Lisa Huang, Mary S. Friedmann, Alison M. Ferry, Judith A. Weinstein, Howard J. TI Facial manifestations of Epstein-Barr virus-related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia; Epstein-Barr virus; lymphoproliferative disease; maintenance chemotherapy ID NERVOUS-SYSTEM INVOLVEMENT; LYMPHOMA; DISORDER; CHILDREN AB Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD. C1 [Lu, Benjamin Y.; Huang, Mary S.; Friedmann, Alison M.; Weinstein, Howard J.] Harvard Med Sch, Massachusetts Gen Hosp Children, Div Pediat Hematol & Oncol, Boston, MA USA. [Kojima, Lisa] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA USA. [Ferry, Judith A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Weinstein, HJ (reprint author), Massachusetts Gen Hosp Children, Div Pediat Hematol & Oncol, 55 Fruit St,Yawkey 8B, Boston, MA 02114 USA. EM hweinstein@mgh.harvard.edu NR 17 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 IS 11 BP 2042 EP 2045 DI 10.1002/pbc.26102 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA EB0HA UT WOS:000387023500028 PM 27392033 ER PT J AU Riley, E Okabe, H Germine, L Wilmer, J Esterman, M DeGutis, J AF Riley, Elizabeth Okabe, Hidefusa Germine, Laura Wilmer, Jeremy Esterman, Michael DeGutis, Joseph TI Gender Differences in Sustained Attentional Control Relate to Gender Inequality across Countries SO PLOS ONE LA English DT Article ID CONTINUOUS PERFORMANCE-TEST; CHILD-DEVELOPMENT; INHIBITORY CONTROL; YOUNG-CHILDREN; TASK; SIMILARITIES; ABILITY; SAMPLE; FACE; AGE AB Sustained attentional control is critical for everyday tasks and success in school and employment. Understanding gender differences in sustained attentional control, and their potential sources, is an important goal of psychology and neuroscience and of great relevance to society. We used a large web-based sample (n = 21,484, from testmybrain.org) to examine gender differences in sustained attentional control. Our sample included participants from 41 countries, allowing us to examine how gender differences in each country relate to national indices of gender equality. We found significant gender differences in certain aspects of sustained attentional control. Using indices of gender equality, we found that overall sustained attentional control performance was lower in countries with less equality and that there were greater gender differences in performance in countries with less equality. These findings suggest that creating sociocultural conditions which value women and men equally can improve a component of sustained attention and reduce gender disparities in cognition. C1 [Riley, Elizabeth; Okabe, Hidefusa; Esterman, Michael; DeGutis, Joseph] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Riley, Elizabeth; DeGutis, Joseph] Harvard Med Sch, Cambridge, MA USA. [Germine, Laura] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wilmer, Jeremy] Wellesley Coll, Dept Psychol, Wellesley, MA 02181 USA. [Esterman, Michael] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Riley, E (reprint author), VA Boston Healthcare Syst, GRECC, Boston, MA USA.; Riley, E (reprint author), Harvard Med Sch, Cambridge, MA USA. EM lissariley@gmail.com OI Germine, Laura/0000-0001-8690-8412 FU US Department of Veterans Affairs grant: VA Advanced Geriatric Fellowship; US Department of Veterans Affairs grant: VA Rehabilitation R&D Center of Excellence Award [B6796-C]; US Department of Veterans Affairs grant: VA Clinical Science R&D Career Development Award [1IK2CX000706-01A2]; VA Advanced Geriatric Fellowship; VA Rehabilitation R&D Center of Excellence Award [B6796-C]; VA Clinical Science R&D Career Development Award [1IK2CX000706-01A2] FX This research was supported by 3 US Department of Veterans Affairs grants: VA Advanced Geriatric Fellowship (ER), VA Rehabilitation R&D Center of Excellence Award (JD, B6796-C), and VA Clinical Science R&D Career Development Award (ME, 1IK2CX000706-01A2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Research supported by VA Advanced Geriatric Fellowship (E.R.), VA Rehabilitation R&D Center of Excellence Award (J.D., B6796-C), and VA Clinical Science R&D Career Development Award (M.E., 1IK2CX000706-01A2). NR 32 TC 1 Z9 1 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 1 PY 2016 VL 11 IS 11 AR e0165100 DI 10.1371/journal.pone.0165100 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6CX UT WOS:000386714200018 PM 27802294 ER PT J AU Abboud, ME Band, R Jia, J Pajerowski, W David, G Guo, M Mechem, C Messe, SR Carr, BG Mullen, MT AF Abboud, Michael E. Band, Roger Jia, Judy Pajerowski, William David, Guy Guo, Michelle Mechem, Crawford Messe, Steven R. Carr, Brendan G. Mullen, Michael T. TI RECOGNITION OF STROKE BY EMS IS ASSOCIATED WITH IMPROVEMENT IN EMERGENCY DEPARTMENT QUALITY MEASURES SO PREHOSPITAL EMERGENCY CARE LA English DT Article DE stroke; thrombolysis; quality measures; CVA ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; HEALTH-CARE PROFESSIONALS; TIME; THROMBOLYSIS; ACCURACY; CINCINNATI; SYSTEM; SCALE; 21ST-CENTURY AB Objective: Hospital arrival via Emergency Medical Services ( EMS) and EMS prenotification are associated with faster evaluation and treatment of stroke. We sought to determine the impact of diagnostic accuracy by prehospital providers on emergency department quality measures. Methods: A retrospective study was performed of patients presenting via EMS between September 2009 and December 2012 with a discharge diagnosis of transient ischemic attack ( TIA), ischemic stroke ( IS), or intracerebral hemorrhage ( ICH). Hospital and EMS databases were used to determine EMS impression, prehospital and in-hospital time intervals, EMS prenotification, NIH stroke scale ( NIHSS), symptom duration, and thrombolysis rate. Results: 399 cases were identified: 14.5% TIA, 67.2% IS, and 18.3% ICH. EMS providers correctly recognized 57.6% of cases. Compared to cases missed by EMS, correctly recognized cases had longer median on-scene time ( 17 vs. 15 min, p = 0.01) but shorter transport times ( 12 vs. 15 min, p = 0.001). Cases correctly recognized by EMS were associated with shorter door-to-physician time ( 4 vs. 11 min, p < 0.001) and shorter door-to-CT time ( 23 vs. 48 min, p < 0.001). These findings were independent of age, NIHSS, symptom duration, and EMS prenotification. Patients with ischemic stroke correctly recognized by EMS were more likely to receive thrombolytic therapy, independent of age, NIHSS, symptom duration both with and without prenotification. Conclusion: Recognition of stroke by EMS providers was independently associated with faster door-to-physician time, faster door-to-CT time, and greater odds of receiving thrombolysis. Quality initiatives to improve EMS recognition of stroke have the potential to improve hospital-based quality of stroke care. C1 [Abboud, Michael E.] Massachusetts Gen Hosp, Emergency Med, Boston, MA 02114 USA. [Abboud, Michael E.] Brigham & Womens Hosp, Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Band, Roger; Carr, Brendan G.] Thomas Jefferson Univ, Emergency Med, Philadelphia, PA 19107 USA. [Pajerowski, William; David, Guy] Univ Penn Wharton Sch, Healthcare Management, Philadelphia, PA USA. [David, Guy; Mullen, Michael T.] Leonard Davis Inst Hlth Econ, Philadelphia, PA USA. [Jia, Judy; Guo, Michelle; Messe, Steven R.; Mullen, Michael T.] Univ Penn, Neurol, Philadelphia, PA 19104 USA. [Mechem, Crawford] Univ Penn, Emergency Med, Philadelphia, PA 19104 USA. [Mechem, Crawford] Philadelphia Fire Dept, Philadelphia, PA USA. RP Mullen, MT (reprint author), Univ Penn, Dept Neurol, 3400 Spruce St,3W Gates Bldg, Philadelphia, PA 19104 USA. EM Michael.Mullen@uphs.upenn.edu FU Leonard David Institute of Health Economics FX This work received funding from the Leonard David Institute of Health Economics. NR 44 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1090-3127 EI 1545-0066 J9 PREHOSP EMERG CARE JI Prehosp. Emerg. Care PD NOV-DEC PY 2016 VL 20 IS 6 BP 729 EP 736 DI 10.1080/10903127.2016.1182602 PG 8 WC Emergency Medicine; Public, Environmental & Occupational Health SC Emergency Medicine; Public, Environmental & Occupational Health GA EA8RS UT WOS:000386906800008 PM 27246289 ER PT J AU Tang, J Baxter, S Menon, A Alaarg, A Sanchez-Gaytan, BL Fay, F Zhao, YM Ouimet, M Braza, MS Longo, VA Abdel-Atti, D Duivenvoorden, R Calcagno, C Storm, G Tsimikas, S Moore, KJ Swirski, FK Nahrendorf, M Fisher, EA Perez-Medina, C Fayad, ZA Reiner, T Mulder, WJM AF Tang, Jun Baxter, Samantha Menon, Arjun Alaarg, Amr Sanchez-Gaytan, Brenda L. Fay, Francois Zhao, Yiming Ouimet, Mireille Braza, Mounia S. Longo, Valerie A. Abdel-Atti, Dalya Duivenvoorden, Raphael Calcagno, Claudia Storm, Gert Tsimikas, Sotirios Moore, Kathryn J. Swirski, Filip K. Nahrendorf, Matthias Fisher, Edward A. Perez-Medina, Carlos Fayad, Zahi A. Reiner, Thomas Mulder, Willem J. M. TI Immune cell screening of a nanoparticle library improves atherosclerosis therapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nanomedicine; drug delivery; immunotherapy; molecular imaging; atherosclerosis ID LIVER-X-RECEPTORS; DENDRITIC CELLS; MACROPHAGE ACCUMULATION; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; REDUCING LIPIDS; AORTIC-WALL; CHOLESTEROL; HDL; EFFICACY AB Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe(-/-)) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases. C1 [Tang, Jun; Baxter, Samantha; Alaarg, Amr; Sanchez-Gaytan, Brenda L.; Fay, Francois; Zhao, Yiming; Braza, Mounia S.; Duivenvoorden, Raphael; Calcagno, Claudia; Perez-Medina, Carlos; Fayad, Zahi A.; Mulder, Willem J. M.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, 1470 Madison Ave, New York, NY 10029 USA. [Tang, Jun; Abdel-Atti, Dalya; Reiner, Thomas] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10065 USA. [Menon, Arjun; Ouimet, Mireille; Moore, Kathryn J.; Fisher, Edward A.] NYU, Sch Med, Marc & Ruti Bell Program Vasc Biol, Div Cardiol,Dept Med, 550 First Ave, New York, NY 10016 USA. [Alaarg, Amr; Storm, Gert] Univ Twente, MIRA Inst Biomed Technol & Tech Med, Dept Biomat Sci & Technol, NL-7500 AE Enschede, Netherlands. [Longo, Valerie A.] Mem Sloan Kettering Canc Ctr, Small Anim Imaging Core Facil, 1275 York Ave, New York, NY 10065 USA. [Storm, Gert] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, NL-3584 CG Utrecht, Netherlands. [Tsimikas, Sotirios] Univ Calif San Diego, Dept Med, Sulpizio Cardiovasc Ctr, 9434 Med Ctr Dr, La Jolla, CA 92037 USA. [Swirski, Filip K.; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Swirski, Filip K.; Nahrendorf, Matthias] Harvard Med Sch, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Mulder, Willem J. M.] Acad Med Ctr, Dept Med Biochem, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Mulder, WJM (reprint author), Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, 1470 Madison Ave, New York, NY 10029 USA.; Mulder, WJM (reprint author), Acad Med Ctr, Dept Med Biochem, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM Willem.mulder@mssm.edu OI Tang, Jun/0000-0002-8285-5111; Moore, kathryn/0000-0003-2505-2547; Fisher, Edward/0000-0001-9802-143X FU National Institute of Health [R01 HL118440, R01HL125703, R01 CA155432, R01 EB009638, K25 EB016673, R01HL123433, P30 CA008748-50]; Harold S. Geneen Charitable Trust Award; European Framework Program 7 grant (FP7-Health: Nano-Athero) [309820]; Dutch network for Nanotechnology NanoNext NL; Netherlands Organisation for Scientific Research Vidi FX We thank the flow cytometry core facility, the preclinical imaging center of Translational and Molecular Imaging Institute, and the quantitative qPCR facility of Icahn School of Medicine at Mount Sinai. We thank the small animal imaging core facility, the genomic core facility, the molecular cytology core facility, and the radiochemistry and molecular imaging probe core of Memorial Sloan Kettering Cancer Center. We thank Dr. Kaley Joyes for editing the manuscript. This work was supported by National Institute of Health Grants R01 HL118440, R01HL125703, and R01 CA155432 (to W.J.M.M.), R01 EB009638 (to Z.A.F.), K25 EB016673 (to T.R.), R01HL123433 (to K.J.M.), and P30 CA008748-50 (to Dr. Jason S. Lewis), as well as a Harold S. Geneen Charitable Trust Award (to Z.A.F.), European Framework Program 7 grant (FP7-Health 309820: Nano-Athero) and the Dutch network for Nanotechnology NanoNext NL (A.A. and G.S.), and a Netherlands Organisation for Scientific Research Vidi (to W.J.M.M.). NR 46 TC 1 Z9 1 U1 5 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 1 PY 2016 VL 113 IS 44 BP E6731 EP E6740 DI 10.1073/pnas.1609629113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA4TR UT WOS:000386608200005 PM 27791119 ER PT J AU Elicker, BM Jones, KT Naeger, DM Frank, JA AF Elicker, Brett M. Jones, Kirk T. Naeger, David M. Frank, James A. TI Imaging of Acute Lung Injury SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Acute lung injury (ALI); Acute respiratory distress syndrome (ARDS); Diffuse alveolar damage (DAD); Acute interstitial pneumonia (AIP); Acute fibrinous organizing pneumonia (AFOP); Acute eosinophilic pneumonia (AEP) ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE INTERSTITIAL PNEUMONIA; DIFFUSE ALVEOLAR DAMAGE; ACUTE EOSINOPHILIC PNEUMONIA; IDIOPATHIC PULMONARY-FIBROSIS; THIN-SECTION CT; RESOLUTION COMPUTED-TOMOGRAPHY; ORGANIZING PNEUMONIA; ACUTE EXACERBATION; BERLIN DEFINITION AB Acute lung injury (ALI) is the clinical syndrome associated with histopathologic diffuse alveolar damage. It is a common cause of acute respiratory symptoms and admission to the intensive care unit. Diagnosis of ALI is typically based on clinical and radiographic criteria; however, because these criteria can be nonspecific, diagnostic uncertainty is common. A multidisciplinary approach that synthesizes clinical, imaging, and pathologic data can ensure an accurate diagnosis. Radiologists must be aware of the radiographic and computed tomographic findings of ALI and its mimics. This article discusses the multidisciplinary diagnosis of ALI from the perspective of the imager. C1 [Elicker, Brett M.] Univ Calif San Francisco, Cardiac & Pulm Imaging Sect, Dept Radiol & Biomed Imaging, 505 Parnassus Ave,Box 0628, San Francisco, CA 94143 USA. [Jones, Kirk T.] Univ Calif San Francisco, Dept Pathol, 505 Parnassus Ave,Box 0102, San Francisco, CA 94143 USA. [Naeger, David M.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 505 Parnassus Ave,Box 0628, San Francisco, CA 94143 USA. [Frank, James A.] San Francisco VA Med Ctr, Div Pulm Crit Care Allergy & Sleep, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. RP Elicker, BM (reprint author), Univ Calif San Francisco, Cardiac & Pulm Imaging Sect, Dept Radiol & Biomed Imaging, 505 Parnassus Ave,Box 0628, San Francisco, CA 94143 USA. EM brett.elicker@ucsf.edu NR 48 TC 1 Z9 1 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD NOV PY 2016 VL 54 IS 6 BP 1119 EP + DI 10.1016/j.rcl.2016.05.006 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EA3ZG UT WOS:000386547200009 PM 27719979 ER PT J AU Price, M Gilman, MD Carter, BW Sabloff, BS Truong, MT Wu, CC AF Price, Melissa Gilman, Matthew D. Carter, Brett W. Sabloff, Bradley S. Truong, Mylene T. Wu, Carol C. TI Imaging of Eosinophilic Lung Diseases SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Eosinophilic pneumonia; Eosinophilic granulomatosis with polyangiitis; Allergic bronchopulmonary aspergillosis; Hypereosinophilic syndromes ID CHURG-STRAUSS-SYNDROME; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; OF-THE-LITERATURE; IDIOPATHIC HYPEREOSINOPHILIC SYNDROME; THIN-SECTION CT; PULMONARY STRONGYLOIDIASIS; FOLLOW-UP; COMPUTED-TOMOGRAPHY; PLEUROPULMONARY PARAGONIMIASIS; TROPICAL EOSINOPHILIA AB Eosinophilic lung diseases encompass a broad range of conditions wherein patients present with pulmonary opacities and eosinophilia of the serum, pulmonary tissue, or bronchoalveolar lavage fluid. Many of these entities can be idiopathic or are secondary to parasitic infection, exposure to drugs, toxins, or radiation. These diseases exhibit a wide range of imaging findings, including consolidation, ground-glass opacities, nodules, and masses. Diagnoses often require bronchoalveolar lavage and/or biopsy to confirm respiratory eosinophilia and to exclude other entities, such as infection or malignancy. Treatment entails administration of corticosteroids, removal of inciting agents, and treatment of underlying infection. C1 [Price, Melissa; Gilman, Matthew D.] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Founders 202, Boston, MA 02114 USA. [Carter, Brett W.; Sabloff, Bradley S.; Truong, Mylene T.; Wu, Carol C.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, 1515 Holcombe Blvd,Unit 1478, Houston, TX 77030 USA. RP Wu, CC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, 1515 Holcombe Blvd,Unit 1478, Houston, TX 77030 USA. EM carolcwu@gmail.com NR 100 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD NOV PY 2016 VL 54 IS 6 BP 1151 EP + DI 10.1016/j.rcl.2016.05.008 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EA3ZG UT WOS:000386547200011 PM 27719981 ER PT J AU Pinciroli, R Mietto, C Piriyapatsom, A Chenelle, CT Thomas, JG Pirrone, M Bry, L Wojtkiewicz, GR Nahrendorf, MP Kacmarek, RM Berra, L AF Pinciroli, Riccardo Mietto, Cristina Piriyapatsom, Annop Chenelle, Christopher T. Thomas, John G. Pirrone, Massimiliano Bry, Lynn Wojtkiewicz, Gregory R. Nahrendorf, Matthias P. Kacmarek, Robert M. Berra, Lorenzo TI Endotracheal Tubes Cleaned With a Novel Mechanism for Secretion Removal: A Randomized Controlled Clinical Study SO RESPIRATORY CARE LA English DT Article DE intubation; ventilation; biofilms; VAP (ventilator-associated pneumonia); airway obstruction ID VENTILATOR-ASSOCIATED PNEUMONIA; COMPUTED-TOMOGRAPHY; MUCUS SHAVER; BIOFILM; DEVICE; OBSTRUCTION; RESISTANCE; CLEARANCE; CATHETERS; DIAMETER AB INTRODUCTION: Intubation compromises mucus clearance, allowing secretions to accumulate inside the endotracheal tube (ETT). The purpose of this trial was to evaluate a novel device for ETT cleaning. We hypothesized that its routine use would reduce tube occlusion due to mucus accumulation, while decreasing airway bacterial colonization. METHODS: Subjects were randomized to either the use of the device every 8 h, or the institutional standard of care (blind tracheal suction) only. ETTs were collected at extubation and analyzed with high-resolution computed tomography (HRCT) for quantification of mucus volume. Microbiological testing was performed on biofilm samples. Vital signs and ventilatory settings were collected at the bedside. In-hospital follow-up was conducted, and a final evaluation survey was completed by respiratory therapists. RESULTS: Seventy-four subjects expected to remain intubated for longer than 48 h were enrolled (77 ETTs, 37 treatment vs 40 controls). Treated tubes showed reduced mucus accumulation (0.56 +/- 0.12 vs 0.71 +/- 0.28 mL; P= .004) and reduced occlusion (6.3 +/- 1.7 vs 8.9 +/- 7.6%; P = .039). The HRCT slice showing the narrowest lumen within each ETT exhibited less occlusion in cleaned tubes (10.6 +/- 8.0 vs 17.7 +/- 13.4%, 95% CI: 2-12.1; P = .007). Data on microbial colonization showed a trend in the treatment group toward a reduced ETT-based biomass of bacteria known to cause ventilator-associated pneumonia. No adverse events were reported. The staff was satisfied by the overall safety and feasibility of the device. CONCLUSION: The endOclear is a safe and effective device. It prevents luminal occlusion, thereby better preserving ETT nominal function. C1 [Pinciroli, Riccardo; Mietto, Cristina; Piriyapatsom, Annop; Pirrone, Massimiliano; Kacmarek, Robert M.; Berra, Lorenzo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, White 434-B,55 Fruit St, Boston, MA 02114 USA. [Chenelle, Christopher T.; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Thomas, John G.] West Virginia Univ, Sch Dent, Morgantown, WV USA. [Bry, Lynn] Brigham & Womens Hosp, Dept Pathol, Ctr Clin & Translat Metagen, 75 Francis St, Boston, MA 02115 USA. [Wojtkiewicz, Gregory R.; Nahrendorf, Matthias P.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, White 434-B,55 Fruit St, Boston, MA 02114 USA. EM lberra@mgh.harvard.edu NR 34 TC 1 Z9 1 U1 6 U2 6 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD NOV PY 2016 VL 61 IS 11 BP 1431 EP 1439 DI 10.4187/respcare.04363 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EA4WX UT WOS:000386617900003 PM 27460104 ER PT J AU Mouallem, A Sarraf, D Chen, XJ Capuano, V Souied, EH Querques, G AF Mouallem, Alexandra Sarraf, David Chen, Xuejing Capuano, Vittorio Souied, Eric H. Querques, Giuseppe TI DOUBLE RETINAL PIGMENT EPITHELIUM TEARS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE anti-VEGF; fluorescein angiography; fundus autofluorescence; neovascular age-related macular degeneration; retinal pigment epithelium tear; spectral-domain optical coherence tomography; vascularized pigment epithelium detachment ID ANTI-VEGF THERAPY; PHOTODYNAMIC THERAPY; RANIBIZUMAB; MECHANISM AB Purpose: To describe the occurrence and treatment outcomes of double retinal pigment epithelium (RPE) tears in neovascular age-related macular degeneration and to elucidate the mechanism of tear development by means of multimodal imaging analysis. Methods: Fundus autofluorescence, spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography were retrospectively studied before and after the occurrence of first and second RPE tears and at the final visit. Results: Twelve eyes of 10 patients that developed double RPE tears, either simultaneously (6 eyes) or at variable intervals after repeated intravitreal anti-vascular endothelial growth factor administration (6 eyes), were included. First RPE tears developed after a mean of 4.5 +/- 2.7 anti-vascular endothelial growth factor injections; second RPE tears developed after a mean of 7.1 +/- 5.2 anti-vascular endothelial growth factor injections. Mean best-corrected visual acuity was 20/63 at baseline evaluation, 20/76 after occurrence of first tear, 20/90 after occurrence of second tear, and 20/95 at final visit (P > 0.05 for all). Multimodal imaging revealed in all cases a Type 1 neovascular lesion adherent to the posterior surface of the RPE and spanning a significant portion of the pigment epithelium detachment with variable orientation; after development of double tears, the RPE seemed retracted on both borders of the neovascular network. Conclusion: Double RPE tears may occur on opposite sides of a vascularized pigment epithelium detachment, in eyes with neovascular age-related macular degeneration after anti-vascular endothelial growth factor therapy, because of neovascular contraction of a Type 1 neovascular complex, adherent to the posterior surface of the RPE and spanning a significant portion of the pigment epithelium detachment area. C1 [Mouallem, Alexandra; Capuano, Vittorio; Souied, Eric H.; Querques, Giuseppe] Univ Paris Est Creteil, Ctr Hosp Intercommunal Creteil, Dept Ophthalmol, Creteil, France. [Sarraf, David; Chen, Xuejing] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Stein Eye Inst, Los Angeles, CA 90095 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. [Sarraf, David] Kaiser Permanente Med Ctr, Woodland Hills, CA USA. RP Querques, G (reprint author), Ctr Hosp Intercommunal Creteil, Dept Ophthalmol, 40 Ave Verdun, F-94000 Creteil, France. EM giuseppe.querques@hotmail.it NR 16 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD NOV PY 2016 VL 36 IS 11 BP 2197 EP 2204 PG 8 WC Ophthalmology SC Ophthalmology GA EB1AY UT WOS:000387079800028 PM 27145251 ER PT J AU Tsai, AC Kohrt, BA Matthews, LT Betancourt, TS Lee, JK Papachristos, AV Weiser, SD Dworkin, SL AF Tsai, Alexander C. Kohrt, Brandon A. Matthews, Lynn T. Betancourt, Theresa S. Lee, Jooyoung K. Papachristos, Andrew V. Weiser, Sheri D. Dworkin, Shari L. TI Promises and pitfalls of data sharing in qualitative research SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Confidentiality; Data sharing; Ethnography; Mixed methods; Qualitative research; Reproducibility; Transparency ID REPRODUCIBLE RESEARCH; NURSES HEALTH; RECOMMENDATIONS; REPLICATION; ETHNOGRAPHY; DEPRESSION; SCIENCE; WOMEN; ECONOMICS; SUPPORT AB The movement for research transparency has gained irresistible momentum over the past decade. Although qualitative research is rarely published in the high-impact journals that have adopted, or are most likely to adopt, data sharing policies, qualitative researchers who publish work in these and similar venues will likely encounter questions about data sharing within the next few years. The fundamental ways in which qualitative and quantitative data differ should be considered when assessing the extent to which qualitative and mixed methods researchers should be expected to adhere to data sharing policies developed with quantitative studies in mind. We outline several of the most critical concerns below, while also suggesting possible modifications that may help to reduce the probability of unintended adverse consequences and to ensure that the sharing of qualitative data is consistent with ethical standards in research. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Tsai, Alexander C.; Matthews, Lynn T.] Massachusetts Gen Hosp, Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.; Betancourt, Theresa S.] Harvard Ctr Populat & Dev Studies, Cambridge, MA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Kohrt, Brandon A.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Betancourt, Theresa S.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Lee, Jooyoung K.] Univ Toronto, Dept Sociol, Toronto, ON, Canada. [Papachristos, Andrew V.] Yale Univ, Dept Sociol, New Haven, CT USA. [Weiser, Sheri D.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Dworkin, Shari L.] Univ Calif San Francisco, Sch Nursing, Dept Social & Behav Sci, San Francisco, CA 94143 USA. RP Tsai, AC (reprint author), MGH Global Hlth, Massachusetts Gen Hosp, 125 Nashua St,Ste 722, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU [K23MH096620]; [K01MH104310]; [K23MH095655] FX No specific funding was received for the preparation of this manuscript. The authors acknowledge salary support through K23MH096620, K01MH104310, and K23MH095655. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 100 TC 0 Z9 0 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2016 VL 169 BP 191 EP 198 DI 10.1016/j.socscimed.2016.08.004 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA EA8CK UT WOS:000386862700023 PM 27535900 ER PT J AU Corritore, E Lee, YS Pasquale, V Liberati, D Hsu, MJ Lombard, CA van der Smissen, P Vetere, A Bonner-Weir, S Piemonti, L Sokal, E Lysy, PA AF Corritore, Elisa Lee, Yong-Syu Pasquale, Valentina Liberati, Daniela Hsu, Mei-Ju Lombard, Catherine Anne van der Smissen, Patrick Vetere, Amedeo Bonner-Weir, Susan Piemonti, Lorenzo Sokal, Etienne Lysy, Philippe A. TI V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Diabetes; Insulin-producing cells; SCID-beige mice; Synthetic modified mRNA; V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) ID EMBRYONIC STEM-CELLS; BETA-LIKE CELLS; IN-VITRO; HUMAN FIBROBLASTS; PROGENITOR CELLS; EXOCRINE CELLS; MYOCARDIAL-INFARCTION; ENDOCRINE-CELLS; ADULT; DIFFERENTIATION AB beta-Cell replacement therapy represents the most promising approach to restore beta-cell mass and glucose homeostasis in patients with type 1 diabetes. Safety and ethical issues associated with pluripotent stem cells stimulated the search for adult progenitor cells with endocrine differentiation capacities. We have already described a model for expansion and differentiation of human pancreatic duct-derived cells (HDDCs) into insulin-producing cells. Here we show an innovative and robust in vitro system for large-scale production of beta-like cells from HDDCs using a nonintegrative RNA-based reprogramming technique. Synthetic modified RNAs for pancreatic transcription factors (pancreatic duodenal homeobox 1, neurogenin3, and V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A [MAFA]) were manufactured and daily transfected in HDDCs without strongly affecting immune response and cell viability. MAFA overexpression was efficient and sufficient to induce beta-cell differentiation of HDDCs, which acquired a broad repertoire of mature beta-cell markers while downregulating characteristic epithelial-mesenchymal transition markers. Within 7 days, MAFA-reprogrammed HDDC populations contained 37% insulin-positive cells and a proportion of endocrine cells expressing somatostatin and pancreatic polypeptide. Ultrastructure analysis of differentiated HDDCs showed both immature and mature insulin granules with light-backscattering properties. Furthermore, in vitro HDDC-derived beta cells (called beta-HDDCs) secreted human insulin and C-peptide in response to glucose, KCI, 3-isobutyl-1-methylxanthine, and tolbutamide stimulation. Transplantation of beta-HDDCs into diabetic SCID-beige mice confirmed their functional glucose-responsive insulin secretion and their capacity to mitigate hyperglycemia. Our data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new beta cells with potential to reverse diabetes. C1 [Corritore, Elisa; Lee, Yong-Syu; Hsu, Mei-Ju; Lombard, Catherine Anne; Sokal, Etienne; Lysy, Philippe A.] Catholic Univ Louvain, Clin Univ St Luc, Inst Rech Expt & Clin, Pediat Res Lab, Brussels, Belgium. [van der Smissen, Patrick] Catholic Univ Louvain, Clin Univ St Luc, de Duve Inst, Brussels, Belgium. [Lysy, Philippe A.] Catholic Univ Louvain, Clin Univ St Luc, Pediat Endocrinol Unit, Brussels, Belgium. [Pasquale, Valentina; Liberati, Daniela; Piemonti, Lorenzo] Ist Sci San Raffaele, Diabet Res Inst, Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Vetere, Amedeo] Broad Inst Harvard & MIT, Chem Biol Program, Cambridge, MA USA. [Bonner-Weir, Susan] Harvard Med Sch, Joslin Diabet Ctr, Islet Cell & Regenerat Biol, Boston, MA USA. RP Lysy, PA (reprint author), Ave Hippocrate 10, B-1200 Brussels, Belgium. EM philippe.lysy@uclouvain.be OI Lombard, Catherine/0000-0002-5653-9545; Pasquale, Valentina/0000-0002-1250-0825 FU Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED); Institut de Recherche Clinique et Experimentale (IREC); Fonds National de la Recherche Scientifique (FNRS); International Society for Pediatric and Adolescent Diabetes (ISPAD) FX We thank J. Ravau and F. Andre (Pole Pediatrie) for their expert technical assistance. This study was supported by grants from the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED), Institut de Recherche Clinique et Experimentale (IREC), Fonds National de la Recherche Scientifique (FNRS), and International Society for Pediatric and Adolescent Diabetes (ISPAD). NR 69 TC 0 Z9 0 U1 1 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD NOV PY 2016 VL 5 IS 11 BP 1525 EP 1537 DI 10.5966/sctm.2015-0318 PG 13 WC Cell & Tissue Engineering SC Cell Biology GA EA2HQ UT WOS:000386413800014 PM 27405779 ER PT J AU Nuschke, A Rodrigues, M Rivera, J Yates, C Whaley, D Stolz, D Griffith, L Wells, A AF Nuschke, Austin Rodrigues, Melanie Rivera, Jaime Yates, Cecelia Whaley, Diana Stolz, Donna Griffith, Linda Wells, Alan TI Epidermal Growth Factor Tethered to beta-Tricalcium Phosphate Bone Scaffolds via a High-Affinity Binding Peptide Enhances Survival of Human Mesenchymal Stem Cells/Multipotent Stromal Cells in an Immune-Competent Parafascial Implantation Assay in Mice SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Multipotent stem cells; Mesenchymal stem cells; Surface-tethered epidermal growth factor; beta-Tricalcium phosphate; Stem cell survival ID FACTOR RECEPTOR; SIGNALING PATHWAY; IN-VIVO; MARROW; DIFFERENTIATION; ANGIOGENESIS; ACTIVATION; MOTILITY; HEART; FASL AB Mesenchymal stem cells/multipotent stromal cells (MSCs) are attractive candidates for cell therapies owing to their ability to differentiate into many lineages. However, these cells often fail to survive when implanted into a harsh wound environment, limiting efficacy in vivo. To improve MSC survival, we previously found that tethered epidermal growth factor (tEGF) molecules that restrict epidermal growth factor receptor (EGFR) signaling to the cell surface provide resistance to death signals. To adapt this system to wound healing, we tethered epidermal growth factor (EGF) to tricalcium phosphate (TCP) particle scaffolds, clinically used in bone healing. Human primary MSCs seeded on TCP and mixed into a collagen-based gel were injected in the perifascial space of immunocompetent mice with or without tEGF attached to the surface. We found that tethering EGF to the TCP scaffolds yielded approximately a fourfold increase in MSC survival compared with non-EGF scaffolds at 21 days, as well as significant improvements in survival in the short term at 2 and 7 days after implantation. Overall, our approach to sustaining EGFR signaling reduced MSC death in vivo and may be useful for future cell therapies where MSCs typically die on implantation. C1 [Nuschke, Austin; Rodrigues, Melanie; Yates, Cecelia; Whaley, Diana; Wells, Alan] Univ Pittsburgh, Dept Pathol, S713 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Whaley, Diana; Stolz, Donna] Univ Pittsburgh, Dept Cell Biol, Pittsburgh, PA USA. [Yates, Cecelia] Univ Pittsburgh, Dept Hlth Promot & Dev, Pittsburgh, PA USA. [Nuschke, Austin; Yates, Cecelia; Stolz, Donna; Wells, Alan] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. [Yates, Cecelia; Wells, Alan] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. [Rivera, Jaime; Griffith, Linda] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Wells, A (reprint author), Univ Pittsburgh, Dept Pathol, S713 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM wellsa@upmc.edu FU NIH [GM063569, GM069668]; National Institute of Biomedical Imaging and Bioengineering-CATER T32 training grant [EB001026]; National Cancer Institute-Skin Biology and Cancer T32 training grant [CA175294] FX We thank the members of the Wells' Laboratory at the University of Pittsburgh and Griffith Laboratory at the Massachusetts Institute of Technology for their helpful and insightful comments on this project. This project was supported by NIH Grants GM063569 and GM069668. A.N. was supported by the National Institute of Biomedical Imaging and Bioengineering-funded CATER T32 (EB001026) and the National Cancer Institute-funded Skin Biology and Cancer T32 (CA175294) training grants. Services were provided in kind by the VA Pittsburgh Health System research and development service line. M.R. is currently affiliated with the Department of Plastic and Reconstructive Surgery, Stanford University, Palo Alto, California, USA. NR 33 TC 0 Z9 0 U1 5 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD NOV PY 2016 VL 5 IS 11 BP 1580 EP 1586 DI 10.5966/sctm.2015-0326 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA EA2HQ UT WOS:000386413800019 PM 27400798 ER PT J AU O'Flynn, E Andrew, J Hutch, A Kelly, C Jani, P Kakande, I Derbew, M Tierney, S Mkandawire, N Erzingatsian, K AF O'Flynn, Eric Andrew, Judith Hutch, Avril Kelly, Caitrin Jani, Pankaj Kakande, Ignatius Derbew, Miliard Tierney, Sean Mkandawire, Nyengo Erzingatsian, Krikor TI The Specialist Surgeon Workforce in East, Central and Southern Africa: A Situation Analysis SO WORLD JOURNAL OF SURGERY LA English DT Article ID NONPHYSICIAN CLINICIAN; COUNTRIES; UGANDA AB In East, Central and Southern Africa accurate data on the current surgeon workforce have previously been limited. In order to ensure that the workforce required for sustainable delivery of surgical care is put in place, accurate data on the number, specialty and distribution of specialist-trained surgeons are crucial for all stakeholders in surgery and surgical training in the region. The surgical workforce in each of the ten member countries of the College of Surgeons of East, Central and Southern Africa (COSECSA) was determined by gathering and crosschecking data from multiple sources including COSECSA records, medical council registers, local surgical societies records, event attendance lists and interviews of Members and Fellows of COSECSA, and validating this by direct contact with the surgeons identified. This data was recorded and analysed in a cloud-based computerised database, developed as part of a collaboration programme with the Royal College of Surgeons in Ireland. A total of 1690 practising surgeons have been identified yielding a regional ratio of 0.53 surgeons per 100,000 population. A majority of surgeons (64 %) practise in the main commercial city of their country of residence and just 9 % of surgeons are female. More than half (53 %) of surgeons in the region are general surgeons. While there is considerable geographic variation between countries, the regional surgical workforce represents less than 4 % of the equivalent number in developed countries indicating the magnitude of the human resource challenge to be addressed. C1 [O'Flynn, Eric; Hutch, Avril] Royal Coll Surgeons Ireland, Dept Surg Affairs, Coll Surg East, Cent & Southern Africa Collaborat Programme, 121 St Stephens Green, Dublin 2, Ireland. [Andrew, Judith; Jani, Pankaj; Kakande, Ignatius; Derbew, Miliard; Mkandawire, Nyengo; Erzingatsian, Krikor] Coll Surg East Cent & Southern Africa, Njiro Rd, Arusha, Tanzania. [Kelly, Caitrin] Massachusetts Gen Hosp, Div Gen Internal Med, Yawkey Bldg 9,55 Fruit St, Boston, MA 02114 USA. [Jani, Pankaj] Univ Nairobi, Sch Med, Dept Surg, Coll Hlth Sci, POB 19676-00202, Nairobi, Kenya. [Kakande, Ignatius] St Francis Hosp Nsambya, Nsambya Rd,Nsambya Hill,POB 7146, Kampala, Uganda. [Derbew, Miliard] Univ Addis Ababa, Sch Med, Coll Hlth Sci, Addis Ababa, Ethiopia. [Mkandawire, Nyengo] Univ Malawi, Dept Surg, Coll Med, Mahatma Gandhi Rd,Private Bag 360, Blantyre 3, Malawi. [Mkandawire, Nyengo] Flinders Univ S Australia, Sch Med, Sturt Rd, Bedford Pk, SA 5042, Australia. [Erzingatsian, Krikor] Univ Zambia, Univ Teaching Hosp, Sch Med, Nationalist Rd,POB 50110, Lusaka, Zambia. [Tierney, Sean] Royal Coll Surgeons Ireland, Dept Surg Affairs, 121 St Stephens Green, Dublin 2, Ireland. RP O'Flynn, E (reprint author), Royal Coll Surgeons Ireland, Dept Surg Affairs, Coll Surg East, Cent & Southern Africa Collaborat Programme, 121 St Stephens Green, Dublin 2, Ireland. EM ericoflynn@rcsi.ie FU Irish Aid; Royal College of Surgeons in Ireland; College of Surgeons of East, Central and Southern Africa FX This project was funded by Irish Aid as part of a wider capacity development collaborative project between the Royal College of Surgeons in Ireland and the College of Surgeons of East, Central and Southern Africa. NR 12 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD NOV PY 2016 VL 40 IS 11 BP 2620 EP 2627 DI 10.1007/s00268-016-3601-3 PG 8 WC Surgery SC Surgery GA EA5XP UT WOS:000386698800011 PM 27283189 ER PT J AU Marti, JL Randolph, G AF Marti, Jennifer L. Randolph, Gregory TI Neural Monitoring in Thyroid Surgery: Is It Evidence Based? Is It Cost Effective?: Reply SO WORLD JOURNAL OF SURGERY LA English DT Letter C1 [Marti, Jennifer L.] NewYork Presbyterian Weill Cornell Med Ctr, New York, NY 10065 USA. [Randolph, Gregory] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Marti, JL (reprint author), NewYork Presbyterian Weill Cornell Med Ctr, New York, NY 10065 USA. EM drjennifermarti@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD NOV PY 2016 VL 40 IS 11 BP 2831 EP 2831 DI 10.1007/s00268-016-3591-1 PG 1 WC Surgery SC Surgery GA EA5XP UT WOS:000386698800044 PM 27272480 ER PT J AU Rosen, CS Matthieu, MM Stirman, SW Cook, JM Landes, S Bernardy, NC Chard, KM Crowley, J Eftekhari, A Finley, EP Hamblen, JL Harik, JM Kehle-Forbes, SM Meis, LA Osei-Bonsu, PE Rodriguez, AL Ruggiero, KJ Ruzek, JI Smith, BN Trent, L Watts, BV AF Rosen, C. S. Matthieu, M. M. Stirman, S. Wiltsey Cook, J. M. Landes, S. Bernardy, N. C. Chard, K. M. Crowley, J. Eftekhari, A. Finley, E. P. Hamblen, J. L. Harik, J. M. Kehle-Forbes, S. M. Meis, L. A. Osei-Bonsu, P. E. Rodriguez, A. L. Ruggiero, K. J. Ruzek, J. I. Smith, B. N. Trent, L. Watts, B. V. TI A Review of Studies on the System-Wide Implementation of Evidence-Based Psychotherapies for Posttraumatic Stress Disorder in the Veterans Health Administration SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Review DE Evidence-based practice; Posttraumatic stress disorders; Psychotherapy; Implementation science; Competency-based training; Diffusion of innovation; Veterans ID COGNITIVE PROCESSING THERAPY; PROLONGED EXPOSURE THERAPY; RANDOMIZED CONTROLLED-TRIAL; RESIDENTIAL-TREATMENT PROGRAMS; NONINFERIORITY CLINICAL-TRIAL; TRAUMATIC BRAIN-INJURY; COMBAT-RELATED PTSD; PSYCHOLOGICAL TREATMENTS; EXPERT RECOMMENDATIONS; TELEMENTAL HEALTH AB Since 2006, the Veterans Health Administration (VHA) has instituted policy changes and training programs to support system-wide implementation of two evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD). To assess lessons learned from this unprecedented effort, we used PubMed and the PILOTS databases and networking with researchers to identify 32 reports on contextual influences on implementation or sustainment of EBPs for PTSD in VHA settings. Findings were initially organized using the exploration, planning, implementation, and sustainment framework (EPIS; Aarons et al. in Adm Policy Ment Health Health Serv Res 38:4-23, 2011). Results that could not be adequately captured within the EPIS framework, such as implementation outcomes and adopter beliefs about the innovation, were coded using constructs from the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework (Glasgow et al. in Am J Public Health 89:1322-1327, 1999) and Consolidated Framework for Implementation Research (CFIR; Damschroder et al. in Implement Sci 4(1):50, 2009). We highlight key areas of progress in implementation, identify continuing challenges and research questions, and discuss implications for future efforts to promote EBPs in large health care systems. C1 [Rosen, C. S.; Stirman, S. Wiltsey; Landes, S.; Crowley, J.; Eftekhari, A.; Rodriguez, A. L.; Ruzek, J. I.; Smith, B. N.; Trent, L.] VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, 795 Willow Rd,334 PTSD, Menlo Pk, CA 94025 USA. [Rosen, C. S.; Stirman, S. Wiltsey; Ruzek, J. I.; Trent, L.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Matthieu, M. M.] St Louis Univ, Sch Social Work, St Louis, MO 63103 USA. [Cook, J. M.] VA Connecticut Hlth Care Syst, Evaluat Div, Natl Ctr PTSD, West Haven, CT USA. [Cook, J. M.] Yale Sch Med, NEPEC 182,950 Campbell Ave, West Haven, CT USA. [Bernardy, N. C.; Hamblen, J. L.; Harik, J. M.] Vet Affairs Med Ctr, Execut Div, Natl Ctr PTSD, White River Jct, VT USA. [Bernardy, N. C.; Hamblen, J. L.; Watts, B. V.] Geisel Sch Med Dartmouth, Dept Psychiat, Hanover, NH USA. [Chard, K. M.] Cincinnati Dept Vet Affairs VA Med Ctr, Cincinnati, OH USA. [Chard, K. M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Finley, E. P.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Finley, E. P.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kehle-Forbes, S. M.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Kehle-Forbes, S. M.; Meis, L. A.; Osei-Bonsu, P. E.] Minneapolis VA Healthcare Syst, Ctr Chron Dis Outcomes Res, Minneapolis, MN USA. [Kehle-Forbes, S. M.; Meis, L. A.; Osei-Bonsu, P. E.] Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Ruggiero, K. J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Ruggiero, K. J.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Ruzek, J. I.] Palo Alto Univ, Palo Alto, CA USA. [Watts, B. V.] Vet Affairs Med Ctr, White River Jct, VT USA. RP Rosen, CS (reprint author), VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, 795 Willow Rd,334 PTSD, Menlo Pk, CA 94025 USA.; Rosen, CS (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. EM craig.rosen@va.gov OI Finley, Erin/0000-0003-4497-7721; Wiltsey Stirman, Shannon/0000-0001-9917-5078 FU U.S. Department of Veterans Affairs; National Center for PTSD; Mental Illness Quality Enhancement Research Initiative FX This review was supported by the U.S. Department of Veterans Affairs, including the National Center for PTSD and the Mental Illness Quality Enhancement Research Initiative. The opinions are those of the authors and do not reflect the position of the U.S. Department of Veterans Affairs. NR 105 TC 2 Z9 2 U1 16 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD NOV PY 2016 VL 43 IS 6 SI SI BP 957 EP 977 DI 10.1007/s10488-016-0755-0 PG 21 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EA1PQ UT WOS:000386364700010 PM 27474040 ER PT J AU Arundel, C Lam, PH Khosla, R Blackman, MR Fonarow, GC Morgan, C Zeng, Q Fletcher, RD Butler, J Wu, WC Deedwania, P Love, TE White, M Aronow, WS Anker, SD Allman, RM Ahmed, A AF Arundel, Cherinne Lam, Phillip H. Khosla, Rahul Blackman, Marc R. Fonarow, Gregg C. Morgan, Charity Zeng, Qing Fletcher, Ross D. Butler, Javed Wu, Wen-Chih Deedwania, Prakash Love, Thomas E. White, Michel Aronow, Wilbert S. Anker, Stefan D. Allman, Richard M. Ahmed, Ali TI Association of 30-Day All-Cause Readmission with Long-Term Outcomes in Hospitalized Older Medicare Beneficiaries with Heart Failure SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE 30-Day all-cause readmission; All-cause mortality; Cost; Heart failure; Medicare beneficiaries ID RENIN-ANGIOTENSIN INHIBITION; PRESERVED EJECTION FRACTION; ACUTE MYOCARDIAL-INFARCTION; CHRONIC KIDNEY-DISEASE; PROPENSITY SCORE; NATURAL-HISTORY; MORTALITY; TRIAL; DEATH; MODE AB BACKGROUND: Heart failure is the leading cause for 30-day all-cause readmission. We examined the impact of 30-day all-cause readmission on long-term outcomes and cost in a propensity score-matched study of hospitalized patients with heart failure. METHODS: Of the 7578 Medicare beneficiaries discharged with a primary diagnosis of heart failure from 106 Alabama hospitals (1998-2001) and alive at 30 days after discharge, 1519 had a 30-day all-cause readmission. Using propensity scores for 30-day all-cause readmission, we assembled a matched cohort of 1516 pairs of patients with and without a 30-day all-cause readmission, balanced on 34 baseline characteristics (mean age 75 years, 56% women, 24% African American). RESULTS: During 2-12 months of follow-up after discharge from index hospitalization, all-cause mortality occurred in 41% and 27% of matched patients with and without a 30-day all-cause readmission, respectively (hazard ratio 1.68; 95% confidence interval 1.48-1.90; P<.001). This harmful association of 30-day all-cause readmission with mortality persisted during an average follow-up of 3.1 (maximum, 8.7) years (hazard ratio 1.33; 95% confidence interval 1.22-1.45; P<.001). Patients with a 30-day all-cause readmission had higher cumulative all-cause readmission (mean, 6.9 vs 5.1; P<.001), a longer cumulative length of stay (mean, 51 vs 43 days; P<.001), and a higher cumulative cost (mean, $38,972 vs $34,025; P=.001) during 8.7 years of follow-up. CONCLUSIONS: Among Medicare beneficiaries hospitalized for heart failure, 30-day all-cause readmission was associated with a higher risk of subsequent all-cause mortality, higher number of cumulative all-cause readmission, longer cumulative length of stay, and higher cumulative cost. Published by Elsevier Inc. C1 [Arundel, Cherinne; Khosla, Rahul; Blackman, Marc R.; Fletcher, Ross D.; Ahmed, Ali] Vet Affairs Med Ctr, 50 Irving St NW, Washington, DC 20422 USA. [Lam, Phillip H.] Georgetown Univ Hosp, Washington Hosp Ctr, Washington, DC 20007 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Morgan, Charity; Ahmed, Ali] Univ Alabama Birmingham, Birmingham, AL USA. [Zeng, Qing] George Washington Univ, Washington, DC 20052 USA. [Butler, Javed] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Wu, Wen-Chih] Vet Affairs Med Ctr, Providence, RI USA. [Deedwania, Prakash] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Love, Thomas E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [White, Michel] Montreal Heart Inst, Quebec City, PQ, Canada. [Aronow, Wilbert S.] New York Med Coll, Valhalla, NY 10595 USA. [Anker, Stefan D.] Univ Med Ctr Gottingen, Dept Cardiol & Pneumol, Gottingen, Germany. [Allman, Richard M.] US Dept Vet Affairs, Geriatr & Extended Care Serv, Washington, DC USA. RP Ahmed, A (reprint author), Washington DC VA Med Ctr, Ctr Hlth & Aging, 50 Irving St NW, Washington, DC 20422 USA. EM aliahmedmdmph@gmail.com FU National Institutes of Health through National Heart, Lung, and Blood Institute [R01-HL085561, R01-HL085561-S, R01-HL097047] FX AA was supported in part by the National Institutes of Health through grants (R01-HL085561, R01-HL085561-S, and R01-HL097047) from the National Heart, Lung, and Blood Institute. NR 26 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD NOV PY 2016 VL 129 IS 11 BP 1178 EP 1184 DI 10.1016/j.amjmed.2016.06.018 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EA1ES UT WOS:000386335900033 PM 27401949 ER PT J AU Oken, E Morton-Eggleston, E Rifas-Shiman, SL Switkowski, KM Hivert, MF Fleisch, AF Mantzoros, C Gillman, MW AF Oken, Emily Morton-Eggleston, Emma Rifas-Shiman, Sheryl L. Switkowski, Karen M. Hivert, Marie-France Fleisch, Abby F. Mantzoros, Christos Gillman, Matthew W. TI Sex-Specific Associations of Maternal Gestational Glycemia with Hormones in Umbilical Cord Blood at Delivery SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE gestational diabetes mellitus; pregnancy; umbilical cord blood; hormones; insulin-like growth factor (IGF); leptin; C-peptide ID IGF-BINDING PROTEIN-1; GROWTH-FACTOR-I; DIABETES-MELLITUS; BODY-COMPOSITION; BIRTH-WEIGHT; CARDIOMETABOLIC RISK; GLUCOSE-INTOLERANCE; FETAL-GROWTH; INSULIN; ADIPONECTIN AB Background Few studies have examined sex-specific associations of maternal gestational glycemia with cord blood hormones, which might predict later health. Methods In 976 women without pre-existing diabetes in the Project Viva cohort, we used linear regression to examine associations of maternal gestational glycemia with cord hormone concentrations, adjusted for maternal characteristics and stratified by infant sex. Results A total of 6.1% of women had gestational diabetes mellitus (GDM), 8.8% isolated hyperglycemia, 3.2% gestational impaired glucose tolerance, and 81.9% were normoglycemic. In boys, compared with infants of normoglycemic mothers, infants of GDM mothers had higher cord levels of IGF-2 (beta 35.55 ng/mL; 95% CI: 2.60, 68.50), IGFBP-3 (111.2 ng/mL; 5.53, 216.8), insulin (4.66 uU/mL; 2.38, 6.95), C-peptide (0.46 ng/mL; 0.25, 0.67), and leptin (3.51 ng/mL; 1.37, 5.64), but lower IGF-1 (-6.71 ng/mL; -12.7, -0.76, adjusted for IGFBP-3). In girls, GDM offspring had higher cord blood levels of IGF-1 adjusted for IGFBP-3 (12.45 ng/mL; 4.85, 20.04). Boys, but not girls, of mothers with abnormal glucose tolerance but not GDM also had higher levels of some hormones. Conclusion GDM was associated with growth factors and adipokines in cord blood from boys, but only IGF-1 in girls. These findings suggest sex differences in responses to fetal overnutrition. C1 [Oken, Emily; Morton-Eggleston, Emma; Rifas-Shiman, Sheryl L.; Switkowski, Karen M.; Hivert, Marie-France; Gillman, Matthew W.] Harvard Med Sch, Dept Populat Med, Obes Prevent Program, Boston, MA USA. [Oken, Emily; Morton-Eggleston, Emma; Rifas-Shiman, Sheryl L.; Switkowski, Karen M.; Hivert, Marie-France; Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. [Oken, Emily; Gillman, Matthew W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Fleisch, Abby F.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Mantzoros, Christos] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. RP Oken, E (reprint author), Harvard Pilgrim Hlth Care Inst, 401 Pk Dr,Suite 401, Boston, MA 02215 USA.; Oken, E (reprint author), Harvard Med Sch, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA 02215 USA. EM emily_oken@hphc.org FU National Institutes of Health [R37 HD034568]; [K24 HD069408]; [P30 DK092924]; [K23 ES024803] FX Project Viva is supported by the National Institutes of Health (R37 HD034568). Dr Oken is additionally supported by K24 HD069408 and P30 DK092924. Dr Fleisch is additionally supported by K23 ES024803. NR 56 TC 0 Z9 0 U1 5 U2 5 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2016 VL 33 IS 13 BP 1273 EP 1281 DI 10.1055/s-0036-1586509 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA EA2DV UT WOS:000386403900009 PM 27490771 ER PT J AU Salafia, CM Thomas, DM Roberts, DJ Straughen, JK Catalano, PM Perez-Avilan, G AF Salafia, Carolyn M. Thomas, Diana M. Roberts, Drucilla J. Straughen, Jennifer K. Catalano, Patrick M. Perez-Avilan, Gabriela TI First Trimester Detection of Placental Disease: Challenges and Opportunities SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE diabetes; obesity; placenta; fetus; ultrasound; Doppler; growth model ID AGE 7 YEARS; BIRTH-WEIGHT; MATERNAL OBESITY; FETAL; OVERWEIGHT; PREGNANCY; PATHOLOGY; STRESS; LEPTIN; SHAPE AB It is generally agreed that placental pathology accounts for the majority of perinatal morbidity and mortality. If a placental prodrome could be diagnosed in vivo, risk for maternal or fetal complications could be estimated and acted upon before clinical symptoms are apparent. This is especially relevant in early diagnoses of gestational diabetes mellitus, which can be controlled through carefully monitored diet and activity changes. To meet this important need, there have been increased efforts to identify early gestation biomarkers of placental dysfunction using innovative imaging technologies. Here we outline innovative quantitative markers of placental shape and their relationship to placental function, clinical implications of these quantifiers, and the most recent mathematical models that utilize placental images to delineate at risk from normal pregnancies. We propose that novel contexts of readily available placental measures and routine collection of in vivo placental images in all pregnancies may be all that are needed to advance the identification of early risk determination of complicated pregnancies from placental images. C1 [Salafia, Carolyn M.] Inst Basic Res Dev Disabil, Placental Modulat Lab, Staten Isl, NY USA. [Salafia, Carolyn M.; Perez-Avilan, Gabriela] Placental Analyt, Div Predict Modeling, New Rochelle, NY USA. [Thomas, Diana M.] Montclair State Univ, Ctr Quantitat Obes Res, Montclair, NJ USA. [Roberts, Drucilla J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Straughen, Jennifer K.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Catalano, Patrick M.] Case Western Reserve Univ, Clin Res Unit, Cleveland, OH 44106 USA. [Catalano, Patrick M.] Case Western Reserve Univ, Dept Obstet & Gynecol, Ctr Reprod Hlth, MetroHlth Med Ctr, Cleveland, OH 44106 USA. RP Salafia, CM (reprint author), Inst Basic Res Dev Disabil, Placental Modulat Lab, 187 Overlook Circle, New Rochelle, NY 10804 USA. EM Carolyn.salafia@gmail.com NR 41 TC 0 Z9 0 U1 4 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2016 VL 33 IS 13 BP 1306 EP 1312 DI 10.1055/s-0036-1586508 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA EA2DV UT WOS:000386403900013 PM 27490774 ER PT J AU Brendel, RW AF Brendel, Rebecca Weintraub TI A Clinical Guide to Psychiatric Ethics SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Book Review C1 [Brendel, Rebecca Weintraub] Harvard Med Sch, Ctr Bioeth, Boston, MA 02115 USA. [Brendel, Rebecca Weintraub] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Brendel, Rebecca Weintraub] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brendel, RW (reprint author), Harvard Med Sch, Ctr Bioeth, Boston, MA 02115 USA.; Brendel, RW (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA.; Brendel, RW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2016 VL 173 IS 11 BP 1153 EP 1154 DI 10.1176/appi.ajp.2016.16070761 PG 2 WC Psychiatry SC Psychiatry GA EA2LE UT WOS:000386423000020 ER PT J AU Hollis, RH Holcomb, CN Valle, JA Smith, BP DeRussy, AJ Graham, LA Richman, JS Itani, KMF Maddox, TM Hawn, MT AF Hollis, Robert H. Holcomb, Carla N. Valle, Javier A. Smith, Burke P. DeRussy, Aerin J. Graham, Laura A. Richman, Joshua S. Itani, Kamal M. F. Maddox, Thomas M. Hawn, Mary T. TI Coronary angiography and failure to rescue after postoperative myocardial infarction in patients with coronary stents undergoing noncardiac surgery SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Postoperative myocardial infarction; Coronary stent; Coronary angiography; Postoperative mortality; Failure to rescue; Cardiac risk index ID DRUG-ELUTING STENT; CARDIAC EVENTS; RISK; OUTCOMES; PATHOPHYSIOLOGY; STRATIFICATION; GUIDELINES AB BACKGROUND: We evaluated coronary angiography use among patients with coronary stents suffering postoperative myocardial infarction (MI) and the association with mortality. METHODS: Patients with prior coronary stenting who underwent inpatient noncardiac surgery in Veterans Affairs hospitals between 2000 and 2012 and experienced postoperative MI were identified. Predictors of 30-day post-MI mortality were evaluated. RESULTS: Following 12,096 operations, 353 (2.9%) patients had postoperative MI and 58 (16.4%) died. Post-MI coronary angiography was performed in 103 (29.2%) patients. Coronary angiography was not associated with 30-day mortality (odds ratio [OR]: .70, 95% CI: .35-1.42). Instead, 30-day mortality was predicted by revised cardiac risk index >= 3 (OR 1.91, 95% CI: 1.04-3.50) and prior bare metal stent (OR 2.12, 95% CI: 1.04-4.33). CONCLUSIONS: Less than one-third of patients with coronary stents suffering postoperative MI underwent coronary angiography. Significant predictors of mortality were higher revised cardiac risk index and prior bare metal stent. These findings highlight the importance of comorbidities in predicting mortality following postoperative MI. Published by Elsevier Inc. C1 [Hollis, Robert H.; Holcomb, Carla N.; Smith, Burke P.; DeRussy, Aerin J.; Graham, Laura A.; Richman, Joshua S.] Univ Alabama Birmingham, Dept Surg, Birmingham Vet Adm Hosp, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL 35294 USA. [Valle, Javier A.; Maddox, Thomas M.] VA Eastern Colorado Hlth Care Syst, Dept Med, Denver, CO USA. [Valle, Javier A.; Maddox, Thomas M.] Univ Colorado, Sch Med, Dept Med, Div Cardiol, Aurora, CO USA. [Itani, Kamal M. F.] Boston Univ, Dept Surg, VA Boston Hlth Care Syst, Boston, MA 02215 USA. [Itani, Kamal M. F.] Harvard Med Sch, Boston, MA USA. [Hawn, Mary T.] Stanford Univ, Dept Surg, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. RP Hawn, MT (reprint author), Stanford Univ, Dept Surg, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. EM mhawn@stanford.edu FU VA HSRD Career Development Award FX The opinions expressed are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs of the United States Government. Dr. Richman was supported by a VA HSRD Career Development Award. NR 16 TC 0 Z9 0 U1 2 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD NOV PY 2016 VL 212 IS 5 BP 814 EP + DI 10.1016/j.amjsurg.2016.07.023 PG 10 WC Surgery SC Surgery GA DZ5UJ UT WOS:000385926700004 PM 27640120 ER PT J AU Burns, JA Botelho, JL Bell, JI Faquin, W Lopez-Guerra, G Ackerman, JL Kobler, JB AF Burns, James A. Botelho, Jaime L. Bell, Jonathan I. Faquin, William Lopez-Guerra, Gerardo Ackerman, Jerome L. Kobler, James B. TI Injectable Aorta Tissue Paste for Vocal Fold Medialization: Residence Time, Biocompatibility, and Comparison to Predicates in a Guinea Pig Subdermal Model SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE laryngeal functional disorders; advanced surgical techniques; reconstruct; vocal cord movement; vocal fold paralysis ID INJECTION LARYNGOPLASTY; CALCIUM HYDROXYLAPATITE; FAT INJECTION; FOLLOW-UP; PARALYSIS; CALCIFICATION; AUGMENTATION; EXPERIENCE; EFFICIENCY; COLLAGEN AB Objectives: Aortic homografts integrate well with laryngeal tissue when used in reconstructive surgery. It was hypothesized that a paste of aortic homograft, rich in slow-to-degrade elastin, would compare favorably in residence time and biocompatibility to predicate materials used for vocal fold injection-medialization. Methods: An injectable aorta paste (AP) was made by pulverizing aortic homografts at -196 degrees C (cryomilling). To assess residence time and biocompatibility, 0.3 cc was injected subdermally in guinea pigs (n = 3 per 2-, 4-, 8-, 16-, 24-week time points) followed by histological analysis. To test particle size versus residence time, APs made using 80 or 200 seconds of cryomilling were compared. Implant characteristics of AP were then compared to Restylane, Radiesse Voice (Hydroxylapatite), Radiesse Voice Gel, and Cymetra in additional animals (n = 6 per 4-, 8-, 12-week time points). Results: Injected AP formed ovoid masses with minimal inflammation. Cellular infiltration was mild and increased with survival time. There was a gradual reduction of implant volume to similar to 40% at 24 weeks. Increased residence time for paste with larger particles (80 cryomilling seconds) was noted. Von Kossa staining showed progressive calcification of the AP. Cymetra was difficult to reconstitute reliably but formed subdermal masses similar to AP in shape, size, and reactivity and without calcification. The other predicates showed good biocompatibility but spread more widely and erratically in the tissue. Conclusion: Aortic paste is easy to create, biocompatible, degrades slowly, and forms well-defined implants in guinea pig subdermal tissue. The AP implants calcified over time, and experiments are ongoing to determine the source of calcification and how it might be controlled or exploited clinically. C1 [Burns, James A.; Botelho, Jaime L.; Bell, Jonathan I.; Lopez-Guerra, Gerardo; Kobler, James B.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Dept Surg, Boston, MA USA. [Faquin, William] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ackerman, Jerome L.] Massachusetts Gen Hosp, Dept Imaging, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Burns, JA (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, One Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM Burns.james@mgh.harvard.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680; Ackerman, Jerome/0000-0001-5176-7496 FU Voice Health Institute; National Philanthropic Trust FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the Voice Health Institute and the National Philanthropic Trust. NR 24 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD NOV PY 2016 VL 125 IS 11 BP 900 EP 911 DI 10.1177/0003489416660114 PG 12 WC Otorhinolaryngology SC Otorhinolaryngology GA DZ5ZL UT WOS:000385941000004 PM 27440067 ER PT J AU Scheveneels, S Boddez, Y Vervliet, B Hermans, D AF Scheveneels, Sara Boddez, Yannick Vervliet, Bram Hermans, Dirk TI The validity of laboratory-based treatment research: Bridging the gap between fear extinction and exposure treatment SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Fear extinction; Exposure therapy; Return of fear; Validity; Experimental psychopathology; Translational research ID VENTROMEDIAL PREFRONTAL CORTEX; COGNITIVE-BEHAVIORAL THERAPY; SOCIAL ANXIETY DISORDER; D-CYCLOSERINE; EXPERIMENTAL PSYCHOPATHOLOGY; PSYCHOLOGICAL TREATMENTS; POSTTRAUMATIC-STRESS; RENEWAL; HUMANS; REINSTATEMENT AB A major objective of experimental psychopathology research is to improve clinical practice via the experimental study of treatment mechanisms. The success of this endeavor depends on the external validity of the procedures used to model the treatment component in the laboratory. We propose a general framework and a set of specific criteria that will allow evaluating whether a certain. laboratory procedure is a valid model for a certain clinical treatment. We illustrate this framework by evaluating the validity of extinction as a laboratory model for clinical exposure therapy. Although we acknowledge the merits of the extinction model, we argue that its validity might not be as firmly established as the research community assumes. We also use extinction as an example to demonstrate how considerations of the proposed criteria can stimulate further improvements to existing models of treatment. We conclude that the systematic assessment of external validity of treatment models is an important step towards bridging the gap between science and practice in the field of experimental psychopathology. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Scheveneels, Sara; Boddez, Yannick; Vervliet, Bram; Hermans, Dirk] Univ Leuven, Ctr Learning Psychol & Expt Psychopathol, Tiensestr 102 Bus 3712, B-3000 Leuven, Belgium. [Vervliet, Bram] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Vervliet, Bram] Harvard Med Sch, Boston, MA USA. RP Scheveneels, S (reprint author), Univ Leuven, Ctr Learning Psychol & Expt Psychopathol, Tiensestr 102 Bus 3712, B-3000 Leuven, Belgium. EM Sara.Scheveneels@ppw.kuleuven.be; Yannick.Boddez@ppw.kuleuven.be; Bram.Vervliet@ppw.kuleuven.be; Dirk.Hermans@ppw.kuleuven.be FU KU Leuven [PF/10/005]; Belgian Science Policy Office Grant [P7/33]; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [PIOF-GA-2013-627743] FX This work was supported by KU Leuven Program Funding Grant PF/10/005 awarded to Dirk Hermans, by the Belgian Science Policy Office Grant P7/33 and by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2013-627743) awarded to Bram Vervliet. NR 94 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD NOV PY 2016 VL 86 SI SI BP 87 EP 94 DI 10.1016/j.brat.2016.08.015 PG 8 WC Psychology, Clinical SC Psychology GA DZ9JT UT WOS:000386191900008 PM 27590839 ER PT J AU Hemington, KS Wu, Q Kucyi, A Inman, RD Davis, KD AF Hemington, Kasey S. Wu, Qi Kucyi, Aaron Inman, Robert D. Davis, Karen D. TI Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Chronic pain; Default mode network; resting state fMRI; Functional connectivity; Salience network ID DEFAULT-MODE NETWORK; TRAUMATIC BRAIN-INJURY; LOW-BACK-PAIN; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; POSTTRAUMATIC-STRESS-DISORDER; RESTING-STATE CONNECTIVITY; ANKYLOSING-SPONDYLITIS; MULTIPLE-SCLEROSIS; SALIENCE NETWORK AB Cortical functioning within the default mode network (DMN) and salience network (SN) is altered in chronic pain patients. The mechanisms underlying these alterations are unknown, but a novel unexamined source is cross-network communication. Aberrant functional connectivity (FC) between the DMN and SN, whose activity is normally anticorrelated, reflects disease severity in many brain disorders. Further, stronger FC between the posterior cingulate cortex (PCC) and anterior insula has been reported in chronic pain, pointing to abnormal DMN-SN interactions. Here, we tested the hypothesis that cross-network FC between the DMN and SN is abnormal in chronic pain, and is related to pain and associated symptoms. We used resting state fMRI to examine FC within and between the DMN and SN in 20 patients with chronic pain due to ankylosing spondylitis and 20 healthy controls. A whole-network analysis revealed that compared to healthy controls, patients exhibited less anticorrelated FC between the SN and DMN, and the degree of cross-network abnormality tracked pain and disease-related symptoms. This suggests that cross-network FC is a metric of functional brain abnormality in chronic pain. In a complementary seed-based analysis, the PCC was strongly connected with the SN and weakly connected with the DMN in chronic pain compared to healthy controls, suggesting that the PCC acts as a hub for altered network interaction. Sensorimotor cortex cross-network FC correlated with measures of physical function, suggesting that physical functioning also impacts brain network interaction in chronic pain. Our study implicates altered communication between brain networks as a key factor underlying chronic pain. C1 [Hemington, Kasey S.; Wu, Qi; Inman, Robert D.; Davis, Karen D.] Toronto Western Hosp, Univ Hlth Network, Krembil Res Inst, Toronto, ON, Canada. [Hemington, Kasey S.; Davis, Karen D.] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Kucyi, Aaron] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Kucyi, Aaron] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Inman, Robert D.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Davis, Karen D.] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Davis, Karen D.] Toronto Western Hosp, 399 Bathurst St,Room MP14-306, Toronto, ON M5T 2S8, Canada. RP Davis, KD (reprint author), Toronto Western Hosp, Univ Hlth Network, Krembil Res Inst, Toronto, ON, Canada.; Davis, KD (reprint author), Univ Toronto, Inst Med Sci, Toronto, ON, Canada.; Davis, KD (reprint author), Univ Toronto, Dept Surg, Toronto, ON, Canada.; Davis, KD (reprint author), Toronto Western Hosp, 399 Bathurst St,Room MP14-306, Toronto, ON M5T 2S8, Canada. EM kdavis@uhnres.utoronto.ca FU Canada Research Chair Program (CRC in Brain and Behaviour); CIHR; University of Toronto Center for the Study of Pain; Canadian Pain Society; Queen Elizabeth II/Purdue Pharma Scholarship in Science and Technology; Arthritis Society of Canada FX This work was supported by Canada Research Chair Program (CRC in Brain and Behaviour) and a CIHR Operating Grant for KDD. Q. Wu was a recipient of the Pain Scientist Scholarship, University of Toronto Center for the Study of Pain, and the Postdoctoral Fellowship, Canadian Pain Society. K.S.H. is the recipient of a Queen Elizabeth II/Purdue Pharma Scholarship in Science and Technology, and an Arthritis Society of Canada Scholarship. The authors thank the participants for volunteering their time. We also thank Adele Carty and Renise Ayearst for clinical data retrieval, Ammepa Anton for patient recruitment, Eugene Hlasny and Keith Ta for expert technical assistance with MRI acquisition, and Joshua Cheng and Marie-Andree Coulombe for data analysis assistance. NR 93 TC 5 Z9 5 U1 4 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD NOV PY 2016 VL 221 IS 8 BP 4203 EP 4219 DI 10.1007/s00429-015-1161-1 PG 17 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA EA1LA UT WOS:000386352500023 PM 26669874 ER PT J AU Golshan, M Cirrincione, CT Sikov, WM Carey, LA Berry, DA Overmoyer, B Henry, NL Somlo, G Port, E Burstein, HJ Hudis, C Winer, E Ollila, DW AF Golshan, Mehra Cirrincione, Constance T. Sikov, William M. Carey, Lisa A. Berry, Donald A. Overmoyer, Beth Henry, Nora L. Somlo, George Port, Elisa Burstein, Harold J. Hudis, Clifford Winer, Eric Ollila, David W. CA Alliance Clinical Trials Oncology TI Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II-III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance) SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Neoadjuvant therapy; HER2-positive breast cancer; Breast conserving therapy ID PREOPERATIVE CHEMOTHERAPY; CONSERVING SURGERY; SYSTEMIC TREATMENT; TRIAL; MANAGEMENT; RATES AB It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed. C1 [Golshan, Mehra] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Cirrincione, Constance T.] Duke Univ, Alliance Stat & Data Ctr, Med Ctr, Durham, NC USA. [Sikov, William M.] Women & Infants Hosp Rhode Isl, Program Womens Oncol, Providence, RI 02908 USA. [Sikov, William M.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Carey, Lisa A.] Univ North Carolina Chapel Hill, Dept Med Oncol, Chapel Hill, NC USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Alliance Stat & Data Ctr, Houston, TX 77030 USA. [Overmoyer, Beth; Burstein, Harold J.; Winer, Eric] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Henry, Nora L.] Univ Michigan, Dept Med Oncol, Ann Arbor, MI 48109 USA. [Somlo, George] City Hope Med Ctr, Dept Med Oncol, Los Angeles, CA USA. [Port, Elisa] Mt Sinai Sch Med, Dept Surg, New York, NY USA. [Hudis, Clifford] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, 1275 York Ave, New York, NY 10021 USA. [Ollila, David W.] Univ North Carolina Chapel Hill, Dept Surg, Chapel Hill, NC USA. RP Golshan, M (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM mgolshan@partners.org FU National Cancer Institute of the National Institutes of Health [U10CA180821, U10CA180882, U10CA180888]; Breast Cancer Research Foundation; Genentech; GlaxoSmithKline FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), as well as U10CA180888 (to SWOG). Also supported in part by funds from the Breast Cancer Research Foundation, Genentech, and GlaxoSmithKline. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 15 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2016 VL 160 IS 2 BP 297 EP 304 DI 10.1007/s10549-016-4006-6 PG 8 WC Oncology SC Oncology GA EA1RU UT WOS:000386370400010 PM 27704226 ER PT J AU Tolaney, SM Nechushtan, H Ron, IG Schoffski, P Awada, A Yasenchak, CA Laird, AD O'Keeffe, B Shapiro, GI Winer, EP AF Tolaney, Sara M. Nechushtan, Hovav Ron, Ilan-Gil Schoffski, Patrick Awada, Ahmad Yasenchak, Chris A. Laird, A. Douglas O'Keeffe, Bridget Shapiro, Geoffrey I. Winer, Eric P. TI Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Metastatic breast cancer; Cabozantinib; Vascular endothelial growth factor receptor; Progression-free survival; Overall survival; Tumor response ID GROWTH-FACTOR; PROGNOSTIC-FACTOR; PROSTATE-CANCER; TUMOR-GROWTH; C-MET; ANGIOGENESIS; EXPRESSION; TRIAL; TRANSITION; INVASION AB Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT). Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS). Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage. In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control. C1 [Tolaney, Sara M.; Shapiro, Geoffrey I.; Winer, Eric P.] Dana Farber Canc Inst, Dept Med Oncol, Breast Oncol Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Tolaney, Sara M.; Shapiro, Geoffrey I.; Winer, Eric P.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Nechushtan, Hovav] Hadassah Hebrew Univ Med Ctr, Dept Oncol, Jerusalem, Israel. [Ron, Ilan-Gil] Tel Aviv Univ, Dept Oncol, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Tel Aviv, Israel. [Schoffski, Patrick] Katholieke Univ Leuven, Leuven Canc Inst, Dept Gen Med Oncol, Leuven, Belgium. [Awada, Ahmad] Univ Libre Bruxelles, Inst Jules Bordet, Med Oncol, Brussels, Belgium. [Yasenchak, Chris A.] Willamette Valley Canc Inst, RiverBend Pavil, Springfield, OR USA. [Laird, A. Douglas; O'Keeffe, Bridget] Exelixis, San Francisco, CA USA. RP Tolaney, SM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Breast Oncol Ctr, 450 Brookline Ave, Boston, MA 02215 USA.; Tolaney, SM (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM stolaney@partners.org FU Exelixis, Inc. FX This study was supported by Exelixis, Inc. Financial support for medical editorial assistance was provided by Exelixis, Inc. NR 24 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2016 VL 160 IS 2 BP 305 EP 312 DI 10.1007/s10549-016-4001-y PG 8 WC Oncology SC Oncology GA EA1RU UT WOS:000386370400011 PM 27714541 ER PT J AU Beaber, EF Tosteson, ANA Haas, JS Onega, T Sprague, BL Weaver, DL McCarthy, AM Doubeni, CA Quinn, VP Skinner, CS Zauber, AG Barlow, WE AF Beaber, Elisabeth F. Tosteson, Anna N. A. Haas, Jennifer S. Onega, Tracy Sprague, Brian L. Weaver, Donald L. McCarthy, Anne Marie Doubeni, Chyke A. Quinn, Virginia P. Skinner, Celette Sugg Zauber, Ann G. Barlow, William E. TI Breast cancer screening initiation after turning 40 years of age within the PROSPR consortium SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast neoplasms; Mass screening; Prevention & control; Primary health care; Early detection of cancer; Mammography ID TASK-FORCE RECOMMENDATION; METAANALYSIS; GUIDELINES; ACCURACY; UPDATE; WOMEN AB Although United States clinical guidelines differ, the earliest recommended age for average risk breast cancer screening is 40 years. Little is known about factors influencing screening initiation. We conducted a cohort study within the National Cancer Institute-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We identified 3413 women on their 40th birthday in primary care networks at Geisel School of Medicine at Dartmouth (DH) and Brigham and Women's Hospital (BWH) during 2011-2013 with no prior breast imaging or breast cancer. Cumulative incidence curves and Cox modeling were used to determine time from the 40th birthday to first breast cancer screening, cohort exit, or 42nd birthday. We calculated hazards ratios and 95 % confidence intervals from multivariable Cox proportional hazards models. Breast cancer screening cumulative incidence by the 42nd birthday was 62.9 % (BWH) and 39.8 % (DH). Factors associated with screening initiation were: a primary care visit within a year (HR 4.99, 95 % CI 4.23-5.89), an increasing number of primary care visits within a year (p for trend < 0.0001), ZIP code of residence annual median household income aecurrency sign$52,000 (HR 0.79, 95 % CI 0.68-0.92), and health insurance type (Medicaid HR 0.72, 95 % CI 0.58-0.88; Medicare HR 0.55, 95 % CI 0.39-0.77; uninsured HR 0.37, 95 % CI 0.25-0.57). Breast cancer screening uptake after the 40th birthday varies by health system, primary care visits, median household income, and health insurance type, suggesting the need for further exploration. Future research should evaluate screening performance metrics after initiation and consider cumulative benefits and risks associated with breast cancer screening over time. C1 [Beaber, Elisabeth F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M3-A306,POB 19024, Seattle, WA 98109 USA. [Tosteson, Anna N. A.; Onega, Tracy] Geisel Sch Med Dartmouth, Dartmouth Inst Hlth Policy & Clin Practice, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Tosteson, Anna N. A.; Onega, Tracy] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, Dept Gen Internal Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. [Onega, Tracy] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Onega, Tracy] Geisel Sch Med Dartmouth, Dept Epidemiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Sprague, Brian L.] Univ Vermont, Dept Surg, 1 S Prospect St, Burlington, VT 05401 USA. [Sprague, Brian L.; Weaver, Donald L.] Univ Vermont, Ctr Canc, 1 S Prospect St, Burlington, VT 05401 USA. [Weaver, Donald L.] Univ Vermont, Dept Pathol, 1 S Prospect St, Burlington, VT 05401 USA. [McCarthy, Anne Marie] Massachusetts Gen Hosp, Dept Gen Internal Med, 50 Staniford St, Boston, MA 02114 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, 3400 Spruce St, Philadelphia, PA 19104 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, 3400 Spruce St, Philadelphia, PA 19104 USA. [Quinn, Virginia P.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, 100 S Los Robles, Pasadena, CA 91101 USA. [Skinner, Celette Sugg] Univ Texas Southwestern, Simmons Comprehens Canc Ctr, Dept Clin Sci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10065 USA. [Barlow, William E.] Canc Res & Biostat, 1730 Minor Ave, Seattle, WA 98101 USA. RP Beaber, EF (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M3-A306,POB 19024, Seattle, WA 98109 USA. EM ebeaber@fredhutch.org FU National Cancer Institute (NCI) [U01CA163304, U54CA163303, U54CA163307, U54CA163313, U54CA163308, U54CA163308-04S1, U54CA163262]; Memorial Sloan Kettering Cancer Center [P30CA008748] FX This work was supported by the National Cancer Institute (NCI)-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium (grant numbers U01CA163304 to M.T., W.B.; U54CA163303 to D.L.W., B.S.; U54CA163307 to A.N.A.T., T.O., J.H.; U54CA163313 to K.A., M.S.; U54CA163308 to C.S.S., E.H.; U54CA163308-04S1 to C.S.S., J.A.T.; and U54CA163262 to A.G.Z., D.A.C., C.A.D., T.R.L.). The Memorial Sloan Kettering Cancer Center Support grant supported A.G.Z (grant number P30CA008748). The authors thank the participating PROSPR Research Centers for the data they have provided for this study. A list of PROSPR investigators and contributing research staff is provided at http://healthcaredelivery.cancer.gov/prospr/. NR 20 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2016 VL 160 IS 2 BP 323 EP 331 DI 10.1007/s10549-016-3990-x PG 9 WC Oncology SC Oncology GA EA1RU UT WOS:000386370400013 PM 27665586 ER PT J AU Goverman, J Schulz, JT AF Goverman, Jeremy Schulz, John T. TI Thigh burns from exploding E-cigarette SO BURNS LA English DT Letter C1 [Goverman, Jeremy; Schulz, John T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Burns, Boston, MA 02115 USA. RP Goverman, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Burns, Boston, MA 02115 USA. EM jgoverman@partners.org NR 3 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-4179 EI 1879-1409 J9 BURNS JI Burns PD NOV PY 2016 VL 42 IS 7 BP 1618 EP 1618 DI 10.1016/j.burns.2016.07.024 PG 1 WC Critical Care Medicine; Dermatology; Surgery SC General & Internal Medicine; Dermatology; Surgery GA EA1BA UT WOS:000386322100034 PM 27554630 ER PT J AU Soler, ZM Kohli, P Storck, KA Schlosser, RJ AF Soler, Zachary M. Kohli, Preeti Storck, Kristina A. Schlosser, Rodney J. TI Olfactory Impairment in Chronic Rhinosinusitis Using Threshold, Discrimination, and Identification Scores SO CHEMICAL SENSES LA English DT Article DE olfaction; prevalence; sinusitis; Sniffin' Sticks ID ENDOSCOPIC SINUS SURGERY; ODOR DISCRIMINATION; TESTS; SMELL; DYSFUNCTION; QUALITY; DISEASE; LIFE AB Differences in testing modalities and cut-points used to define olfactory dysfunction contribute to the wide variability in estimating the prevalence of olfactory dysfunction in chronic rhinosinusitis (CRS). The aim of this study is to report the prevalence of olfactory impairment using each component of the Sniffin' Sticks test (threshold, discrimination, identification, and total score) with age-adjusted and ideal cut-points from normative populations. Patients meeting diagnostic criteria for CRS were enrolled from rhinology clinics at a tertiary academic center. Olfaction was assessed using the Sniffin' Sticks test. The study population consisted of 110 patients. The prevalence of normosmia, hyposmia, and anosmia using total Sniffin' Sticks score was 41.8%, 20.0%, and 38.2% using age-appropriate cut-points and 20.9%, 40.9%, and 38.2% using ideal cut-points. Olfactory impairment estimates for each dimension mirrored these findings, with threshold yielding the highest values. Threshold, discrimination, and identification were also found to be significantly correlated to each other (P < 0.001). In addition, computed tomography scores, asthma, allergy, and diabetes were found to be associated with olfactory dysfunction. In conclusion, the prevalence of olfactory dysfunction is dependent upon olfactory dimension and if age-adjusted cut-points are used. The method of olfactory testing should be chosen based upon specific clinical and research goals. C1 [Soler, Zachary M.; Kohli, Preeti; Storck, Kristina A.; Schlosser, Rodney J.] Med Univ South Carolina, Div Rhinol & Sinus Surg, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Dept Surg, 109 Bee St, Charleston, SC 29401 USA. RP Soler, ZM (reprint author), Med Univ South Carolina, Div Rhinol & Sinus Surg, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM solerz@musc.edu NR 25 TC 0 Z9 0 U1 7 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD NOV PY 2016 VL 41 IS 9 BP 713 EP 719 DI 10.1093/chemse/bjw080 PG 7 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DZ8NB UT WOS:000386126000492 ER PT J AU Holbrook, EH AF Holbrook, Eric H. TI Trans-nasal electrical stimulation of the olfactory bulb SO CHEMICAL SENSES LA English DT Meeting Abstract CT 17th International Symposium on Olfaction and Taste (ISOT) CY JUN 05-09, 2016 CL Yokohama, JAPAN C1 [Holbrook, Eric H.] Harvard Med Sch, Massachsetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X EI 1464-3553 J9 CHEM SENSES JI Chem. Senses PD NOV PY 2016 VL 41 IS 9 MA PA09-5 BP E125 EP E125 PG 1 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA DZ8NB UT WOS:000386126000045 ER PT J AU Azar, ST Miller, EA McGuier, DJ Stevenson, MT O'Donnell, E Olsen, N Spence, N AF Azar, Sandra T. Miller, Elizabeth A. McGuier, Devin J. Stevenson, Michael T. O'Donnell, Ellen Olsen, Nina Spence, Noel TI Maternal Social Information Processing and the Frequency and Severity of Mother-Perpetrated Physical Abuse SO CHILD MALTREATMENT LA English DT Article DE abusive parents; child abuse; etiology; physical abuse; recidivism; child maltreatment ID PARENT OPINION QUESTIONNAIRE; CHILD MALTREATMENT; INTELLECTUAL DISABILITIES; UNREALISTIC EXPECTATIONS; ADOLESCENT MOTHERS; COGNITIVE APPROACH; SUBSTANCE USE; RE-REPORTS; RISK; ATTRIBUTIONS AB The frequency and severity of physical abuse influences children's outcomes, yet little theory-based research has explored what predicts its course. This study examined the potential role of social information processing (SIP) factors in the course of abuse. Mothers with histories of perpetrating physical abuse (N = 62) completed measures of SIP, and the frequency and severity of mother-perpetrated physical abuse were collected from Child Protection Services records. Poorer problem-solving capacities were significantly related to greater frequency of physical abuse. Hostile attributions toward children were positively associated with abuse severity. Controlling for demographics and co-occurrence of neglect, SIP factors together accounted for a significant proportion of variance in the frequency of physical abuse, but not severity. With the exception of unrealistic expectations, preliminary evidence supported a link between maternal SIP and the course of abuse perpetration. Future research directions and implications for intervention are discussed. C1 [Azar, Sandra T.; Miller, Elizabeth A.; McGuier, Devin J.] Penn State Univ, Dept Psychol, 360 Moore Bldg, University Pk, PA 16802 USA. [Stevenson, Michael T.] Tufts Univ, Medford, MA 02155 USA. [O'Donnell, Ellen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Olsen, Nina] Karmoy DPS, Helsefonna, Norway. [Spence, Noel] Clark Univ, Worcester, MA 01610 USA. RP Azar, ST (reprint author), Penn State Univ, Dept Psychol, 360 Moore Bldg, University Pk, PA 16802 USA. EM sta10@psu.edu FU National Institute of Mental Health [5R29MH046940] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant to the first author from the National Institute of Mental Health (5R29MH046940). NR 75 TC 0 Z9 0 U1 9 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5595 EI 1552-6119 J9 CHILD MALTREATMENT JI Child Maltreatment PD NOV PY 2016 VL 21 IS 4 BP 308 EP 316 DI 10.1177/1077559516668047 PG 9 WC Family Studies; Social Work SC Family Studies; Social Work GA DZ7PB UT WOS:000386057200005 ER PT J AU Snodgrass, MN Shields, J Rai, HM AF Snodgrass, Megan N. Shields, Jenna Rai, Hema TI Efficacy and Safety of Fondaparinux in Patients With Suspected Heparin-Induced Thrombocytopenia SO CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS LA English DT Article DE anticoagulants; clinical pharmacology; factor Xa inhibitors; hypercoagulability; thrombocytopenia ID CASE SERIES; ANTIBODIES; HIT AB Objective: Heparin-induced thrombocytopenia (HIT) occurs in up to 5% of patients exposed to unfractionated heparin for 5 or more days. Direct thrombin inhibitors (DTIs) are currently the only Food and Drug Administration (FDA)-approved agents for the treatment of HIT. The purpose of this study is to determine whether fondaparinux is an appropriate first-line alternative anticoagulant in patients with suspected or confirmed HIT. Methods: A retrospective study was conducted by identifying all patients who received a DTI or fondaparinux during a 5 year period, August 2009-August 2014. Patients were included if they had a HIT panel/serotonin-release assay analysis (regardless of the result) and were initiated on a DTI or fondaparinux for alternative anticoagulation. The primary outcome was new, recurrent, or progressive thromboembolic event. Secondary outcomes included bleeding events, platelet count recovery, and hospital stay. Results: A total of 1022 patients were evaluated, and 47 patients met the inclusion criteria. Twelve patients were HIT positive and 35 were HIT negative. Seven (14.9%) of the 47 patients experienced a new thrombosis, none of whom were on fondaparinux only (FONDA). There were 4 new minor bleeds, with 1 bleed as a result of being on fondaparinux. FONDA treatment resulted in a slightly shorter median duration of hospital stay compared to the DTI-only group and the DTI followed by fondaparinux group. There is a potential for cost savings with fondaparinux due to the ease of administration and availability to be given in the outpatient setting. Conclusion: In this small retrospective review, fondaparinux appeared similarly efficacious and safe compared to DTIs for the treatment of suspected HIT. C1 [Snodgrass, Megan N.] Butler Vet Affairs Med Ctr, Cranberry Community Based Outpatient Clin, 900 Commonwealth Dr,Suite 900, Cranberry Township, PA 16066 USA. [Shields, Jenna; Rai, Hema] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Snodgrass, MN (reprint author), Butler Vet Affairs Med Ctr, Cranberry Community Based Outpatient Clin, 900 Commonwealth Dr,Suite 900, Cranberry Township, PA 16066 USA. EM megan.snodgrass3@va.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1076-0296 EI 1938-2723 J9 CLIN APPL THROMB-HEM JI Clin. Appl. Thromb.-Hemost. PD NOV PY 2016 VL 22 IS 8 BP 712 EP 717 DI 10.1177/1076029616646873 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DZ7BW UT WOS:000386019900002 PM 27179015 ER PT J AU Kelesoglu, FM Aygun, E Okumus, NK Ersoy, A Karapinar, E Saglam, N Aydim, NG Senay, BB Gonultas, S Sarisik, E Can, MZ Atay, S Basbug, D Tiryaki, FK Ozer, S Durmus, RB Orem, F Atay, T Acar, A Yilmaz, Y Kaya, S Ciftkaya, A Sarac, Z Makar, CC Saracoglu, B Dogdu, G Omeroglu, RE AF Kelesoglu, Fatih Mehmet Aygun, Erhan Okumus, Nazli Kubra Ersoy, Aysenur Karapinar, Edanur Saglam, Nesibe Aydim, Nur Gokce Senay, Beyza Betul Gonultas, Sumeyye Sarisik, Elif Can, Melike Zeynep Atay, Sirin Basbug, Dilruba Tiryaki, Feyza Kubra Ozer, Sena Durmus, Rana Berru Orem, Fatih Atay, Tugrul Acar, Ahmet Yilmaz, Yasin Kaya, Seyma Ciftkaya, Aylin Sarac, Zeynep Makar, Cagri Can Saracoglu, Basak Dogdu, Gafur Omeroglu, Rukiye Eker TI Evaluation of subclinical inflammation in familial Mediterranean fever patients: relations with mutation types and attack status: a retrospective study SO CLINICAL RHEUMATOLOGY LA English DT Article DE C-reactive protein; Familial Mediterranean fever; Neutrophil to lymphocyte ratio; Platelet to lymphocyte ratio; Subclinical inflammation ID NEUTROPHIL-LYMPHOCYTE RATIO; NEUTROPHIL/LYMPHOCYTE RATIO; DISEASE; PREDICTOR; CANCER; SPECTRUM; OUTCOMES AB Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease of childhood and adulthood. Development of systemic amyloidosis and frequent attack influence quality of life and survival. There is sporadic evidence indicating subclinical inflammation in patients with FMF. We aimed to assess subclinical inflammation using neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and C-reactive protein (CRP) in pediatric patients with FMF in the attack-free period. In this retrospective study, we reviewed the files of all FMF patients in our pediatric rheumatology outpatient clinic in a tertiary center and enrolled those with sufficient clinical and laboratory data. We also enrolled 73 controls. We grouped the patients according to being in attack period or attack-free period. We compared CRP, NLR, PLR, and WBC (white blood cell) levels between different mutations and polymorphisms. We also compared patients in the attack period with those in attack-free period. We enrolled 61 patients in attack period, 509 patients in attack-free period, and 73 controls. There was no difference between patients with different mutations with respect to NLR or PLR levels in the attack-free period. However, CRP levels were higher in patients with homozygous exon 10 mutations, especially those with homozygous M694V mutations compared with other mutations. However, CRP levels were mostly normal in these patients. Our data are against the reported fact that patients with FMF have higher NLR or PLR levels in attack-free periods. However, CRP levels were higher in the presence of homozygous exon 10 mutations (in particular homozygous M694V mutations). C1 [Kelesoglu, Fatih Mehmet; Aygun, Erhan; Okumus, Nazli Kubra; Ersoy, Aysenur; Karapinar, Edanur; Saglam, Nesibe; Aydim, Nur Gokce; Senay, Beyza Betul; Gonultas, Sumeyye; Sarisik, Elif; Can, Melike Zeynep; Atay, Sirin; Basbug, Dilruba; Tiryaki, Feyza Kubra; Ozer, Sena; Durmus, Rana Berru; Orem, Fatih; Kaya, Seyma; Ciftkaya, Aylin; Sarac, Zeynep; Makar, Cagri Can; Saracoglu, Basak; Omeroglu, Rukiye Eker] Istanbul Univ, Istanbul Med Sch, Dept Pediat Rheumatol, Millet Caddesi, TR-34093 Fatih Istanbul, Turkey. [Atay, Tugrul] Haseki Educ & Training Hosp, Dept Pediat, Vatan Caddesi, TR-34093 Istanbul, Turkey. [Acar, Ahmet] Harvard Med Sch, Massachusetts Gen Hosp, Dept Publ Hlth Stat, Boston, MA USA. [Acar, Ahmet] Istanbul Univ, Publ Hlth Stat, Istanbul Fac Med, TR-34093 Istanbul, Turkey. [Yilmaz, Yasin] Istanbul Univ, Istanbul Med Sch, Dept Pediat, Millet Caddesi, TR-34093 Fatih Istanbul, Turkey. [Dogdu, Gafur] Istanbul Univ, Istanbul Med Sch, Dept Pediat Cardiol, Millet Caddesi, TR-34093 Fatih Istanbul, Turkey. RP Kelesoglu, FM (reprint author), Istanbul Univ, Istanbul Med Sch, Dept Pediat Rheumatol, Millet Caddesi, TR-34093 Fatih Istanbul, Turkey. EM fatihmk@istanbul.edu.tr; dr.erhanaygun@gmail.com; okumusnazli@gmail.com; eraysenur@gmail.com; edanurkarapinarr@gmail.com; saglamnes@gmail.com; ngokceaydin@gmail.com; beyzabetulsenay@gmail.com; sumeyyegonultas@gmail.com; elifsarisik@hotmail.com; mzeynepcan@gmail.com; siringsl@gmail.com; dilrubabasbug@gmail.com; feyzatiryaki94@gmail.com; drsenaozer@gmail.com; ranaberrudurmus@gmail.com; merohitaf@hotmail.com; drtatay@gmail.com; aacar@mgh.harvard.edu; seymakaya17@gmail.com; aylinciftkaya@gmail.com; bzsarac@gmail.com; ccanmakar@gmail.com; basaksaracoglu@gmail.com; rukiye@istanbul.edu.tr NR 24 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD NOV PY 2016 VL 35 IS 11 BP 2757 EP 2763 DI 10.1007/s10067-016-3275-0 PG 7 WC Rheumatology SC Rheumatology GA EA1OP UT WOS:000386362000017 PM 27106545 ER PT J AU Eisen, A Giugliano, RP AF Eisen, Alon Giugliano, Robert P. TI Advances in the field of proprotein convertase subtilisin kexin type 9 inhibitors SO CURRENT OPINION IN CARDIOLOGY LA English DT Review DE cardiovascular events; low-density lipoprotein; monoclonal antibody; proprotein convertase subtilisin kexin type 9; secondary prevention ID HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; DENSITY-LIPOPROTEIN CHOLESTEROL; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; PLACEBO-CONTROLLED TRIAL; EVOLOCUMAB AMG 145; CARDIOVASCULAR RISK PATIENTS; RANDOMIZED CONTROLLED-TRIAL; STATIN-INTOLERANT PATIENTS; HUMAN MONOCLONAL-ANTIBODY; DOUBLE-BLIND AB Purpose of reviewProprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are promising therapies that inhibit the degradation of low-density lipoprotein (LDL) receptors in the hepatocyte and thus increase LDL cholesterol (LDL-C) uptake from the blood. This review summarizes main findings in the field of PCSK9 inhibitors, from basic mechanism to clinical studies, and aims to provide a contemporary and practical overview of the clinical implication and future directions with PCSK9 inhibitors.Recent findingsMonoclonal antibodies that inhibit PCSK9 reduce LDL-C levels by 40-70% across a wide range of patients with various LDL-C levels, and with different lipid-lowering regimens. These agents significantly reduce apolipoprotein B and lipoprotein (a), may have a potential role in plaque stabilization in acute coronary syndromes, and are safe and tolerable, even among statin-intolerant patients. Preliminary data with evolocumab and alirocumab demonstrate the potential reduction of cardiovascular (CV) events. These PCSK9 inhibitors were recently approved for clinical use, and recommended in the 2016 American College of Cardiology expert consensus document for nonstatin therapy for LDL-C lowering.SummaryPCSK9 inhibitors are novel promising therapies to reduce LDL-C. Ongoing phase 3 clinical trials with more than 70000 high-risk patients will examine their safety and efficacy in reducing cardiovascular disease. C1 Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. Harvard Med Sch, Dept Med, Boston, MA USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org FU Amgen FX R.P.G.: Clinical trials/research support to his institution from Amgen; Honoraria for CME lectures from Amgen, Daiichi Sankyo, and Merck; Consultancies with Amarin, American College of Cardiology, Amgen, Boehringer Ingelheim, CVS Caremark, Daiichi Sankyo, Merck, Pfizer, and Stealth Peptides. NR 55 TC 1 Z9 1 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0268-4705 EI 1531-7080 J9 CURR OPIN CARDIOL JI Curr. Opin. Cardiol. PD NOV PY 2016 VL 31 IS 6 BP 644 EP 653 DI 10.1097/HCO.0000000000000332 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA1JU UT WOS:000386349200010 PM 27661220 ER PT J AU Shah, HS Gao, H Morieri, ML Skupien, J Marvel, S Pare, G Mannino, GC Buranasupkajorn, P Mendonca, C Hastings, T Marcovina, SM Sigal, RJ Gerstein, HC Wagner, MJ Motsinger-Reif, AA Buse, JB Kraft, P Mychaleckyj, JC Doria, A AF Shah, Hetal S. Gao, He Morieri, Mario Luca Skupien, Jan Marvel, Skylar Pare, Guillaume Mannino, Gaia C. Buranasupkajorn, Patinut Mendonca, Christine Hastings, Timothy Marcovina, Santica M. Sigal, Ronald J. Gerstein, Hertzel C. Wagner, Michael J. Motsinger-Reif, Alison A. Buse, John B. Kraft, Peter Mychaleckyj, Josyf C. Doria, Alessandro TI Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial SO DIABETES CARE LA English DT Article ID LONG NONCODING RNAS; ALL-CAUSE MORTALITY; EPIDEMIOLOGIC ANALYSIS; SEVERE HYPOGLYCEMIA; CANDIDATE GENE; ASSOCIATION; DISEASE; HEMOGLOBIN; RISK; MELLITUS AB OBJECTIVE To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality. RESULTS Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 X 10(-9) and P = 2 X 10(-8), respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS >= 2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029). CONCLUSIONS Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be C1 [Shah, Hetal S.; Gao, He; Morieri, Mario Luca; Skupien, Jan; Mannino, Gaia C.; Buranasupkajorn, Patinut; Mendonca, Christine; Hastings, Timothy; Doria, Alessandro] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Shah, Hetal S.; Gao, He; Morieri, Mario Luca; Skupien, Jan; Mannino, Gaia C.; Buranasupkajorn, Patinut; Doria, Alessandro] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Skupien, Jan] Jagiellonian Univ, Coll Med, Dept Metab Dis, Krakow, Poland. [Marvel, Skylar; Motsinger-Reif, Alison A.] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC USA. [Marvel, Skylar; Motsinger-Reif, Alison A.] North Carolina State Univ, Dept Stat, Raleigh, NC USA. [Pare, Guillaume; Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada. [Pare, Guillaume; Gerstein, Hertzel C.] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON L8S 4L8, Canada. [Pare, Guillaume; Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Buranasupkajorn, Patinut] Chulalongkorn Univ, Fac Med, Dept Med, Bangkok, Thailand. [Marcovina, Santica M.] Univ Washington, Dept Med, Seattle, WA USA. [Marcovina, Santica M.] Northwest Lipid Metab & Diabet Res Labs, Seattle, WA USA. [Sigal, Ronald J.] Univ Calgary, Cumming Sch Med, Dept Med, Fac Med, Calgary, AB T2N 1N4, Canada. [Sigal, Ronald J.] Univ Calgary, Cumming Sch Med, Dept Cardiac Sci, Fac Med, Calgary, AB T2N 1N4, Canada. [Sigal, Ronald J.] Univ Calgary, Cumming Sch Med, Dept Community Hlth Sci, Fac Med, Calgary, AB T2N 1N4, Canada. [Sigal, Ronald J.] Univ Calgary, Fac Kinesiol, Calgary, AB T2N 1N4, Canada. [Wagner, Michael J.] Univ N Carolina, Ctr Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Buse, John B.] Univ N Carolina, Dept Med, Sch Med, Chapel Hill, NC USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mychaleckyj, Josyf C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. RP Doria, A (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA.; Doria, A (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM alessandro.doria@joslin.haivard.edu FU National Institutes of Health (NIH) [HL110400, HL110380]; NIH [DK36836, NCRR 1S10RR028832-01]; National Center for Advancing Translational Sciences (NCATS), NIH [UL1TR001111]; NCATS, NIH [UL1TR001111]; Hearst Foundation; William Randolph Hearst Fellowship; Alberta Innovates-Health Solutions; Health Senior Scholar Award; JDRF [3-2009-397]; National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers and Clinical and Translational Science Awards FX The ACCORD genome-wide association analysis was supported by National Institutes of Health (NIH) grants HL110400 (to A.D.) and HL110380 (to J.B.B.). The project described was also supported by NIH grant DK36836 (Advanced Genomics and Genetics Core of the Diabetes Research Center at the Joslin Diabetes Center) and the National Center for Advancing Translational Sciences (NCATS), NIH, through grant UL1TR001111. J.B.B. was also supported by the NCATS, NIH, through grant UL1TR001111. M.L.M. was supported by the Hearst Foundation with a William Randolph Hearst Fellowship. R.J.S. was supported by Alberta Innovates-Health Solutions with a Health Senior Scholar Award. J.S. was supported by JDRF grant 3-2009-397. The ACCORD study (ClinicalTrials.gov identifier NCT00000620) was supported by National Heart, Lung, and Blood Institute contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010. Other components of the NIH, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers and Clinical and Translational Science Awards provided support at many sites.; Part of the genome-wide analysis was conducted on the Orchestra High Performance Computer Cluster at Harvard Medical School (http://rc.hms.harvard.edu). This NIH-supported shared facility consists of thousands of processing cores and terabytes of associated storage and is partially provided through grant NCRR 1S10RR028832-01. NR 34 TC 2 Z9 2 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2016 VL 39 IS 11 BP 1915 EP 1924 DI 10.2337/dc16-0285 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA1BZ UT WOS:000386328800021 PM 27527847 ER PT J AU Katz, LL Anderson, BJ McKay, SV Izquierdo, R Casey, TL Higgins, LA Wauters, A Hirst, K Nadeau, KJ AF Katz, Lorraine Levitt Anderson, Barbara J. McKay, Siripoom V. Izquierdo, Roberto Casey, Terri L. Higgins, Laurie A. Wauters, Aimee Hirst, Kathryn Nadeau, Kristen J. CA TODAY Study Grp TI Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID QUALITY-OF-LIFE; GLYCEMIC CONTROL; CLINICAL CHARACTERISTICS; CHILDHOOD OVERWEIGHT; GLUCOSE-TOLERANCE; AFRICAN-AMERICAN; CONTROLLED-TRIAL; ADOLESCENTS; PREVALENCE; DEPRESSION AB OBJECTIVE To identify factors that predict medication adherence and to examine relationships among adherence, glycemic control, and indices of insulin action in TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth). RESEARCH DESIGN AND METHODS A total of 699 youth 10-17 years old with recent-onset type 2 diabetes and 80% adherence to metformin therapy for >= 8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking >= 80% of medication; low adherence was defined as taking <80% of medication. Depressive symptoms, insulin sensitivity (1/fasting insulin), insulinogenic index, and oral disposition index (oDI) were measured. Survival analysis examined the relationship between medication adherence and loss of glycemic control. Generalized linear mixed models analyzed trends in adherence over time. RESULTS In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. Longitudinally, participants with high adherence had significantly greater insulin sensitivity and oDI than those with low adherence. CONCLUSIONS In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. Medication adherence was positively associated with insulin sensitivity and oDI, but, because of disease progression, adherence did not predict long-term treatment success. C1 [Katz, Lorraine Levitt] Univ Penn, Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Katz, Lorraine Levitt] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Anderson, Barbara J.; McKay, Siripoom V.] Baylor Coll Med, Houston, TX 77030 USA. [Anderson, Barbara J.] Texas Childrens Hosp, Houston, TX 77030 USA. [Izquierdo, Roberto] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Casey, Terri L.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Higgins, Laurie A.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Wauters, Aimee] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hirst, Kathryn] George Washington Univ, Biostat Ctr, Rockville, MD 20852 USA. [Nadeau, Kristen J.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. RP Hirst, K (reprint author), George Washington Univ, Biostat Ctr, Rockville, MD 20852 USA. EM khirst@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health Office of the Director [U01-DK-61212, U01-DK-61230, U01-DK-61239, U01-DK-61242, U01-DK-61254] FX This work was completed with funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health Office of the Director through grants U01-DK-61212, U01-DK-61230, U01-DK-61239, U01-DK-61242, and U01-DK-61254. NR 47 TC 0 Z9 0 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2016 VL 39 IS 11 BP 1956 EP 1962 DI 10.2337/dc15-2296 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA1BZ UT WOS:000386328800026 PM 27352955 ER PT J AU Colberg, SR Sigal, RJ Yardley, JE Riddell, MC Dunstan, DW Dempsey, PC Horton, ES Castorino, K Tate, DF AF Colberg, Sheri R. Sigal, Ronald J. Yardley, Jane E. Riddell, Michael C. Dunstan, David W. Dempsey, Paddy C. Horton, Edward S. Castorino, Kristin Tate, Deborah F. TI Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association SO DIABETES CARE LA English DT Article ID INTERMITTENT HIGH-INTENSITY; RANDOMIZED CONTROLLED-TRIAL; SUBCUTANEOUS INSULIN INFUSION; LIFE-STYLE INTERVENTIONS; POSTPRANDIAL GLYCEMIC EXCURSION; GLUCOSE MONITORING SYSTEMS; FATTY LIVER-DISEASE; RESISTANCE EXERCISE; SEDENTARY BEHAVIOR; AEROBIC EXERCISE C1 [Colberg, Sheri R.] Old Dominion Univ, Dept Human Movement Sci, Norfolk, VA USA. [Sigal, Ronald J.] Univ Calgary, Fac Med, Dept Med, Calgary, AB, Canada. [Sigal, Ronald J.] Univ Calgary, Fac Med, Dept Cardiac Sci, Calgary, AB, Canada. [Sigal, Ronald J.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. [Sigal, Ronald J.] Univ Calgary, Fac Kinesiol, Calgary, AB, Canada. [Yardley, Jane E.] Univ Alberta, Dept Social Sci, Augusta Campus, Camrose, AB, Canada. [Riddell, Michael C.] York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON, Canada. [Dunstan, David W.; Dempsey, Paddy C.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Horton, Edward S.] Harvard Med Sch, Boston, MA USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Castorino, Kristin] William Sansum Diabet Ctr, Santa Barbara, CA USA. [Tate, Deborah F.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC USA. RP Colberg, SR (reprint author), Old Dominion Univ, Dept Human Movement Sci, Norfolk, VA USA. EM scolberg@odu.edu NR 185 TC 8 Z9 8 U1 15 U2 15 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2016 VL 39 IS 11 BP 2065 EP 2079 DI 10.2337/dc16-1728 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA1BZ UT WOS:000386328800040 PM 27926890 ER PT J AU Yoon, SS Kuo, B AF Yoon, Sonia S. Kuo, Braden TI Training in Gastrointestinal Motility SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article ID GASTROENTEROLOGY; FELLOWSHIP C1 [Yoon, Sonia S.] Univ Rochester, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Rochester, NY 14642 USA. [Kuo, Braden] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Ctr Neurointestinal Hlth,GI Motil Lab,Dept Med, Boston, MA USA. RP Yoon, SS (reprint author), Univ Rochester, Med Ctr, Dept Med, Div Gastroenterol & Hepatol, Rochester, NY 14642 USA. EM sonia.yoon@gmail.com NR 11 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD NOV PY 2016 VL 61 IS 11 BP 3105 EP 3107 DI 10.1007/s10620-016-4295-y PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA3TW UT WOS:000386529000005 PM 27638833 ER PT J AU Kaplan, DE Dai, F Skanderson, M Aytaman, A Baytarian, M D'Addeo, K Fox, R Hunt, K Knott, A Mehta, R Pedrosa, M Pocha, C Valderrama, A Taddei, T AF Kaplan, David E. Dai, Feng Skanderson, Melissa Aytaman, Ayse Baytarian, Michelle D'Addeo, Kathryn Fox, Rena Hunt, Kristel Knott, Astrid Mehta, Rajni Pedrosa, Marcos Pocha, Christine Valderrama, Adriana Taddei, Tamar CA VOCAL Study Grp TI Recalibrating the Child-Turcotte-Pugh Score to Improve Prediction of Transplant-Free Survival in Patients with Cirrhosis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Human; Cirrhosis; Natural history; Survival; MELD; Predictive models; Creatinine ID STAGE LIVER-DISEASE; HEPATIC-ENCEPHALOPATHY; HEPATOCELLULAR-CARCINOMA; END; MODEL; MELD; MORTALITY; CLASSIFICATION; VALIDITY; SURGERY AB The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. However, the cutpoints for stratifying laboratory variables in CTP have never been validated. The objective of this study was to identify evidence-based cutpoints for the CTP laboratory subscores to improve its predictive capacity for transplant-free survival. Retrospective observational study. Using a cohort of 30,897 cirrhotic US Veteran patients with at least 5 years of follow-up, we performed Cox proportional hazard survival model iterations varying the upper and lower cutpoints for INR, total bilirubin and albumin CTP subscores. Cutpoints yielding the highest Harrell's C-statistics for concordance with transplant-free survival were incorporated into a modified CTP (mCTP) score. Validation of the mCTP was performed at multiple time frames within the follow-up period of the cohort and within subsets defined by disease etiology. Modification of CTP cutpoints increased the Harrell's C-statistic for age- and gender-adjusted Cox proportional hazard models from 0.701 +/- A 0.002 to 0.709 +/- A 0.002 and the risk ratio per unit change from 1.49 (1.48-1.50) to 1.53 (1.52-1.54). The modified cutpoints showed superiority in predicting 5-year transplant-free survival in various disease etiology subgroups. A mCTP substituting serum creatinine for INR performed superiorly for predicting 5-year transplant-free survival. We propose an evidence-based recalibration of CTP score cutpoints that optimizes this model's capacity to predict transplant-free survival in patients with cirrhosis. The CTP score remains the best predictor of 5-year overall and transplant-free survival in patients with cirrhosis. C1 [Kaplan, David E.] Corporal Michael J Crescenz VA Med Ctr, Gastroenterol Sect, Dept Med, 3900 Woodland Ave,Bldg 21,Room A422, Philadelphia, PA 19104 USA. [Dai, Feng; Skanderson, Melissa; D'Addeo, Kathryn; Mehta, Rajni; Taddei, Tamar] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Aytaman, Ayse] VA New York Harbor Hlth Care Syst, 800 Poly Pl, Brooklyn, NY 11209 USA. [Baytarian, Michelle; Pedrosa, Marcos] Boston VA Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. [Fox, Rena] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. [Hunt, Kristel] James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. [Knott, Astrid; Pocha, Christine] Minneapolis VA Hlth Care Syst, One Vet Dr, Minneapolis, MN 55417 USA. [Valderrama, Adriana] Bayer HealthCare Pharmaceut, 100 Bayer Blvd, Whippany, NJ 07981 USA. RP Kaplan, DE (reprint author), Corporal Michael J Crescenz VA Med Ctr, Gastroenterol Sect, Dept Med, 3900 Woodland Ave,Bldg 21,Room A422, Philadelphia, PA 19104 USA. EM dakaplan@mail.med.upenn.edu FU Bayer Healthcare Pharmaceuticals; VA HIV, Hepatitis and Public Health Pathogens Programs in the Office of Public Health/Clinical Public Health FX This work was supported by unrestricted research funds from Bayer Healthcare Pharmaceuticals and the VA HIV, Hepatitis and Public Health Pathogens Programs in the Office of Public Health/Clinical Public Health. NR 33 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD NOV PY 2016 VL 61 IS 11 BP 3309 EP 3320 DI 10.1007/s10620-016-4239-6 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EA3TW UT WOS:000386529000030 PM 27405990 ER PT J AU Minguez-Alarcon, L Souter, I Chiu, YH Williams, PL Ford, JB Ye, X Calafat, AM Hauser, R AF Minguez-Alarcon, Lidia Souter, Irene Chiu, Yu -Han Williams, Paige L. Ford, Jennifer B. Ye, Xiaoyun Calafat, Antonia M. Hauser, Russ CA Earth Study Team TI Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center SO ENVIRONMENTAL RESEARCH LA English DT Article DE DINCH metabolites; Epidemiology; Markers of ovarian response; Phthalates; Reproductive health ID VASCULAR FRACTION DIFFERENTIATION; DIISONONYL ESTER; ADIPOSE-TISSUE; EXPOSURE; HEALTH; POPULATION; CARE AB Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (-325 pmol/l, p=0.09) and number of retrieved oocytes (-1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health. (C) 2016 Elsevier Inc. All rights reserved. C1 [Minguez-Alarcon, Lidia; Ford, Jennifer B.; Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Chiu, Yu -Han] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Williams, Paige L.; Hauser, Russ] Dept Epidemiol, Boston, MA USA. [Williams, Paige L.; Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Souter, Irene; Hauser, Russ] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Souter, Irene; Hauser, Russ] Harvard Med Sch, Boston, MA USA. [Ye, Xiaoyun; Calafat, Antonia M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. RP Minguez-Alarcon, L (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. EM lminguez@hsph.harvard.edu FU NIH from the National Institute of Environmental Health Sciences (NIEHS) [R01ES022955, R01ES009718, R01ES000002] FX NIH grants R01ES022955, R01ES009718, and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS). NR 30 TC 0 Z9 0 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD NOV PY 2016 VL 151 BP 595 EP 600 DI 10.1016/j.envres.2016.08.012 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EA2HO UT WOS:000386413600063 PM 27591839 ER PT J AU Karimi, M Bahrami, S Ravari, SB Zangabad, PS Mirshekari, H Bozorgomid, M Shahreza, S Sori, M Hamblin, MR AF Karimi, Mahdi Bahrami, Sajad Ravari, Soodeh Baghaee Zangabad, Parham Sahandi Mirshekari, Hamed Bozorgomid, Mahnaz Shahreza, Somayeh Sori, Masume Hamblin, Michael R. TI Albumin nanostructures as advanced drug delivery systems SO EXPERT OPINION ON DRUG DELIVERY LA English DT Review DE Human serum albumin; bovine serum albumin; ovalbumin; nanoparticles; drug delivery systems ID HUMAN-SERUM-ALBUMIN; RESPONSE-SURFACE METHODOLOGY; BLOOD-BRAIN-BARRIER; CANCER-CELLS; TARGETED DELIVERY; BSA NANOPARTICLES; ANTISENSE OLIGONUCLEOTIDE; PROTEIN NANOPARTICLES; PANCREATIC-CANCER; CARCINOMA-CELLS AB Introduction: One of the biggest impacts that the nanotechnology has made on medicine and biology, has been in the area of drug delivery systems (DDSs). Many drugs suffer from serious problems concerning insolubility, instability in biological environments, poor uptake into cells and tissues, sub-optimal selectivity for targets and unwanted side effects. Nanocarriers can be designed as DDSs to overcome many of these drawbacks. One of the most versatile building blocks to prepare these nanocarriers is the ubiquitous, readily available and inexpensive protein, serum albumin. Areas covered: This review covers the use of different types of albumin (human, bovine, rat, and chicken egg) to prepare nanoparticle and microparticle-based structures to bind drugs. Various methods have been used to modify the albumin structure. A range of targeting ligands can be attached to the albumin that can be recognized by specific cell receptors that are expressed on target cells or tissues. Expert opinion: The particular advantages of albumin used in DDSs include ready availability, ease of chemical modification, good biocompatibility, and low immunogenicity. The regulatory approvals that have been received for several albumin-based therapeutic agents suggest that this approach will continue to be successfully explored. C1 [Karimi, Mahdi; Bahrami, Sajad; Sori, Masume] Iran Univ Med Sci, Fac Adv Technol Med, Dept Med Nanotechnol, Tehran, Iran. [Bahrami, Sajad] USERN, NRA, Tehran, Iran. [Ravari, Soodeh Baghaee] Univ North Carolina Greensboro, Joint Sch Nanosci & Nanoengn, Greensboro, NC USA. [Zangabad, Parham Sahandi] Sharif Univ Technol, Dept Mat Sci & Engn, Tehran, Iran. [Mirshekari, Hamed] Iran Univ Med Sci, ANNRG, Tehran, Iran. [Bozorgomid, Mahnaz] Islamic Azad Univ, Cent Tehran Branch, Dept Appl Chem, Tehran, Iran. [Shahreza, Somayeh] Univ Tehran, Univ Coll Sci, Sch Biol, Dept Microbiol, Tehran, Iran. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. EM hamblin@helix.mgh.harvard.edu FU US NIH [R01A1050875] FX MR Hamblin was supported by US NIH grant R01A1050875. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 128 TC 3 Z9 3 U1 37 U2 37 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1742-5247 EI 1744-7593 J9 EXPERT OPIN DRUG DEL JI Expert Opin. Drug Deliv. PD NOV PY 2016 VL 13 IS 11 BP 1609 EP 1623 DI 10.1080/17425247.2016.1193149 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EA1VZ UT WOS:000386381500011 PM 27216915 ER PT J AU Darst, BF Bilgel, M Koscik, RL Hermann, BP Jedynak, BM Johnson, SC Engelman, CD AF Darst, Burcu F. Bilgel, Murat Koscik, Rebecca L. Hermann, Bruce P. Jedynak, Bruno M. Johnson, Sterling C. Engelman, Corinne D. TI Using LASSO Regression to Identify Gene-Gene and Gene-Environment Interactions Influencing Cognitive Function in those with Increased Alzheimer's Risk SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 24-26, 2016 CL Toronto, CANADA SP Int Genet Epidemiol Soc C1 [Darst, Burcu F.; Engelman, Corinne D.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. [Bilgel, Murat] Johns Hopkins Univ, Sch Engn, Dept Biomed Engn, Baltimore, MD USA. [Bilgel, Murat] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Koscik, Rebecca L.; Hermann, Bruce P.; Johnson, Sterling C.; Engelman, Corinne D.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI USA. [Hermann, Bruce P.; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI USA. [Hermann, Bruce P.] Univ Wisconsin, Dept Neurol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Jedynak, Bruno M.] Portland State Univ, Dept Math & Stat, Portland, OR 97207 USA. [Johnson, Sterling C.; Engelman, Corinne D.] Univ Wisconsin, Sch Med & Publ Hlth, Alzheimers Dis Res Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2016 VL 40 IS 7 MA 59 BP 630 EP 631 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DZ7HF UT WOS:000386034800066 ER PT J AU Kraja, AT Chasman, DI Sung, YJ Aschard, H Manning, AK Feitosa, MF Winkler, T Zhu, XF Province, MA AF Kraja, Aldi T. Chasman, Daniel I. Sung, Yun J. Aschard, Hugues Manning, Alisa K. Feitosa, Mary F. Winkler, Thomas Zhu, Xiaofeng Province, Michael A. CA CHARGE Gene-Lifestyle Interactions TI Blood Pressure Gene x Alcohol Exposure Interactions Capture Association Pleiotropy SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 24-26, 2016 CL Toronto, CANADA SP Int Genet Epidemiol Soc C1 [Kraja, Aldi T.; Feitosa, Mary F.; Province, Michael A.] Washington Univ, Sch Med, Div Stat Genom, Dept Genet,Ctr Genome Sci & Syst Biol, St Louis, MO USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.; Aschard, Hugues] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Sung, Yun J.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Manning, Alisa K.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Ctr Genet Res, Boston, MA 02114 USA. [Winkler, Thomas] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, Regensburg, Germany. [Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RI Feitosa, Mary/K-8044-2012 OI Feitosa, Mary/0000-0002-0933-2410 NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2016 VL 40 IS 7 MA 104 BP 646 EP 647 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DZ7HF UT WOS:000386034800110 ER PT J AU Manning, AK Lent, S Jones, M AF Manning, Alisa K. Lent, Samantha Jones, Michelle CA CHARGE TI Integration of Whole Genome Sequence and Epigenomic Data Highlights Regulatory Activity in the Genomic Architecture of Glycemic Traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 24-26, 2016 CL Toronto, CANADA SP Int Genet Epidemiol Soc C1 [Manning, Alisa K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lent, Samantha] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Jones, Michelle] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2016 VL 40 IS 7 MA 116 BP 651 EP 651 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DZ7HF UT WOS:000386034800122 ER PT J AU Schmidt, ACS Bhatt, AB AF Schmidt, Ada C. Stefanescu Bhatt, Ami B. TI Increasing the evidence base in adult congenital heart disease SO HEART LA English DT Editorial Material C1 [Schmidt, Ada C. Stefanescu] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Heart, Adult Congenital Heart Dis Program, Boston, MA 02115 USA. [Bhatt, Ami B.] Harvard Med Sch, Dept Cardiol, Boston, MA USA. RP Bhatt, AB (reprint author), Massachusetts Gen Hosp, Adult Congenital Heart Dis Program, Ctr Heart, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM abhatt@partners.org OI Stefanescu Schmidt, Ada/0000-0002-5692-2616 NR 6 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD NOV 1 PY 2016 VL 102 IS 21 BP 1701 EP 1702 DI 10.1136/heartjnl-2016-309904 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA2XI UT WOS:000386459500004 ER PT J AU Mareckova, K Holsen, LM Admon, R Makris, N Seidman, L Buka, S Whitfield-Gabrieli, S Goldstein, JM AF Mareckova, Klara Holsen, Laura M. Admon, Roee Makris, Nikos Seidman, Larry Buka, Stephen Whitfield-Gabrieli, Susan Goldstein, Jill M. TI Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses SO HUMAN BRAIN MAPPING LA English DT Article DE dysphoric mood state; sex; functional magnetic resonance imaging; generalized psychophysiological interaction; negative affect; International Affective Picture System; Research Domain Criteria ID AMYGDALA FUNCTIONAL CONNECTIVITY; MEDIAL PREFRONTAL CORTEX; PRENATAL STRESS; NERVOUS-SYSTEM; EMOTIONAL REACTIVITY; CIRCUITRY ACTIVITY; AROUSAL CIRCUITRY; MAJOR DEPRESSION; HORMONAL CYCLE; LIFE STRESS AB Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n=99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen-level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733-3744, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Mareckova, Klara; Holsen, Laura M.; Goldstein, Jill M.] Harvard Med Sch, Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA USA. [Mareckova, Klara] Masaryk Univ, CEITEC Cent European Inst Technol, Brain & Mind Res Programme, Brno, Czech Republic. [Admon, Roee] Harvard Med Sch, McLean Hosp, Ctr Depress Anxiety & Stress Res, Boston, MA USA. [Makris, Nikos; Goldstein, Jill M.] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neurosci, Athinoula A Martinos Ctr, Boston, MA 02114 USA. [Seidman, Larry] Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr, Div Publ Psychiat, Boston, MA 02115 USA. [Seidman, Larry] Harvard Med Sch, Boston, MA USA. [Buka, Stephen] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Whitfield-Gabrieli, Susan] MIT, McGovern Inst Brain Res, Boston, MA USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Div Womens Hlth, Connors Ctr, One Brigham Circle,1620 Tremont St, Boston, MA 02120 USA. EM jill_goldstein@hms.harvard.edu FU NIMH [R03 MH105585, R01 MH56956]; ORWH-NIMH [P50 MH082679]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NIH) [UL1 RR025758]; European Social Fund; Government of Czech Republic [CZ.1.07/2.3.00/30.0009]; European Union; Ministry of Education, Youth and Sports of the Czech Republic / MEYS [CEITEC 2020, LQ1601] FX Contract grant sponsor: NIMH R03 MH105585, ORWH-NIMH P50 MH082679, and NIMH R01 MH56956 Phase III (JMG PI across studies); Contract grant sponsor: Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NIH #UL1 RR025758); Contract grant sponsor: European Social Fund and Government of Czech Republic (Employment of Newly Graduated Doctors of Science for Scientific Excellence; CZ.1.07/2.3.00/30.0009); Contract grant sponsor: European Union (Marie Curie Intra-European Fellowship for Career Development); Contract grant sponsor: The Ministry of Education, Youth and Sports of the Czech Republic / MEYS (CEITEC 2020; LQ1601) NR 70 TC 1 Z9 1 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD NOV PY 2016 VL 37 IS 11 BP 3733 EP 3744 DI 10.1002/hbm.23271 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DZ7VM UT WOS:000386075900003 PM 27246897 ER PT J AU Pfuhl, G King, JA Geisler, D Roschinski, B Ritschel, F Seidel, M Bernardoni, F Muller, DK White, T Roessner, V Ehrlich, S AF Pfuhl, Gerit King, Joseph A. Geisler, Daniel Roschinski, Benjamin Ritschel, Franziska Seidel, Maria Bernardoni, Fabio Mueller, Dirk K. White, Tonya Roessner, Veit Ehrlich, Stefan TI Preserved white matter microstructure in young patients with anorexia nervosa? SO HUMAN BRAIN MAPPING LA English DT Article DE diffusion tensor imaging; tractography; fractional anisotropy; machine learning algorithm; anorexia nervosa ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; TENSOR IMAGING DTI; FUNCTIONAL CONNECTIVITY; CORTICAL SURFACE; BULIMIA-NERVOSA; DIFFUSION MRI; HUMAN BRAIN; GLOBAL TRACTOGRAPHY; ADOLESCENT PATIENTS AB econstruction A massive but reversible reduction of cortical thickness and subcortical gray matter (GM) volumes in Anorexia Nervosa (AN) has been recently reported. However, the literature on alterations in white matter (WM) volume and microstructure changes in both acutely underweight AN (acAN) and after recovery (recAN) is sparse and results are inconclusive. Here, T1-weighted and diffusion-weighted MRI data in a sizable sample of young and medication-free acAN (n=35), recAN (n=32), and age-matched female healthy controls (HC, n=62) were obtained. For analysis, a well-validated global probabilistic tractography r algorithm including rigorous motion correction implemented in FreeSurfer: TRACULA (TRActs Constrained by UnderLying Anatomy) were used. Additionally, a clustering algorithm and a multivariate pattern classification technique to WM metrics to predict group membership were applied. No group differences in either WM volume or WM microstructure were detected with standard analysis procedures either in acAN or recAN relative to HC after controlling for the number of performed statistical tests. These findings were not affected by age, IQ, or psychiatric symptoms. While cluster analysis was unsuccessful at discriminating between groups, multivariate pattern classification showed some ability to separate acAN from HC (but not recAN from HC). However, these results were not compatible with a straightforward hypothesis of impaired WM microstructure. The current findings suggest that WM integrity is largely preserved in non-chronic AN. This finding stands in contrast to findings in GM, but may help to explain the relatively intact cognitive performance of young patients with AN and provide the basis for the fast recovery of GM structures. Hum Brain Mapp 37:4069-4083, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Pfuhl, Gerit; King, Joseph A.; Geisler, Daniel; Roschinski, Benjamin; Ritschel, Franziska; Seidel, Maria; Bernardoni, Fabio; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Dept Child & Adolescent Psychiat, Eating Disorders Res & Treatment Ctr, Fac Med, Dresden, Germany. [Pfuhl, Gerit] UiT Arctic Univ Norway, Dept Psychol, Trondheim, Norway. [Pfuhl, Gerit] Norwegian Univ Sci & Technol, Dept Psychol, Trondheim, Norway. [King, Joseph A.; Geisler, Daniel; Ritschel, Franziska; Seidel, Maria; Bernardoni, Fabio; Ehrlich, Stefan] Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany. [Mueller, Dirk K.] Tech Univ Dresden, Dept Psychiat, Dresden, Germany. [Mueller, Dirk K.] Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany. [White, Tonya] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [White, Tonya] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ehrlich, Stefan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Ehrlich, S (reprint author), Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany. EM stefan.ehrlich@tu-dresden.De FU Deutsche Forschungsgemeinschaft; Roland Ernst Stiftung [EH 367/5-1, SFB 940/1] FX Contract grant sponsor: Deutsche Forschungsgemeinschaft as well as the Roland Ernst Stiftung; Contract grant numbers: EH 367/5-1 & SFB 940/1. NR 82 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD NOV PY 2016 VL 37 IS 11 BP 4069 EP 4083 DI 10.1002/hbm.23296 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DZ7VM UT WOS:000386075900028 PM 27400772 ER PT J AU Villena, JF Polimeridis, AG Eryaman, Y Adalsteinsson, E Wald, LL White, JK Daniel, L AF Villena, Jorge Fernandez Polimeridis, Athanasios G. Eryaman, Yigitcan Adalsteinsson, Elfar Wald, Lawrence L. White, Jacob K. Daniel, Luca TI Fast Electromagnetic Analysis of MRI Transmit RF Coils Based on Accelerated Integral Equation Methods SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Electromagnetic modeling; Green functions; integral equations; magnetic resonance imaging ID EMPIRICAL INTERPOLATION; 8 CHANNELS; SCATTERING; DESIGN; MODELS; EXCITATION; SIMULATIONS; COMPUTATION; RADIATION; BODIES AB A fast frequency domain full-wave electromagnetic simulation method is introduced for the analysis of MRI coils loaded with the realistic human body models. The approach is based on integral equation methods decomposed into two domains: 1) theRF coil array and shield, and 2) the human body region where the load is placed. The analysis of multiple coil designs is accelerated by introducing the precomputed magnetic resonance Green functions (MRGFs), which describe how the particular body model used responds to the incident fields from external sources. These MRGFs, which are precomputed once for a given body model, can be combined with any integral equation solver and reused for the analysis of many coil designs. This approach provides a fast, yet comprehensive, analysis of coil designs, including the port S-parameters and the electromagnetic field distribution within the inhomogeneous body. The method solves the full-wave electromagnetic problem for a head array in few minutes, achieving a speed up of over 150 folds with root mean square errors in the electromagnetic field maps smaller than 0.4% when compared to the unaccelerated integral equation-based solver. This enables the characterization of a large number of RF coil designs in a reasonable time, which is a first step toward an automatic optimization of multiple parameters in the design of transmit arrays, as illustrated in this paper, but also receive arrays. C1 [Villena, Jorge Fernandez; Adalsteinsson, Elfar; White, Jacob K.; Daniel, Luca] MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, Cambridge, MA 02139 USA. [Polimeridis, Athanasios G.] Skolkovo Inst Sci & Technol, Skolkovo, Moscow Oblast, Russia. [Eryaman, Yigitcan] Univ Minnesota Twin Cities, Minneapolis, MN USA. [Adalsteinsson, Elfar] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Adalsteinsson, Elfar; Wald, Lawrence L.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Wald, Lawrence L.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Villena, JF (reprint author), MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, Cambridge, MA 02139 USA. EM jvillena@mit.edu FU National Institute of Health [R01EB006847]; Comunidad de Madrid; Madrid MIT M+ Vision Consortium; Skolkovo-MIT initiative in Computational Mathematics FX This work was supported by the National Institute of Health under Grant R01EB006847, Comunidad de Madrid and the Madrid MIT M+ Vision Consortium, and the Skolkovo-MIT initiative in Computational Mathematics. Asterisk indicates corresponding author. NR 40 TC 0 Z9 0 U1 3 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD NOV PY 2016 VL 63 IS 11 BP 2250 EP 2261 DI 10.1109/TBME.2016.2521166 PG 12 WC Engineering, Biomedical SC Engineering GA DZ9ZL UT WOS:000386242300003 PM 26812686 ER PT J AU Safdar, N Abbo, LM Knobloch, MJ Seo, SK AF Safdar, Nasia Abbo, Lilian M. Knobloch, Mary Jo Seo, Susan K. TI Research Methods in Healthcare Epidemiology: Survey and Qualitative Research SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID MIXED METHODS AB Surveys are one of the most frequently employed study designs in healthcare epidemiology research. Generally easier to undertake and less costly than many other study designs, surveys can be invaluable to gain insights into opinions and practices in large samples and may be descriptive and/or be used to test associations. In this context, qualitative research methods may complement this study design either at the survey development phase and/or at the interpretation/extension of results stage. This methods article focuses on key considerations for designing and deploying surveys in healthcare epidemiology and antibiotic stewardship, including identification of whether or not de novo survey development is necessary, ways to optimally lay out and display a survey, denominator measurement, discussion of biases to keep in mind particularly in research using surveys, and the role of qualitative research methods to complement surveys. We review examples of surveys in healthcare epidemiology and antimicrobial stewardship and review the pros and cons of methods used. A checklist is provided to help aid design and deployment of surveys in healthcare epidemiology and antimicrobial stewardship. C1 [Safdar, Nasia; Knobloch, Mary Jo] William S Middleton Mem Vet Adm Med Ctr, Dept Med, Madison, WI USA. [Safdar, Nasia] Univ Wisconsin, Dept Med, Div Infect Dis, Madison, WI USA. [Abbo, Lilian M.] Univ Miami, Miller Sch Med, Dept Med, Div Infect Dis, Miami, FL 33136 USA. [Abbo, Lilian M.] Jackson Hlth Syst, Miami, FL USA. [Seo, Susan K.] Mem Sloan Kettering Canc Ctr, Dept Med, Infect Dis Serv, New York, NY 10021 USA. RP Safdar, N (reprint author), 5138 MFCB 1685 Highland Ave, Madison, WI 53703 USA. EM ns2@medicine.wisc.edu FU National Institutes of Health/National Cancer Institute Cancer Center [P30 CA008748]; Veterans Health Administration National Center for Patient Safety, Patient Safety Center of Inquiry, US Department of Veterans Affairs FX National Institutes of Health/National Cancer Institute Cancer Center Support (grant P30 CA008748 to S.K.S.); and Veterans Health Administration National Center for Patient Safety, Patient Safety Center of Inquiry, US Department of Veterans Affairs. NR 17 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD NOV PY 2016 VL 37 IS 11 BP 1272 EP 1277 DI 10.1017/ice.2016.171 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EA2EA UT WOS:000386404400002 PM 27514583 ER PT J AU Howitt, BE Nucci, MR Young, RH AF Howitt, Brooke E. Nucci, Marisa R. Young, Robert H. TI XXIX. Dr Hazel Mansell Gore SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Biographical-Item DE Hazel Mansell Gore; gynecologic pathology; history of pathology C1 [Howitt, Brooke E.; Nucci, Marisa R.] Brigham & Womens Hosp, Div Womens & Perinatal Pathol, 75 Francis St, Boston, MA 02115 USA. [Young, Robert H.] Harvard Med Sch, James Homer Wright Pathol Labs, Massachusetts Gen Hosp, Boston, MA USA. RP Howitt, BE (reprint author), Brigham & Womens Hosp, Dept Pathol, Amory 3,75 Francis St, Boston, MA 02115 USA. EM bhowitt@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2016 VL 35 IS 6 BP 598 EP 605 DI 10.1097/PGP.0000000000000327 PG 8 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA EA2IH UT WOS:000386415500015 PM 27662037 ER PT J AU O'Sullivan, BJ Steele, T Ellul, MA Kirby, E Duale, A Kier, G Crooks, D Jacob, A Solomon, T Michael, BD AF O'Sullivan, B. J. Steele, T. Ellul, M. A. Kirby, E. Duale, A. Kier, G. Crooks, D. Jacob, A. Solomon, T. Michael, B. D. TI When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Autoimmune; Clinical features; Diagnosis; Encephalitis ID NEUROMYOTONIA ISAACS SYNDROME; CENTRAL-NERVOUS-SYSTEM; ACQUIRED NEUROMYOTONIA; LIMBIC ENCEPHALITIS; AUTOIMMUNE CHANNELOPATHIES; CLINICAL SPECTRUM; MORVANS-SYNDROME; AUTOANTIBODIES; GUIDELINES; EPILEPSY AB Patients with voltage-gated potassium channel (VGKC)-complex antibodies are increasingly recognized as having central, peripheral or combined phenotypes. With increasing awareness, more patients are tested and the clinical spectrum is expanding. Consequently, clinicians may be uncertain as to which patients should or should not be tested. Previous studies have identified common clinical features, but none has looked at the usefulness of these in predicting seropositive disease. We conducted a case control study of patients tested for VGKC-complex antibodies over 10 years at a regional tertiary neurology centre determining which clinical/biochemical features were associated with antibody-positive disease. We found a marked increase in the numbers tested, although the percentage positive remained low. Antibody titre was highest in central disease (p < 0.001). Time from presentation to testing was shorter in those with VGKC-disease (p = 0.01). Seizures were present in 11 (69%) of those with VGKC-disease versus three (18%) without (odds ratio [OR] 10.3, 95% confidence interval [CI]: 2.0-52.7, p = 0.005). There was an inverse correlation between the antibody titre and serum sodium. A multivariate model selected seizures and hyponatraemia as predictive of VGKC disease (sensitivity 75% and specificity 82%); faciobrachial dystonic movements were specific but insensitive. Interestingly serum alkaline phosphatase was higher in those with VGKC-disease (p = 0.016) and highest in those with peripheral disease (p = 0.015). An ALP > 70 u/L was strongly associated with antibody positivity (OR 4.11 95% CI: 1.43-11.8, p = 0.007) with a sensitivity of 74.2%. The presence of seizures, faciobrachial movements, and hyponatraemia should raise suspicion of VGKC-disease; alkaline phosphatase may represent a novel biomarker, particularly in those with peripheral disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [O'Sullivan, B. J.; Steele, T.; Ellul, M. A.; Kirby, E.; Duale, A.; Kier, G.; Jacob, A.; Solomon, T.; Michael, B. D.] Walton Ctr NHS Fdn Trust, Dept Neurosci, Liverpool, Merseyside, England. [Ellul, M. A.; Solomon, T.; Michael, B. D.] Univ Liverpool, Inst Infect & Global Hlth, Dept Clin Infect Microbiol & Immunol, Ronald Ross Bldg,8 West Derby St, Liverpool, Merseyside, England. [Kier, G.; Crooks, D.] Walton Ctr NHS Fdn Trust Liverpool, Dept Neuropathol, Liverpool, Merseyside, England. [Solomon, T.; Michael, B. D.] Univ Liverpool, NIHR Hlth Protect Res Unit Emerging & Zoonot Infe, Liverpool L69 3BX, Merseyside, England. [Michael, B. D.] Harvard Med Sch, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Michael, BD (reprint author), Walton Ctr NHS Fdn Trust, Dept Neurosci, Liverpool, Merseyside, England.; Michael, BD (reprint author), Univ Liverpool, Inst Infect & Global Hlth, Dept Clin Infect Microbiol & Immunol, Ronald Ross Bldg,8 West Derby St, Liverpool, Merseyside, England.; Michael, BD (reprint author), Univ Liverpool, NIHR Hlth Protect Res Unit Emerging & Zoonot Infe, Liverpool L69 3BX, Merseyside, England.; Michael, BD (reprint author), Harvard Med Sch, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM benmic@liv.ac.uk FU NIHR; National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at the University of Liverpool; Public Health England (PHE); Liverpool School of Tropical Medicine (LSTM) FX BDM is a NIHR Clinical Lecturer and received funding as part of a NIHR Doctoral Research Fellowship. BDM and TS receive support from a NIHR Programme grant as part of the ENCEPH-UK study. The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England (PHE) and Liverpool School of Tropical Medicine (LSTM). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. We are thankful for the assistance of the Buxton Laboratory team at the Walton Centre NHS Foundation Trust. The authors are very grateful for the critical review of Professor Angela Vincent. NR 35 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD NOV PY 2016 VL 33 BP 198 EP 204 DI 10.1016/j.jocn.2016.04.021 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DZ9JW UT WOS:000386192200035 PM 27469409 ER PT J AU Chung, CY Koffie, RM Dewitt, JC Aronson, JP AF Chung, Charlotte Y. Koffie, Robert M. Dewitt, John C. Aronson, Joshua P. TI Thoracic exophytic ependymoma masquerading as a benign extra-axial tumor SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Exophytic spinal tumor; Intradural extramedullary spinal tumor; Spinal ependymoma ID SPINAL-CORD TUMORS AB Spinal tumors are conventionally differentiated based on location in relation to the spinal cord. Benign spinal tumors such as schwannomas and meningiomas are typically extra-axial (intradural extramedullary) lesions, whereas more aggressive primary spinal tumors such as ependymomas are typically intramedullary masses. Rarely, ependymomas can have both intramedullary and extramedullary components (typically referred to as exophytic ependymomas). We report a case of a spinal exophytic ependymoma that radiographically masqueraded as a benign intradural extramedullary lesion causing cord compression and. neurologic deficit in a 47-year-old man. The diagnosis of exophytic ependymoma was made intra-operatively, with resultant gross total resection of the extramedullary portion and subtotal resection of the intramedullary portion. Histopathological examination confirmed ependymoma with World Health Organization grade II/IV. Pre-operative suspicion of an exophytic ependymoma influences operative planning and clinical management. We review the literature and discuss clinical management strategies for these interesting spinal tumors. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chung, Charlotte Y.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Koffie, Robert M.; Aronson, Joshua P.] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. [Dewitt, John C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Aronson, JP (reprint author), 15 Parkman St WACC 021, Boston, MA 02114 USA. EM jparonson@post.harvard.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD NOV PY 2016 VL 33 BP 221 EP 225 DI 10.1016/j.jocn.2016.03.031 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DZ9JW UT WOS:000386192200041 PM 27578528 ER PT J AU Bick, SKB Redjal, N AF Bick, Sarah K. B. Redjal, Navid TI Acute lymphocytic leukemia presenting as a single brain mass SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Brain mass; Intracranial leukemic deposit; Leukemia ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NERVOUS-SYSTEM INVOLVEMENT; GRANULOCYTIC SARCOMA; MANAGEMENT; MIMICKING; CHLOROMA AB Hematologic malignancies most commonly spread to the central nervous system via leptomeningeal infiltration. We present a unique case of a woman who presented with a right parietal mass as the initial manifestation of B cell acute lymphocytic leukemia. Because the diagnosis was unclear at the time of presentation she underwent surgical debulking of the mass prior to treatment with chemotherapy. Unfortunately, she relapsed several months after treatment and ultimately entered hospice care. We review the literature surrounding management considerations in patients with intracranial leukemic involvement. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Bick, Sarah K. B.; Redjal, Navid] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. RP Bick, SKB (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St, Boston, MA 02114 USA. EM Sbick@partners.org NR 18 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD NOV PY 2016 VL 33 BP 244 EP 246 DI 10.1016/j.jocn.2016.05.008 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DZ9JW UT WOS:000386192200049 PM 27430416 ER PT J AU Paholpak, P Carr, AR Barsuglia, JP Barrows, RJ Jimenez, E Lee, GJ Mendez, MF AF Paholpak, Pongsatorn Carr, Andrew R. Barsuglia, Joseph P. Barrows, Robin J. Jimenez, Elvira Lee, Grace J. Mendez, Mario F. TI Person-Based Versus Generalized Impulsivity Disinhibition in Frontotemporal Dementia and Alzheimer Disease SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article DE disinhibition; frontotemporal dementia; Alzheimer disease; Frontal System Behavior Scale ID SUPERIOR TEMPORAL SULCUS; BEHAVIORAL-VARIANT; LOBAR DEGENERATION; SOCIAL COGNITION; ORBITOFRONTAL CORTEX; RATING-SCALE; FDG-PET; BRAIN; APATHY; MIND AB Background: While much disinhibition in dementia results from generalized impulsivity, in behavioral variant frontotemporal dementia (bvFTD) disinhibition may also result from impaired social cognition. Objective: To deconstruct disinhibition and its neural correlates in bvFTD vs. early-onset Alzheimer's disease (eAD). Methods: Caregivers of 16 bvFTD and 21 matched-eAD patients completed the Frontal Systems Behavior Scale disinhibition items. The disinhibition items were further categorized into (1) person-based subscale which predominantly associated with violating social propriety and personal boundary and (2) generalized-impulsivity subscale which included nonspecific impulsive acts. Subscale scores were correlated with grey matter volumes from tensor-based morphometry on magnetic resonance images. Results: In comparison to the eAD patients, the bvFTD patients developed greater person-based disinhibition (P < 0.001) but comparable generalized impulsivity. Severity of person-based disinhibition significantly correlated with the left anterior superior temporal sulcus (STS), and generalized-impulsivity correlated with the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (aTL). Conclusions: Person-based disinhibition was predominant in bvFTD and correlated with the left STS. In both dementia, violations of social propriety and personal boundaries involved fronto-parieto-temporal network of Theory of Mind, whereas nonspecific disinhibition involved the OFC and aTL. C1 [Paholpak, Pongsatorn; Carr, Andrew R.; Barrows, Robin J.; Jimenez, Elvira; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Paholpak, Pongsatorn] Khon Kaen Univ, Dept Psychiat, Khon Kaen, Thailand. [Carr, Andrew R.; Barsuglia, Joseph P.; Barrows, Robin J.; Jimenez, Elvira; Mendez, Mario F.] Greater Los Angeles VA Healthcare Syst, West Los Angeles, CA USA. [Jimenez, Elvira; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Lee, Grace J.] Loma Linda Univ, Dept Psychol, Sch Behav Hlth, Loma Linda, CA 92350 USA. RP Paholpak, P (reprint author), Greater Los Angeles VA Healthcare Ctr, Neurobehav Serv 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ppaholpak@yahoo.com FU National Institute on Aging (NIA) [5R01AG034499-05]; VA GRECC Advanced Fellowship in Geriatrics FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grant 5R01AG034499-05 from the National Institute on Aging (NIA). A. R. Carr and J. P. Barsuglia were funded by the VA GRECC Advanced Fellowship in Geriatrics. NR 51 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0891-9887 EI 1552-5708 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD NOV PY 2016 VL 29 IS 6 BP 344 EP 351 DI 10.1177/0891988716666377 PG 8 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA DZ7IS UT WOS:000386038900005 ER PT J AU Brisac, C Salloum, S Yang, V Schaefer, EAK Holmes, JA Chevaliez, S Hong, J Carlton-Smith, C Alatrakchi, N Kruger, A Lin, WY Chung, RT AF Brisac, Cynthia Salloum, Shadi Yang, Victor Schaefer, Esperance A. K. Holmes, Jacinta A. Chevaliez, Stephane Hong, Jian Carlton-Smith, Charlie Alatrakchi, Nadia Kruger, Annie Lin, Wenyu Chung, Raymond T. TI IQGAP2 is a novel interferon-alpha antiviral effector gene acting non-conventionally through the NF-kappa B pathway SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatitis C virus (HCV); Antiviral response; IQGAP protein ID HEPATITIS-C VIRUS; HEPATOCELLULAR-CARCINOMA; CELL-SURVIVAL; HOST GENES; REPLICATION; EXPRESSION; INFECTION; IDENTIFICATION; RECRUITMENT; ACTIVATION AB Background & Aims: Type I interferons (IFN) provide the first line of defense against invading pathogens but its mechanism of action is still not well understood. Using unbiased genome-wide siRNA screens, we recently identified IQ-motif containing GTPase activating protein 2 (IQGAP2), a tumor suppressor predominantly expressed in the liver, as a novel gene putatively required for IFN antiviral response against hepatitis C virus (HCV) infection. Here we sought to characterize IQGAP2 role in IFN response. Methods: We used transient small interfering RNA knockdown strategy in hepatic cell lines highly permissive to JFH1 strain of HCV infection. Results: We found that IQGAP2 acts downstream of IFN binding to its receptor, and independently of the JAK-STAT pathway, by physically interacting with RelA (also known as p65), a subunit of the NF-kappa B transcription factor. Interestingly, our data reveal a mechanism distinct from the well-characterized role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) in IFN production. Indeed, IFN alone was sufficient to stimulate NF-kappa B-dependent transcription in the absence of viral infection. Finally, both IQGAP2 and RelA were required for the induction by IFN of a subset of IFN-stimulated genes (ISG) with known antiviral properties. Conclusions: Our data identify a novel function for IQGAP2 in IFN antiviral response in hepatoma cells. We demonstrate the involvement of IQGAP2 in regulating ISG induction by IFN in an NF-kappa B-dependent manner. The IQGAP2 pathway may provide new targets for antiviral strategies in the liver, and may have a wider therapeutic implication in other disease pathogeneses driven by NF-kappa B activation. Lay summary: In this study, we identify a novel mechanism of action of interferon involving the IQGAP2 protein and the NF-kappa B pathway that is ultimately protective against hepatitis C virus infection. This newly identified pathway functions independently of the well-known STAT pathway and may therefore provide new targets for antiviral strategies in the liver. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Brisac, Cynthia; Salloum, Shadi; Yang, Victor; Schaefer, Esperance A. K.; Holmes, Jacinta A.; Chevaliez, Stephane; Hong, Jian; Carlton-Smith, Charlie; Alatrakchi, Nadia; Kruger, Annie; Lin, Wenyu; Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Boston, MA 02114 USA. [Brisac, Cynthia; Salloum, Shadi; Yang, Victor; Schaefer, Esperance A. K.; Holmes, Jacinta A.; Chevaliez, Stephane; Hong, Jian; Carlton-Smith, Charlie; Alatrakchi, Nadia; Kruger, Annie; Lin, Wenyu; Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Div, Dept Med, Boston, MA 02114 USA. [Chevaliez, Stephane] Hop Henri Mondor, INSERM, U955, Dept Virol, Creteil, France. RP Chung, RT (reprint author), Harvard Med Sch, Dept Med, Gastrointestinal Unit, Massachusetts Gen Hosp, Warren 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU NIH [U19 AI082630] FX This work was supported by NIH U19 AI082630 (R.T.C.). NR 50 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2016 VL 65 IS 5 BP 972 EP 979 DI 10.1016/j.jhep.2016.06.028 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DZ9IB UT WOS:000386187400014 PM 27401546 ER PT J AU Dougherty, DD Chou, T Corse, AK Arulpragasam, AR Widge, AS Cusin, C Evans, KC Greenberg, BD Haber, SN Deckersbach, T AF Dougherty, Darin D. Chou, Tina Corse, Andrew K. Arulpragasam, Amanda R. Widge, Alik S. Cusin, Cristina Evans, Karleyton C. Greenberg, Benjamin D. Haber, Suzanne N. Deckersbach, Thilo TI Acute deep brain stimulation changes in regional cerebral blood flow in obsessive-compulsive disorder SO JOURNAL OF NEUROSURGERY LA English DT Article DE deep brain stimulation; positron emission tomography; obsessive-compulsive disorder; ventral capsule/ventral striatum; cortico-striatal-thalamic-cortical circuit; functional neurosurgery ID VOLUME AB OBJECTIVE Deep brain stimulation (DBS) is a reversible, nonlesion-based treatment for patients with intractable obsessive-compulsive disorder (OCD). The first studies on DBS for OCD stimulating the ventral capsule/ventral striatum (VC/VS) yielded encouraging results for this neuroanatomical site's therapeutic efficacy. This investigation was conducted to better understand which regions of the cortico-striatal-thalamic-cortical network were acutely affected by VC/VS DBS for OCD. Furthermore, the objective was to identify which brain regions demonstrated changes in perfusion, as stimulation was applied across a dorsoventral lead axis that corresponded to different anatomical locations in the VC/VS. METHODS Six patients receiving VC/VS DBS for OCD underwent oxygen-15 positron emission tomography (O-15-PET) scanning. Monopolar DBS was delivered at each of the 4 different electrodes on the stimulating lead in the VC/VS. The data were analyzed using SPM5. Paired t-tests were run in SPSS to identify significant changes in regional cerebral blood flow (rCBF) between stimulation conditions. Pearson's r correlations were run between these significant changes in rCBF and changes in OCD and depressive symptom severity. RESULTS Perfusion in the dorsal anterior cingulate cortex (dACC) significantly increased when monopolar DBS was turned on at the most ventral DBS contact, and this increase in dACC activity was correlated with reductions in depressive symptom severity (r(5) = -0.994, p = 0.001). Perfusion in the thalamus, striatum, and globus pallidus significantly increased when DBS was turned on at the most dorsal contact. CONCLUSIONS DBS of the VC/VS appears to modulate activity in the regions implicated in the pathophysiology of OCD. Different regions in the cortico-striatal-thalamic-cortical circuit showed increased perfusion based on whether the stimulation was more ventral or dorsal along the lead axis in the VC/VS. Evidence was found that DBS at the most ventral site was associated with clinical changes in depressive symptom severity, but not OCD symptom severity. C1 [Dougherty, Darin D.; Chou, Tina; Corse, Andrew K.; Arulpragasam, Amanda R.; Widge, Alik S.; Cusin, Cristina; Evans, Karleyton C.; Deckersbach, Thilo] Massachusetts Gen Hosp, Dept Psychiat, Div Neurotherapeut, Charlestown, MA USA. [Dougherty, Darin D.; Chou, Tina; Corse, Andrew K.; Arulpragasam, Amanda R.; Widge, Alik S.; Cusin, Cristina; Evans, Karleyton C.; Deckersbach, Thilo] Harvard Med Sch, Charlestown, MA USA. [Chou, Tina] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Widge, Alik S.] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Greenberg, Benjamin D.] Butler Hosp, Dept Psychiat & Behav Sci, Providence, RI 02906 USA. [Greenberg, Benjamin D.] Brown Med Sch, Providence, RI USA. [Haber, Suzanne N.] Univ Rochester, Med Ctr, Dept Physiol & Pharmacol, Rochester, NY 14642 USA. RP Dougherty, DD (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 Thirteenth St,Off 2612, Charlestown, MA 02129 USA. EM ddougherty@partners.org FU Conte NIH Grant [5R01MH073111]; National Science Foundation [DGE 1144152] FX The research reported in this manuscript was funded by a Conte NIH Grant #5R01MH073111. The preparation of this manuscript was supported in part by the National Science Foundation Graduate Research Fellowship Program under Grant #DGE 1144152 to Tina Chou. NR 22 TC 1 Z9 1 U1 4 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD NOV PY 2016 VL 125 IS 5 BP 1087 EP 1093 DI 10.3171/2015.9.JNS151387 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DZ8FK UT WOS:000386106100005 PM 26894459 ER PT J AU Hashmi, A Guckenberger, M Kersh, R Gerszten, PC Mantel, F Grills, IS Flickinger, JC Shin, JH Fahim, DK Winey, B Oh, K Cho, BCJ Letourneau, D Sheehan, J Sahgal, A AF Hashmi, Ahmed Guckenberger, Matthias Kersh, Ron Gerszten, Peter C. Mantel, Frederick Grills, Inga S. Flickinger, John C. Shin, John H. Fahim, Daniel K. Winey, Brian Oh, Kevin Cho, B. C. John Letourneau, Daniel Sheehan, Jason Sahgal, Arjun TI Re-irradiation stereotactic body radiotherapy for spinal metastases: a multi-institutional outcome analysis SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE spinal metastases; re-irradiation; stereotactic body radiotherapy; stereotactic radiosurgery; salvage; oncology ID LOCAL TUMOR-CONTROL; CELL LUNG-CANCER; RADIATION-THERAPY; CLINICAL ARTICLE; BONE METASTASES; SINGLE; RADIOSURGERY; EFFICACY; CORD; CONSORTIUM AB OBJECTIVE This study is a multi-institutional pooled analysis specific to imaging-based local control of spinal metastases in patients previously treated with conventional external beam radiation therapy (cEBRT) and then treated with re irradiation stereotactic body radiotherapy (SBRT) to the spine as salvage therapy, the largest such study to date. METHODS The authors reviewed cases involving 215 patients with 247 spinal target volumes treated at 7 institutions. Overall survival was calculated on a patient basis, while local control was calculated based on the spinal target volume treated, both using the Kaplan-Meier method. Local control was defined as imaging-based progression within the SBRT target volume. Equivalent dose in 2-Gy fractions (EQD2) was calculated for the cEBRT and SBRT course using an alpha/beta of 10 for tumor and 2 for both spinal cord and cauda equina. RESULTS The median total dose/number of fractions of the initial cEBRT was 30 Gy/10. The median SBRT total dose and number of fractions were 18 Gy and 1, respectively. Sixty percent of spinal target volumes were treated with single fraction SBRT (median, 16.6 Gy and EQD2/10 = 36.8 Gy), and 40% with multiple-fraction SBRT (median 24 Gy in 3 fractions, EQD2/10 = 36 Gy). The median time interval from cEBRT to re-irradiation SBRT was 13.5 months, and the median duration of patient follow-up was 8.1 months. Kaplan-Meier estimates of 6- and 12-month overall survival rates were 64% and 48%, respectively; 13% of patients suffered a local failure, and the 6- and 12-month local control rates were 93% and 83%, respectively. Multivariate analysis identified Karnofsky Performance Status (KPS) < 70 as a significant prognostic factor for worse overall survival, and single-fraction SBRT as a significant predictive factor for better local control. There were no cases of radiation myelopathy, and the vertebral compression fracture rate was 4.5%. CONCLUSIONS Re-irradiation spine SBRT is effective in yielding imaging-based local control with a clinically acceptable safety profile. A randomized trial would be required to determine the optimal fractionation. C1 [Hashmi, Ahmed; Sahgal, Arjun] Univ Toronto, Sunnybrook Odette Canc Ctr, Dept Radiat Oncol, Toronto, ON M5S 1A1, Canada. [Cho, B. C. John; Letourneau, Daniel] Univ Toronto, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON M5S 1A1, Canada. [Kersh, Ron] Riverside Med Ctr, Dept Radiat Oncol, Newport News, VA USA. [Gerszten, Peter C.] Univ Pittsburgh, Med Ctr, Dept Neurosurg, Pittsburgh, PA USA. [Flickinger, John C.] Univ Pittsburgh, Dept Radiat Oncol, Med Ctr, Pittsburgh, PA USA. [Guckenberger, Matthias; Mantel, Frederick] Univ Wurzburg, Dept Radiat Oncol, Wurzburg, Germany. [Grills, Inga S.] William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI USA. [Fahim, Daniel K.] William Beaumont Hosp, Dept Neurosurg, Royal Oak, MI 48072 USA. [Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Winey, Brian; Oh, Kevin] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sheehan, Jason] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA. [Guckenberger, Matthias] Univ Zurich, Dept Radiat Oncol, Zurich, Switzerland. RP Sahgal, A (reprint author), Univ Toronto, Dept Radiat Oncol, Sunnybrook Hlth Sci Ctr, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM arjun.sahgal@sunnybrook.ca OI Guckenberger, Matthias/0000-0002-7146-9071 FU Elekta AB FX This research was supported by Elekta AB as a research grant to the principal investigator Dr. Matthias Guckenberger. Each author belongs to the Elekta Spine Study Consortium, which is supported by Elekta AB. Dr. Arjun Sahgal has received honoraria for past educational seminars from Medtronic and Elekta AB and research grants from Elekta AB. The data collection, interpretation, writing and final approval was independent of industry participation. Dr. Grills also reports an ownership interest in Greater Michigan Gamma Knife. NR 30 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD NOV PY 2016 VL 25 IS 5 BP 646 EP 653 DI 10.3171/2016.4.SPINE151523 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DZ8FN UT WOS:000386106400015 PM 27341054 ER PT J AU Huang, JS Terrones, L Simmons, AN Kaye, W Strigo, I AF Huang, Jeannie S. Terrones, Laura Simmons, Alan N. Kaye, Walter Strigo, Irina TI Pilot Study of Functional Magnetic Resonance Imaging Responses to Somatic Pain Stimuli in Youth With Functional and Inflammatory Gastrointestinal Disease SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE functional magnetic resonance imaging; inflammatory bowel disease; interoception; irritable bowel syndrome ID IRRITABLE-BOWEL-SYNDROME; MAJOR DEPRESSIVE DISORDER; CHRONIC BACK-PAIN; QUALITY-OF-LIFE; BRAIN RESPONSES; ABDOMINAL-PAIN; VISCERAL PAIN; PLACEBO ANALGESIA; ANTICIPATION; ADOLESCENTS AB Background:Brain-gut axis signaling modifies gastrointestinal symptomatology. Altered neural processing of intestinal pain signals involves interoceptive brain regions in adults with functional and inflammatory gastrointestinal disorders. Although these disorders frequently present in childhood, there are no published studies in youth. We determined whether neural processing of somatic pain stimuli differs in adolescents and young adults (AYA) with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), as compared to healthy controls (HC).Methods:IBS and IBD AYA (16-20 years) underwent anticipated and thermal pain stimuli of low and high intensity on their forearm and simultaneous blood oxygen level-dependent functional magnetic resonance imaging. Data from adult HC were used for comparison. Subjects answered surveys evaluating alexithymia, anxiety, depression, and pain catastrophizing. Group data were compared using linear mixed effects and analysis of variance.Results:Study groups were similar by sex but not age. Significant group by pain condition interactions were observed in interoceptive brain regions during pain anticipation, and within perceptual brain regions during perceived pain. Higher activation within interoceptive brain regions during anticipated pain was observed in IBS compared with IBD and HC subjects. IBD patients demonstrated increased activation in perceptual brain regions during experienced pain as compared to IBS and HC.Conclusions:IBS and IBD AYA demonstrate altered neural processing of somatic pain compared with each other and with HC. Our results suggest that neuromodulatory interventions targeting interoceptive brain circuits in IBS and perceptual brain regions in IBD may be effective. C1 [Huang, Jeannie S.; Terrones, Laura] Rady Childrens Hosp, Dept Pediat, San Diego, CA USA. [Huang, Jeannie S.; Terrones, Laura] Univ Calif San Diego, San Diego, CA 92103 USA. [Simmons, Alan N.; Kaye, Walter] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Simmons, Alan N.] Vet Affairs Hlth Syst, Ctr Excellence Stress & Mental Hlth, San Francisco, CA USA. [Strigo, Irina] San Francisco VA Med Ctr, San Francisco, CA USA. RP Huang, JS (reprint author), 9500 Gilman Dr,MC 0984, La Jolla, CA 92093 USA. EM jshuang@ucsd.edu FU Clinical and Translational Research Institute, University of California San Diego; Price Foundation; Peterson Foundation; National Institutes of Health of CTSA [UL RR031980, UL1TR000100]; United States (US) Department of Veterans Affairs CS RD Service [I01-CX-000816] FX Funding received from the Clinical and Translational Research Institute, University of California San Diego, the Price Foundation, and the Peterson Foundation. The project described was partially supported by the National Institutes of Health, Grant UL RR031980 for years 1 and 2 of CTSA funding and/ or UL1TR000100 during year 3 and beyond of CTSA funding and in part by I01-CX-000816 from the United States (US) Department of Veterans Affairs CS R&D Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or VA. NR 50 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD NOV PY 2016 VL 63 IS 5 BP 500 EP 507 DI 10.1097/MPG.0000000000001390 PG 8 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA EA1KE UT WOS:000386350200021 PM 27574880 ER PT J AU Frakes, M Jena, AB AF Frakes, Michael Jena, Anupam B. TI Does medical malpractice law improve health care quality? SO JOURNAL OF PUBLIC ECONOMICS LA English DT Article DE Malpractice; Health care quality; Deterrence; Defensive medicine ID REGIONAL-VARIATIONS; DEFENSIVE MEDICINE; LIABILITY SYSTEM; REFORM; IMPACT; EXPERIENCE; PHYSICIANS; INSURANCE; ERRORS; DETER AB We assess the potential for medical liability forces to deter medical errors and improve health care treatment quality, identifying liability's influence by drawing on variations in the manner by which states formulate the negligence standard facing physicians. Using hospital discharge records from the National Hospital Discharge Survey and clinically-validated quality metrics inspired by the Agency for Health Care Research and Quality, we find evidence suggesting that treatment quality may improve upon reforms that expect physicians to adhere to higher quality clinical standards. We do not find evidence, however, suggesting that treatment quality may deteriorate following reforms to liability standards that arguably condone the delivery of lower quality care. Similarly, we do not find evidence of deterioration in health care quality following remedy-focused liability reforms such as caps on non-economic damages awards. (C) 2016 Elsevier B.V. All rights reserved. C1 [Frakes, Michael] Duke Univ, Durham, NC 27706 USA. [Frakes, Michael; Jena, Anupam B.] NBER, Cambridge, MA 02138 USA. [Jena, Anupam B.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Frakes, M (reprint author), Duke Univ, Durham, NC 27706 USA.; Frakes, M (reprint author), NBER, Cambridge, MA 02138 USA. EM michael.frakes@law.duke.edu FU National Institute on Aging [T32-AG00186]; Office of the Director, National Institutes of Health (NIH) [1DP5OD017897-01] FX We are grateful to Amy Finkelstein and Jon Gruber for their guidance and advice. We are likewise grateful for helpful comments received from Ronen Avraham, Bernie Black, Amitabh Chandra, David Hyman, Louis Kaplow, Justin McCrary, Michelle Mello, Mark Ramseyer, Max Schazenbach, Steve Shavell, Charlie Silver, Holger Spamann, Brad Wendel, Kathy Zeiler and seminar participants at the NBER Summer Institute Law and Economics Workshop, the NBER Summer Institute Health Care Workshop, the Harvard Law, Economics & Organization Seminar, the Northwestern Law and Economics Colloquium, the Northwestern Faculty Colloquium, the Midwestern Law and Economics Association Annual Meeting, the University of Texas Medical Malpractice Roundtable, the Cornell Law School Faculty Workshop and the Cornell Law School Faculty Retreat. We are also thankful to Negasi Beyene, Maria Owings and the staff at the Research Data Center at the National Center for Health Statistics for their help with the National Hospital Discharge Survey files and to Ronen Avraham for providing data on state tort laws. Frakes acknowledges support from the National Institute on Aging, Grant Number T32-AG00186 and Jena acknowledges support from the Office of the Director, National Institutes of Health (NIH Early Independence Award, 1DP5OD017897-01). NR 45 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0047-2727 J9 J PUBLIC ECON JI J. Public Econ. PD NOV PY 2016 VL 143 BP 142 EP 158 DI 10.1016/j.jpubeco.2016.09.002 PG 17 WC Economics SC Business & Economics GA EA2FI UT WOS:000386407800012 ER PT J AU Afari, N Gasperi, M Forsberg, CW Goldberg, J Buchwald, D Krieger, JN AF Afari, Niloofar Gasperi, Marianna Forsberg, Christopher W. Goldberg, Jack Buchwald, Dedra Krieger, John N. TI Heritability of Lower Urinary Tract Symptoms in Men: A Twin Study SO JOURNAL OF UROLOGY LA English DT Article DE lower urinary tract symptoms; quantitative trait; heritable; twins ID BENIGN PROSTATIC HYPERPLASIA; POPULATION-BASED SURVEY; QUALITY-OF-LIFE; OVERACTIVE BLADDER; DETERMINING ZYGOSITY; CONCORDANCE RATES; INCONTINENCE; WOMEN; ERA; AGE AB Purpose: Symptoms of urinary irritation, urgency, frequency and obstruction, known as lower urinary tract symptoms, are common in urological practice. However, little is known about the etiology or pathogenesis of lower urinary tract symptoms, especially the relative contributions of genetic and environmental factors to the development of these symptoms. We used a classic twin study design to examine the relative contributions of genetic and environmental factors to the occurrence of lower urinary tract symptoms in middle-aged men. Materials and Methods: Twins were members of the Vietnam Era Twin Registry. We used a mail survey to collect data on lower urinary tract symptoms using the I-PSS (International Prostate Symptom Score) instrument. Twin correlations and biometric modeling were used to determine the relative genetic and environmental contributions to variance in I-PSS total score and individual items. Results: Participants were 1,002 monozygotic and 580 dizygotic middle-aged male twin pairs (mean age 50.2 years, SD 3.0). Nearly 25% of the sample had an I-PSS greater than 8, indicating at least moderate lower urinary tract symptoms. The heritability of the total I-PSS was 37% (95% CI 32-42). Heritability estimates ranged from 21% for nocturia to 40% for straining, with moderate heritability (34% to 36%) for urinary frequency and urgency. Conclusions: Genetic factors provide a moderate contribution (20% to 40%) to lower urinary tract symptoms in middle-aged men, suggesting that environmental factors may also contribute substantially to lower urinary tract symptoms. Future research is needed to define specific genetic and environmental mechanisms that underlie the development of these symptoms and conditions associated with lower urinary tract symptoms. C1 [Afari, Niloofar; Gasperi, Marianna] VA Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Afari, Niloofar; Gasperi, Marianna] Univ Calif San Diego, San Diego, CA 92103 USA. [Forsberg, Christopher W.; Goldberg, Jack] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Vietnam Era Twin Registry, Seattle, WA USA. [Goldberg, Jack; Krieger, John N.] Univ Washington, Seattle, WA 98195 USA. [Buchwald, Dedra] Washington State Univ, Elson S Floyd Coll Med, Seattle, WA USA. [Buchwald, Dedra] Washington State Univ, Elson S Floyd Coll Med, Spokane, WA USA. RP Afari, N (reprint author), 9500 Gilman Dr,0737, La Jolla, CA 92093 USA. EM nafari@ucsd.edu FU National Institutes of Health MAPP Research Network Grant [U01 DK082325] FX Supported by the National Institutes of Health MAPP Research Network Grant U01 DK082325. NR 30 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD NOV PY 2016 VL 196 IS 5 BP 1486 EP 1491 DI 10.1016/j.juro.2016.06.018 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DZ6EJ UT WOS:000385954100055 PM 27312318 ER PT J AU Charidimou, A Viswanathan, A AF Charidimou, Andreas Viswanathan, Anand TI Cognitive status after intracerebral haemorrhage SO LANCET NEUROLOGY LA English DT Letter ID CEREBRAL AMYLOID ANGIOPATHY; CORTICAL SUPERFICIAL SIDEROSIS C1 [Charidimou, Andreas; Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA 02115 USA. RP Charidimou, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2016 VL 15 IS 12 BP 1206 EP 1206 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA EA0YO UT WOS:000386315700014 PM 27751547 ER PT J AU Ascherio, A Schwarzschild, MA AF Ascherio, Alberto Schwarzschild, Michael A. TI The epidemiology of Parkinson's disease: risk factors and prevention SO LANCET NEUROLOGY LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; URIC-ACID LEVELS; CALCIUM-CHANNEL BLOCKERS; BODY-MASS INDEX; AMYOTROPHIC-LATERAL-SCLEROSIS; RANDOMIZED CONTROLLED-TRIAL; COA REDUCTASE INHIBITORS; TIME PHYSICAL-ACTIVITY; LIPID-LOWERING DRUGS; PROSPECTIVE COHORT AB Since 2006, several longitudinal studies have assessed environmental or behavioural factors that seem to modify the risk of developing Parkinson's disease. Increased risk of Parkinson's disease has been associated with exposure to pesticides, consumption of dairy products, history of melanoma, and traumatic brain injury, whereas a reduced risk has been reported in association with smoking, caffeine consumption, higher serum urate concentrations, physical activity, and use of ibuprofen and other common medications. Randomised trials are investigating the possibility that some of the negative risk factors might be neuroprotective and thus beneficial in individuals with early Parkinson's disease, particularly with respect to smoking (nicotine), caffeine, and urate. In the future, it might be possible to identify Parkinson's disease in its prodromal phase and to promote neuroprotective interventions before the onset of motor symptoms. At this time, however, the only intervention that seems justifiable for the primary prevention of Parkinson's disease is the promotion of physical activity, which is likely to be beneficial for the prevention of several chronic diseases. C1 [Ascherio, Alberto] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA USA. [Ascherio, Alberto] Brigham & Womens Hosp, Channing Lab, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Med Sch, Boston, MA USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Ascherio, A (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM aascheri@hsph.harvard.edu FU National Institutes of Health; Department of Defense; National Multiple Sclerosis Society; ALS Therapy Alliance; Accelerated Cure Project; Michael J Fox Foundation; Almirall; Bayer; Parkinson's Disease Foundation; Biotie Therapeutics; Hoffman Foundation; Target ALS FX AA reports grants from the National Institutes of Health, the Department of Defense, the National Multiple Sclerosis Society, the ALS Therapy Alliance, the Accelerated Cure Project, and the Michael J Fox Foundation; and personal fees from Almirall and Bayer. MAS reports grants from the National Institutes of Health, the Michael J Fox Foundation, the Parkinson's Disease Foundation, and the Department of Defense; personal fees from Biotie Therapeutics; and grants from the Hoffman Foundation and Target ALS. NR 238 TC 1 Z9 1 U1 29 U2 29 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2016 VL 15 IS 12 BP 1255 EP 1270 PG 16 WC Clinical Neurology SC Neurosciences & Neurology GA EA0YO UT WOS:000386315700021 ER PT J AU Shah, H Albanese, E Duggan, C Rudan, I Langa, KM Carrillo, MC Chan, KY Joanette, Y Prince, M Rossor, M Saxena, S Snyder, HM Sperling, R Varghese, M Wang, HL Wortmann, M Dua, T AF Shah, Hirai Albanese, Emiliano Duggan, Cynthia Rudan, Igor Langa, Kenneth M. Carrillo, Maria C. Chan, Kit Yee Joanette, Yves Prince, Martin Rossor, Martin Saxena, Shekhar Snyder, Heather M. Sperling, Reisa Varghese, Mathew Wang, Huali Wortmann, Marc Dua, Tarun TI Research priorities to reduce the global burden of dementia by 2025 SO LANCET NEUROLOGY LA English DT Article ID LEON-THAL SYMPOSIUM; HEALTH RESEARCH INVESTMENTS; SETTING PRIORITIES; GRAND CHALLENGES; MENTAL-HEALTH; ROADMAP; PREVENTION; STRATEGY AB At the First WHO Ministerial Conference on Global Action Against Dementia in March, 2015, 160 delegates, including representatives from 80 WHO Member States and four UN agencies, agreed on a call for action to reduce the global burden of dementia by fostering a collective effort to advance research. To drive this effort, we completed a globally representative research prioritisation exercise using an adapted version of the Child Health and Nutrition Research Initiative method. We elicited 863 research questions from 201 participants and consolidated these questions into 59 thematic research avenues, which were scored anonymously by 162 researchers and stakeholders from 39 countries according to five criteria. Six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers. Other priorities related to diagnosis, biomarkers, treatment development, basic research into disease mechanisms, and public awareness and understanding of dementia. Research priorities identified by this systematic international process should be mapped onto the global dementia research landscape to identify crucial gaps and inform and motivate policy makers, funders, and researchers to support and conduct research to reduce the global burden of dementia. Efforts are needed by all stakeholders, including WHO, WHO Member States, and civil society, to continuously monitor research investments and progress, through international platforms such as a Global Dementia Observatory. With established research priorities, an opportunity now exists to translate the call for action into a global dementia action plan to reduce the global burden of dementia. C1 [Shah, Hirai] Columbia Univ, Dept Neurol, New York, NY USA. [Albanese, Emiliano] Univ Geneva, Dept Psychiat, Geneva, Switzerland. [Duggan, Cynthia] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Rudan, Igor; Chan, Kit Yee] Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland. [Rudan, Igor; Chan, Kit Yee] Univ Edinburgh, Usher Inst, WHO Collaborating Ctr Populat Hlth Res andTrainin, Edinburgh, Midlothian, Scotland. [Langa, Kenneth M.] Univ Michigan, VA Ctr Clin Management Res, Inst Healthcare Policy & Innovat, Dept Internal Med,Inst Social Res, Ann Arbor, MI 48109 USA. [Carrillo, Maria C.; Snyder, Heather M.] Alzheimers Assoc, Med & Sci Relat Div, Chicago, IL USA. [Chan, Kit Yee] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Nossal Inst Global Hlth, Melbourne, Vic, Australia. [Joanette, Yves] Canadian Inst Hlth Res, Inst Aging, Montreal, PQ, Canada. [Joanette, Yves] World Dementia Council, London, England. [Prince, Martin] Kings Coll London, Ctr Global Mental Hlth, Hlth Serv & Populat Res Dept, London, England. [Rossor, Martin] UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat, London, England. [Saxena, Shekhar; Dua, Tarun] WHO, Dept Mental Hlth & Subst Abuse, Geneva, Switzerland. [Sperling, Reisa] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, Ctr Alzheimer Res & Treatment, Boston, MA USA. [Varghese, Mathew] Natl Inst Mental Hlth & Neurosci, Dept Psychiat, Bangalore, Karnataka, India. [Wang, Huali] Peking Univ, Beijing Municipal Key Lab Translat Res Diag & Tre, Natl Clin Res Ctr Mental Disorders, Dementia Care & Res Ctr,Inst Mental Hlth,Hosp 6, Beijing, Peoples R China. [Wortmann, Marc] Alzheimers Dis Int, London, England. RP Dua, T (reprint author), WHO, Programme Neurol Dis & Neurosci Evidence Res & Ac, Dept Mental Hlth & Subst Abuse, CH-1211 Geneva 27, Switzerland. EM duat@who.int FU US National Institute on Aging; NIHR Queen Square Dementia Biomedical Research Unit; UK Department of Health FX KML has received grants from the US National Institute on Aging. MR is NIHR National Director for Dementia Research and receives funding from the NIHR Queen Square Dementia Biomedical Research Unit. RS is a member of the US NIH National Advisory Council on Aging. We thank the UK Department of Health for the financial support provided to undertake this work. We also thank all experts and stakeholders across all world regions who contributed to the original research questions and scored the thematic research avenues. NR 31 TC 3 Z9 3 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2016 VL 15 IS 12 BP 1283 EP 1292 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EA0YO UT WOS:000386315700023 ER PT J AU Lee, JC Su, SY Changou, CA Yang, RS Tsai, KS Collins, MT Orwoll, ES Lin, CY Chen, SH Shih, SR Lee, CH Oda, Y Billings, SD Li, CF Nielsen, GP Konishi, E Petersson, F Carpenter, TO Sittampalam, K Huang, HY Folpe, AL AF Lee, Jen-Chieh Su, Sheng-Yao Changou, Chun A. Yang, Rong-Sen Tsai, Keh-Sung Collins, Michael T. Orwoll, Eric S. Lin, Chung-Yen Chen, Shu-Hwa Shih, Shyang-Rong Lee, Cheng-Han Oda, Yoshinao Billings, Steven D. Li, Chien-Feng Nielsen, G. Petur Konishi, Eiichi Petersson, Fredrik Carpenter, Thomas O. Sittampalam, Kesavan Huang, Hsuan-Ying Folpe, Andrew L. TI Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors SO MODERN PATHOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; FRIZZLED-RELATED PROTEIN-4; FACTOR-I; INDUCED OSTEOMALACIA; MITOGENIC ACTIVITY; FGF23 EXPRESSION; BONE; MATRIX; RNA; IDENTIFICATION AB Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1-FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1-FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1-FGFR1 and FN1-FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1-FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins. C1 [Lee, Jen-Chieh] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept & Grad Inst Pathol, Coll Med, 7 Chung Shan South Rd, Taipei 10002, Taiwan. [Su, Sheng-Yao; Lin, Chung-Yen; Chen, Shu-Hwa] Acad Sinica, Inst Informat Sci, Taipei, Taiwan. [Su, Sheng-Yao] Natl Yang Ming Univ, Acad Sinica, Inst Biomed Informat, Bioinformat Program,Taiwan Int Grad Program, Taipei, Taiwan. [Changou, Chun A.] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan. [Changou, Chun A.] Taipei Med Univ, Grad Inst Translat Med, Integrated Lab, Ctr Translat Med, Taipei, Taiwan. [Yang, Rong-Sen] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Dept Orthoped, Taipei, Taiwan. [Tsai, Keh-Sung; Shih, Shyang-Rong] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Collins, Michael T.] NIH, Skeletal Clin Studies Unit, Bldg 10, Bethesda, MD 20892 USA. [Orwoll, Eric S.] Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97201 USA. [Lee, Cheng-Han] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. [Lee, Cheng-Han] Royal Alexandra Hosp, Edmonton, AB, Canada. [Oda, Yoshinao] Kyushu Univ, Grad Sch Med Sci, Dept Anat Pathol, Fukuoka, Japan. [Billings, Steven D.] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Li, Chien-Feng] Chi Mei Med Ctr, Dept Pathol, Tainan, Taiwan. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Konishi, Eiichi] Kyoto Prefectural Univ Med, Dept Pathol, Kyoto, Japan. [Petersson, Fredrik] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore. [Carpenter, Thomas O.] Yale Univ, Sch Med, Dept Pediat Endocrinol, New Haven, CT USA. [Sittampalam, Kesavan] Singapore Gen Hosp, Pathol Dept, Singapore, Singapore. [Huang, Hsuan-Ying] Chang Gung Univ, Coll Med, Kaohsiung Chang Gung Mem Hosp, Dept Pathol, Kaohsiung, Taiwan. [Folpe, Andrew L.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA. RP Lee, JC (reprint author), Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept & Grad Inst Pathol, Coll Med, 7 Chung Shan South Rd, Taipei 10002, Taiwan.; Folpe, AL (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA. EM leejenchieh@ntuh.gov.tw; Folpe.Andrew@mayo.edu OI Lee, Jen-Chieh/0000-0001-7739-5934 FU Ministry of Science and Technology, Taiwan [MOST 104-2628-B-002-003-MY2]; National Taiwan University Hospital, Taipei, Taiwan [NTUH 105-S3041] FX This work was supported by research funds from Ministry of Science and Technology, Taiwan (MOST 104-2628-B-002-003-MY2) and National Taiwan University Hospital, Taipei, Taiwan (NTUH 105-S3041) to Dr Jen-Chieh Lee. We thank Dr Chih-Chien Hung for his assistance in collecting materials; Mr Yung-Chuan Chung, Mr Ren-Wei Wang, Ms Ying-Ying Chuang, and the NTUH sequencing core laboratory for the technical assistance; and Mr Grant Perry for his selfless dedications and generous contributions to this research. URLs for the raw data of RNA-seq: http://www.ncbi.nlm.nih.gov/sra/?term= SRX1560738 (sample PMT-50) http://www.ncbi.nlm.nih.gov/sra/?term= SRX1560739 (sample PMT-16 and -17). NR 46 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2016 VL 29 IS 11 BP 1335 EP 1346 DI 10.1038/nnodpathol.2016.137 PG 12 WC Pathology SC Pathology GA EA2EE UT WOS:000386404800005 PM 27443518 ER PT J AU Rosa-Rosa, JM Leskela, S Cristobal-Lana, E Santon, A Lopez-Garcia, MA Munoz, G Perez-Mies, B Biscuola, M Prat, J Esther, OE Soslow, RA Matias-Guiu, X Palacios, J AF Rosa-Rosa, Juan M. Leskela, Susanna Cristobal-Lana, Eva Santon, Almudena Angeles Lopez-Garcia, Ma Munoz, Gloria Perez-Mies, Belen Biscuola, Michele Prat, Jaime Esther, Oliva E. Soslow, Robert A. Matias-Guiu, Xavier Palacios, Jose TI Molecular genetic heterogeneity in undifferentiated endometrial carcinomas SO MODERN PATHOLOGY LA English DT Article ID EXONUCLEASE DOMAIN MUTATIONS; CANCER; PROGRESSION; DEFICIENCY; EXPRESSION; FEATURES; ARID1A AB Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value. C1 [Rosa-Rosa, Juan M.; Leskela, Susanna; Cristobal-Lana, Eva; Santon, Almudena; Perez-Mies, Belen; Palacios, Jose] Univ Alcala De Henares, IRYCIS, Hosp Univ Ramon & Cajal, Serv Anat Patol, Madrid, Spain. [Angeles Lopez-Garcia, Ma; Biscuola, Michele] Hosp Univ Virgen Rocio, Dept Pathol, Seville, Spain. [Angeles Lopez-Garcia, Ma; Biscuola, Michele] Inst Biomed Sevilla IBIS, Seville, Spain. [Munoz, Gloria] Hosp Univ Ramon & Cajal, IRYCIS, UCA Genom Traslac, Madrid, Spain. [Prat, Jaime] Autonomous Univ Barcelona, Hosp Santa Creu & St Pau, Dept Pathol, Barcelona, Spain. [Esther, Oliva E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, Dept Pathol, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA. [Matias-Guiu, Xavier] Univ Lleida, IRB Lleida, Inst Recerca Biomed Lleida, Dept Pathol & Mol Genet HUAV,Dept Ciencies Med Ba, Lleida, Spain. [Matias-Guiu, Xavier] Hosp Univ Bellvitge, Dept Pathol, Barcelona, Spain. RP Rosa-Rosa, JM; Palacios, J (reprint author), Hosp Ramon & Cajal, Serv Anat Patol, Ctra Colmenar Viejo Km 9,100, E-28034 Madrid, Spain. EM juanmanuel.rosa@salud.madrid.org; jose.palacios@salud.madrid.org RI Prat, Jaime/G-4679-2011; matias-guiu, xavier/C-3039-2009 OI matias-guiu, xavier/0000-0002-7201-6605 FU Institute Carlos III (ISCIII) - European Development Regional Fund, 'A way to achieve Europe' FEDER [PIE15/00050, PI13/02477, RD12/00360011, RD12/0036/0017, RD12/0036/0013, RD12/0036/0064]; Fundacio La Marato de TV3 [2/C2013]; ISCIII [PI13/02477, RD12/0036/0064] FX This project was supported by grants from Institute Carlos III (ISCIII) (PIE15/00050, PI13/02477, RD12/00360011, RD12/0036/0017, RD12/0036/0013, and RD12/0036/0064), co-financed by the European Development Regional Fund, 'A way to achieve Europe' FEDER, and by Fundacio La Marato de TV3 (2/C2013). JMR-R and EC-L are PhD investigators funded by ISCIII (RD12/0036/0064). SLs is a PhD investigator funded by ISCIII (PI13/02477). NR 23 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2016 VL 29 IS 11 BP 1390 EP 1398 DI 10.1038/modpathol.2016.132 PG 9 WC Pathology SC Pathology GA EA2EE UT WOS:000386404800010 PM 27491810 ER PT J AU Astarita, S Caruso, L Barron, AM Rissmiller, P AF Astarita, Sara Caruso, Linda Barron, Anne Marie Rissmiller, Patricia TI Experiences in Sexual Health Among Women After Hematopoietic Stem Cell Transplantation SO ONCOLOGY NURSING FORUM LA English DT Article DE women; sexual health; sexuality; stem cell transplantation; education; quality of life ID BONE-MARROW-TRANSPLANTATION; CASE-MATCHED CONTROLS; QUALITY-OF-LIFE; CANCER; SURVIVORS AB Purpose/Objectives: To explore the experiences in sexual health among women after hematopoietic stem cell transplantation (HSCT). Research Approach: A qualitative phenomenologic approach was used to explore sexual health after HSCT. Setting: The leukemia and bone marrow transplantation outpatient clinic at Massachusetts General Hospital in Boston. Participants: This study included five women aged 18 years or older with a prior diagnosis of leukemia or lymphoma requiring HSCT who were at least three months post-HSCT and were sexually active prior to HSCT. Participants did not experience menopause pre-HSCT and did not show signs of relapsed disease or vaginal graft-versus-host disease. Methodologic Approach: A semistructured interview was conducted and included one open-ended question regarding sexual health after participants' HSCT and several follow-up questions. The interviews were audio recorded without participant identifiers. Interviews were then transcribed and analyzed. Primary investigators and an expert reviewer analyzed data using content analysis to identify themes from the interviews. Findings: Six themes emerged from the interviews: (a) relationship changes, (b) significant and concerning physical changes, (c) sense of loss and powerful emotional impact, (d) fatigue, (e) body image, and (f) educational needs. Conclusions: Findings portray women's experiences in sexual health post-HSCT and demonstrate the emotional and physical consequences that arise from HSCT-related complications. A need exists for greater support and education for women regarding sexual health post-HSCT, as well as improved education among clinicians regarding sexual health complications experienced by this population. Women articulated their desire for same-sex providers to educate them on the sexual health side effects of HSCT. Interpretation: Sexual health education is needed immediately prior to and following HSCT. Implications for practice include designating time for pre-and post-HSCT education, improving current sexual health education provided by HSCT clinicians, engaging same-sex providers to discuss sexual health with patients, and increasing nurses' expertise in this area. C1 [Astarita, Sara; Caruso, Linda] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barron, Anne Marie; Rissmiller, Patricia] Simmons Coll, Sch Nursing & Hlth Sci, Boston, MA 02115 USA. RP Astarita, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM astarita@simmons.edu NR 13 TC 0 Z9 0 U1 4 U2 4 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X EI 1538-0688 J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2016 VL 43 IS 6 BP 754 EP 759 DI 10.1188/16.ONF.754-759 PG 6 WC Oncology; Nursing SC Oncology; Nursing GA EA1EY UT WOS:000386336500016 ER PT J AU Zhong, NS Moon, HS Lee, KH Mahayiddin, AA Boonsawat, W Isidro, MGD Bai, CX Mueller, A Metzdorf, N Anzueto, A AF Zhong, Nanshan Moon, Hwa S. Lee, Kwan H. Mahayiddin, Aziah A. Boonsawat, Watchara Isidro, Marie G. D. Bai, ChunXue Mueller, Achim Metzdorf, Norbert Anzueto, Antonio TI TIOtropium Safety and Performance In Respimat((R)) (TIOSPIRTM): Analysis of Asian cohort of COPD patients SO RESPIROLOGY LA English DT Article DE chronic obstructive pulmonary disease; clinical respiratory medicine; clinical trials ID OBSTRUCTIVE PULMONARY-DISEASE; HEALTH OUTCOMES; TRIAL; EFFICACY; EXACERBATIONS; BRONCHODILATOR; PREVENTION; SALMETEROL; COUNTRIES; PACIFIC AB Background and objective The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here. Methods TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 mu g with HandiHaler 18 mu g in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW). ResultsIn Asia (n=2356), time to death was similar for Respimat 5 and 2.5 mu g versus HandiHaler 18 mu g (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 mu g, but increased for 2.5 mu g versus HandiHaler 18 mu g (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions. ConclusionSimilar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 mu g and HandiHaler 18 mu g in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW. Asian cohort analysis in TIOtropium Safety and Performance In Respimat In Respimat((R)) (TIOSPIRTM) COPD trial demonstrates that, analogous to the global analysis, tiotropium Respimat 5 mu g and HandiHaler 18 mu g have similar safety and exacerbation efficacy. However, patients in Asia had fewer, but more severe, exacerbations than patients from the rest of the world. C1 [Zhong, Nanshan] Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. [Moon, Hwa S.] Catholic Univ Korea, Dept Internal Med, Seoul, South Korea. [Lee, Kwan H.] Yeungnam Univ Med Ctr, Dept Internal Med, Daegu, South Korea. [Mahayiddin, Aziah A.] Kuala Lumpur Hosp, Inst Resp Med, Kuala Lumpur, Malaysia. [Boonsawat, Watchara] Khon Kaen Univ, Srinagarind Hosp, Div Resp Med, Dept Med, Khon Kaen, Thailand. [Isidro, Marie G. D.] West Visayas State Univ Med Ctr, Jaro Iloilo City, Philippines. [Bai, ChunXue] Shanghai ZhonShan Hosp, Dept Pulm Med, Shanghai, Peoples R China. [Mueller, Achim] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Metzdorf, Norbert] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr, Pulmonary Crit Care Div, 111E,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Anzueto, A (reprint author), Univ Texas Hlth Sci Ctr, Pulmonary Crit Care Div, 111E,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM anzueto@uthscsa.edu NR 27 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD NOV PY 2016 VL 21 IS 8 BP 1397 EP 1403 DI 10.1111/resp.12856 PG 7 WC Respiratory System SC Respiratory System GA DZ4YD UT WOS:000385866900011 PM 27490162 ER PT J AU Arcaya, MC Tucker-Seeley, RD Kim, R Schnake-Mahl, A So, M Subramanian, SV AF Arcaya, Mariana C. Tucker-Seeley, Reginald D. Kim, Rockli Schnake-Mahl, Alina So, Marvin Subramanian, S. V. TI Research on neighborhood effects on health in the United States: A systematic review of study characteristics SO SOCIAL SCIENCE & MEDICINE LA English DT Review DE Neighborhoods; Study design; Multi-level; Social epidemiology; USA ID PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; PROSTATE-CANCER; RESEARCH AGENDA; DEPRESSIVE SYMPTOMS; RACIAL DISPARITIES; AFRICAN-AMERICAN; MENTAL-HEALTH; OLDER-ADULTS; MULTILEVEL AB Neighborhood effects on health research has grown over the past 20 years. While the substantive findings of this literature have been published in systematic reviews, meta-analyses, and commentaries, operational details of the research have been understudied. We identified 7140 multi-level neighborhoods and health papers published on US populations between 1995 and 2014, and present data on the study characteristics of the 256 papers that met our inclusion criteria. Our results reveal rapid growth in neighborhoods and health research in the mid-2000s, illustrate the dominance of observational cross-sectional study designs, and show a heavy reliance on single-level, census-based neighborhood definitions. Socioeconomic indicators were the most commonly analyzed neighborhood variables and body mass was the most commonly studied health outcome. Well-known challenges associated with neighborhood effects research were infrequently acknowledged. We discuss how these results move the agenda forward for neighborhoods and health research. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Arcaya, Mariana C.] MIT, Cambridge, MA 02139 USA. [Tucker-Seeley, Reginald D.; Kim, Rockli; Schnake-Mahl, Alina; So, Marvin; Subramanian, S. V.] Harvard Chan Sch Publ Hlth, Boston, MA USA. [Tucker-Seeley, Reginald D.] Dana Farber Canc Inst, Boston, MA USA. RP Subramanian, SV (reprint author), Dept Social & Behav Sci, 677 Huntington Ave,Kresge Bldg 7th Floor,716, Boston, MA 02115 USA. EM svsubram@hsph.harvard.edu FU NCI Career Development Grant [K01 CA169041]; Robert Wood Johnson Foundation Investigator Award in Health Policy Research FX SVS, RTS and MA conceptualized the study. RK, ASM, and MS conducted the review and entered the data. RK created the graphics and tables. MA wrote the first draft of the manuscript. RK, RTS, and SVS provided critical edits, and contributed to the writing. RTS and SVS provided overall supervision to the study. The authors would like to thank Galina Gheihman for her research assistance in conducting the review. RTS is funded by an NCI Career Development Grant (K01 CA169041). SVS was supported, in part, by a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. NR 87 TC 1 Z9 1 U1 12 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2016 VL 168 SI SI BP 16 EP 29 DI 10.1016/j.socscimed.2016.08.047 PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DZ9HW UT WOS:000386186900003 PM 27637089 ER PT J AU Skelley, NW Yarholar, LM Richardson, LC AF Skelley, Nathan W. Yarholar, Lauren M. Richardson, Lars C. TI Pilot and Passenger Injuries Associated with Powered Parachutes SO AEROSPACE MEDICINE AND HUMAN PERFORMANCE LA English DT Article DE powered parachute; sport pilot; ultralight; injuries; orthopedic; parachutist; accident investigation; passenger health ID PARAGLIDING ACCIDENTS; EPIDEMIOLOGY AB BACKGROUND: Powered parachutes are becoming a popular form of sport flying. No previous study has reviewed injuries in this sport. The purpose of this study was to describe the injuries associated with powered parachute flying, the flight factors involved in an incident, and the impact an incident has on current sport involvement. METHODS: National Transportation Safety Board incident reports involving powered parachutes between 2004 and 2015 were reviewed. Internet searches were performed to contact involved pilots to find further information. RESULTS: There were 71 incidents reported involving 117 people. Of these, 10 incidents involved 14 fatalities (12.0%). Of the 14 fatalities, 11 (78.5%) occurred in midflight. Pilot error was the most common finding for an incident and accounted for 53/71 incidents (74.6%). The main error was misjudging the distance required for takeoff and landing.This accounted for 37/71 incidents (52.1%). Orthopedic extremity injuries were the most common severe injuries reported. Surgical intervention was needed in 43.8% of injuries and 48.0% of those involved fractures. The median return to work was 14 d (range 0-180 d). Only 4/53 (7.5%) of the pilots contacted continued to fly powered parachutes. DISCUSSION: Powered parachute participants are at risk for unique injuries compared to other forms of flight. A powered parachute injury can have a significant impact on future pilot involvement in the sport. This study provides evidence for design changes in the aircraft and helps direct pilot training. This information can improve the safety and well-being of participants so they can continue to fly powered parachutes.d C1 [Skelley, Nathan W.] Washington Univ, Sch Med, Barnes Jewish Hosp, Dept Orthopaed Surg, St Louis, MO USA. [Yarholar, Lauren M.] St Louis Univ, Sch Med, Div Plast & Reconstruct Surg, St Louis, MO USA. [Skelley, Nathan W.; Richardson, Lars C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Cambridge, MA USA. RP Skelley, NW (reprint author), MGH Sports Med, 4th Floor,175 Cambridge St, Boston, MA 02114 USA. EM nskelley@mgh.harvard.edu NR 16 TC 0 Z9 0 U1 4 U2 4 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 2375-6314 EI 2375-6322 J9 AEROSP MED HUM PERF JI Aerosp. Med.Hum. Perform. PD NOV PY 2016 VL 87 IS 11 BP 947 EP 953 DI 10.3357/AMHP.4619.2016 PG 7 WC Biophysics; Public, Environmental & Occupational Health; Medicine, Research & Experimental SC Biophysics; Public, Environmental & Occupational Health; Research & Experimental Medicine GA DZ5NK UT WOS:000385908600007 PM 27779954 ER PT J AU Safarpour, D Willis, AW AF Safarpour, Delaram Willis, Allison W. TI Clinical Epidemiology, Evaluation, and Management of Dementia in Parkinson Disease SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Review DE Parkinson disease; dementia; mild cognitive impairment; Parkinson disease with dementia; epidemiology ID MINI-MENTAL-STATE; TRANSCRANIAL MAGNETIC STIMULATION; MONTREAL COGNITIVE ASSESSMENT; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; DOUBLE-BLIND; DIAGNOSTIC-CRITERIA; SCREENING DEMENTIA; LEWY BODIES; LONG-TERM AB The prevalence of neurodegenerative diseases such as Parkinson disease (PD) will increase substantially, due to the aging of the population and improved treatments leading to better disease-related outcomes. Dementia is the most common nonmotor symptom in PD, and most patients with PD will have cognitive dysfunction and cognitive decline in the course of their disease. The development of cognitive dysfunction in PD greatly limits the ability to participate in activities of daily living and can be a tipping point for nursing home placement or major caregiver stress. Understanding the different causes of dementia and how to reduce the incidence and impact of secondary cognitive dysfunction in PD are necessary skills for primary care physicians and neurologists. In this review, we discuss the clinical epidemiology of dementia in PD with an emphasis on preventable cognitive dysfunction, present tools for outpatient evaluation of cognitive dysfunction, and describe current pharmacological treatments for dementia in PD. C1 [Safarpour, Delaram; Willis, Allison W.] Univ Penn, Perelman Sch Med, Dept Neurol, Blockley Hall,723,423 Guardian Dr, Philadelphia, PA 19104 USA. [Safarpour, Delaram] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Willis, Allison W.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Blockley Hall,723,423 Guardian Dr, Philadelphia, PA 19104 USA. [Willis, Allison W.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Willis, Allison W.] Univ Penn, Perelman Sch Med, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Willis, AW (reprint author), Univ Penn, Perelman Sch Med, Dept Neurol, Blockley Hall,723,423 Guardian Dr, Philadelphia, PA 19104 USA.; Willis, AW (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Blockley Hall,723,423 Guardian Dr, Philadelphia, PA 19104 USA. EM allison.willis@uphs.upenn.edu FU NINDS NIH HHS [K23 NS081087] NR 87 TC 0 Z9 0 U1 15 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD NOV PY 2016 VL 31 IS 7 BP 585 EP 594 DI 10.1177/1533317516653823 PG 10 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA DZ2VY UT WOS:000385701000006 PM 27295974 ER PT J AU Calvo-Rodriguez, M Garcia-Durillo, M Villalobos, C Nunez, L AF Calvo-Rodriguez, Maria Garcia-Durillo, Monica Villalobos, Carlos Nunez, Lucia TI In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk and loss of store-operated Ca2+ entry (SOCE) in rat hippocampal neurons SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Aging; Hippocampal neurons; Store-operated calcium entry; ER-mitochondria cross talking; Stim1; Orai1 ID MITOCHONDRIAL CALCIUM UNIPORTER; ALZHEIMERS-DISEASE; CELL-PROLIFERATION; A-BETA; NEUROPROTECTION; STIMULATION; DYSFUNCTION; LYMPHOCYTES; ACTIVATION; MECHANISMS AB Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to sub cellular Ca2+ homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated Ca2+ entry (SOCE). In addition, Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria sustains energy production but mitochondrial Ca2+ overload promotes apoptosis. We have addressed whether SOCE and ER mitochondria Ca2+ transfer are influenced by culture time in long-term cultures of rat hippocampal neurons, a model of neuronal aging. We found that short-term cultured neurons show large SOCE, low Ca2+ store content and no functional coupling between ER and mitochondria. In contrast, in long-term cultures reflecting aging neurons, SOCE is essentially lost, Stim1 and Orai1 are downregulated, Ca2+ stores become overloaded, Ca2+ release is enhanced, expression of the mitochondrial Ca2+ uniporter (MCU) increases and most Ca2+ released from the ER is transferred to mitochondria. These results suggest that neuronal aging is associated to increased ER-mitochondrial cross talking and loss of SOCE. This subcellular Ca2+ remodeling might contribute to cognitive decline and susceptibility to neuron cell death in the elderly. (C) 2016 Elsevier B.V. All rights reserved. C1 [Calvo-Rodriguez, Maria; Garcia-Durillo, Monica; Villalobos, Carlos; Nunez, Lucia] CSIC, IBGM, Valladolid, Spain. [Nunez, Lucia] Univ Valladolid, Dept Bioquim & Biol Mol Fisiol, Valladolid, Spain. [Calvo-Rodriguez, Maria] Massachusetts Gen Hosp, Dept Neurol, Alzheimer Res Unit, 114 16th St, Charlestown, MA 02129 USA. [Calvo-Rodriguez, Maria] Harvard Med Sch, 114 16th St, Charlestown, MA 02129 USA. RP Villalobos, C (reprint author), CSIC, IBGM, Valladolid, Spain. EM carlosv@ibgm.uva.es FU Ministry of Economy and Competitiveness (Spain) [BFU2012-37146, BFU2015-70131R]; Regional Government of Castilla y Leon (Spain) [VA145U13, BIO/VA33/13]; European Social Fund FX This work was supported by grants BFU2012-37146 and BFU2015-70131R from Ministry of Economy and Competitiveness (Spain) and grants VA145U13 and BIO/VA33/13 from Regional Government of Castilla y Leon (Spain). MCR was supported by a pre-doctoral fellowship from Regional Government of Castilla y Leon (Spain) and the European Social Fund. NR 42 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD NOV PY 2016 VL 1863 IS 11 BP 2637 EP 2649 DI 10.1016/j.bbamcr.2016.08.001 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DY7SP UT WOS:000385329900009 PM 27503411 ER PT J AU Moussawi, K Kalivas, PW Lee, JW AF Moussawi, Khaled Kalivas, Peter W. Lee, Jong W. TI Abstinence From Drug Dependence After Bilateral Globus Pallidus Hypoxic-Ischemic Injury SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID BRAIN C1 [Moussawi, Khaled; Lee, Jong W.] Harvard Med Sch, Boston, MA USA. [Moussawi, Khaled; Lee, Jong W.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Moussawi, Khaled] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kalivas, Peter W.] Med Univ South Carolina, Dept Neurosci, Charleston, SC USA. RP Moussawi, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Wang Ambulatory Care Ctr, Suite 835,55 Fruit St, Boston, MA 02114 USA. EM kmoussawi@partners.org FU NIDA NIH HHS [R01 DA012513] NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 1 PY 2016 VL 80 IS 9 BP E79 EP E80 DI 10.1016/j.biopsych.2016.04.005 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0FA UT WOS:000385511700014 PM 27311800 ER PT J AU Ferguson, BJ Marler, S Altstein, LL Lee, EB Mazurek, MO McLaughlin, A Macklin, EA McDonnell, E Davis, DJ Belenchia, AM Gillespie, CH Peterson, CA Bauman, ML Margolis, KG Veenstra-VanderWeele, J Beversdorf, DQ AF Ferguson, Bradley J. Marler, Sarah Altstein, Lily L. Lee, Evon Batey Mazurek, Micah O. McLaughlin, Aaron Macklin, Eric A. McDonnell, Erin Davis, Daniel J. Belenchia, Anthony M. Gillespie, Catherine H. Peterson, Catherine A. Bauman, Margaret L. Margolis, Kara Gross Veenstra-VanderWeele, Jeremy Beversdorf, David Q. TI Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Autism spectrum disorder; Cortisol; Cytokines; Stress; Gastrointestinal disorders ID IRRITABLE-BOWEL-SYNDROME; ACUTE MENTAL STRESS; SALIVARY CORTISOL; ALPHA-AMYLASE; BRAIN IL-6; HPA-AXIS; CHILDREN; INTERLEUKIN-6; ANXIETY; BEHAVIORS AB Many children and adolescents with autism spectrum disorder (ASD) have significant gastrointestinal (GI) symptoms, but the etiology is currently unknown. Some individuals with ASD show altered reactivity to stress and altered immune markers relative to typically-developing individuals, particularly stress responsive cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Acute and chronic stress is associated with the onset and exacerbation of GI symptoms in those without ASD. The present study examined whether GI symptoms in ASD were associated with increases in cortisol, a stress-associated endocrine marker, and TNF-alpha and IL-6 in response to stress. As hypothesized, a greater amount of lower GI tract symptoms were significantly associated with post-stress cortisol concentration. The relationship between cortisol response to stress and GI functioning was greater for children who had a history of regressive autism. Exploratory analyses revealed significant correlations between cortisol response, intelligence, and inappropriate speech. In contrast, symptoms of the lower GI tract were not associated with levels of TNF-alpha or IL-6. Significant correlations were found, however, between TNF-alpha and IL-6 and irritability, socialization, and intelligence. These findings suggest that individuals with ASD and symptoms of the lower GI tract may have an increased response to stress, but this effect is not associated with concomitant changes in TNF-alpha and IL-6. The relationship between cortisol stress response and lower GI tract symptoms in children with regressive autism, as well as the relationships between cortisol, IL-6, and intelligence in ASD, warrant further investigation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ferguson, Bradley J.; Beversdorf, David Q.] Univ Missouri, Interdisciplinary Neurosci Program, Columbia, MO 65211 USA. [Marler, Sarah] Vanderbilt Univ, Med Ctr, Dept Child & Adolescent Psychiat, Nashville, TN USA. [Altstein, Lily L.; Macklin, Eric A.; McDonnell, Erin] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Lee, Evon Batey] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. [Lee, Evon Batey] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Lee, Evon Batey] Vanderbilt Univ, Dept Psychiat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Ferguson, Bradley J.; Mazurek, Micah O.; Beversdorf, David Q.] Univ Missouri, Thompson Ctr Autism & Neurodev Disorders, Columbia, MO 65211 USA. [McLaughlin, Aaron] Univ Missouri, Sch Med, Columbia, MO 65211 USA. [Mazurek, Micah O.] Univ Missouri, Dept Hlth Psychol, Columbia, MO 65211 USA. [Macklin, Eric A.] Harvard Med Sch, Boston, MA USA. [Bauman, Margaret L.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Margolis, Kara Gross] Columbia Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, New York, NY 10027 USA. [Veenstra-VanderWeele, Jeremy] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Veenstra-VanderWeele, Jeremy] Columbia Univ, Sackler Inst Dev Psychobiol, New York, NY 10027 USA. [Veenstra-VanderWeele, Jeremy] New York Presbyterian Hosp, New York State Psychiat Inst, Ctr Autism & Dev Brain, New York, NY USA. [Beversdorf, David Q.] Univ Missouri, William & Nancy Thompson Chair Radiol, Dept Radiol, Columbia, MO 65211 USA. [Beversdorf, David Q.] Univ Missouri, William & Nancy Thompson Chair Radiol, Dept Neurol, Columbia, MO 65211 USA. [Beversdorf, David Q.] Univ Missouri, William & Nancy Thompson Chair Radiol, Dept Psychol Sci, Columbia, MO 65211 USA. [Davis, Daniel J.; Gillespie, Catherine H.] Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. [Belenchia, Anthony M.; Peterson, Catherine A.] Univ Missouri, Dept Nutr & Exercise Physiol, Columbia, MO 65211 USA. RP Beversdorf, DQ (reprint author), Univ Missouri, Dept Radiol, DC 069-10,One Hosp Dr, Columbia, MO 65212 USA. EM beversdorfd@health.mssouri.edu OI Mazurek, Micah/0000-0001-7715-6538; Macklin, Eric/0000-0003-1618-3502 FU Health Resources Services Administration (HRSA) [UA3MC11054] FX This research was supported by a grant given to the Autism Treatment Network, Autism Intervention Research Network on Physical Health by the Health Resources Services Administration (HRSA Grant# UA3MC11054). This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. This work was conducted through the Autism Speaks Autism Treatment Network serving as the Autism Intervention Research Network on Physical Health. We would also like to thank the families, their children, and all of the research staff involved in this project. NR 46 TC 1 Z9 1 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD NOV PY 2016 VL 58 BP 57 EP 62 DI 10.1016/j.bbi.2016.05.009 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DZ5MG UT WOS:000385905600009 PM 27181180 ER PT J AU Shaffer, KM Riklin, E Jacobs, JM Rosand, J Vranceanu, AM AF Shaffer, Kelly M. Riklin, Eric Jacobs, Jamie M. Rosand, Jonathan Vranceanu, Ana-Maria TI Mindfulness and Coping Are Inversely Related to Psychiatric Symptoms in Patients and Informal Caregivers in the Neuroscience ICU: Implications for Clinical Care SO CRITICAL CARE MEDICINE LA English DT Article DE actor-partner interdependence model; coping; depression; informal caregiver; mindfulness; neuroscience ICU; posttraumatic stress ID POSTTRAUMATIC-STRESS-DISORDER; CORONARY-HEART-DISEASE; QUALITY-OF-LIFE; STROKE SURVIVORS; SPOUSAL CAREGIVERS; CANCER-PATIENTS; CHRONIC ILLNESS; INTENSIVE-CARE; BRAIN-INJURY; DEPRESSION AB Objective: To assess the correlation of psychosocial resiliency factors (mindfulness and coping) with symptoms of posttraumatic stress, anxiety, and depression in patients recently admitted to the neuroscience ICU and their primary informal caregivers. Design: A descriptive, cross-sectional correlational study. Setting: Neuroscience ICU in a major medical center. Participants: A total of 78 dyads of patients (total n = 81) and their primary caregivers (total n = 92) from June to December 2015. Study enrollment occurred within the first 2 weeks of patient admission to the neuroscience ICU. Intervention: None. Measurements and Main Results: Dyads completed self-report measures of mindfulness (Cognitive and Affective Mindfulness Scale-Revised), coping (Measure of Coping Status-A), posttraumatic stress (Posttraumatic Checklist Specific Stressor), anxiety (Hospital Anxiety and Depression Scale-A), and depression (Hospital Anxiety and Depression Scale-D). Rates of clinically significant posttraumatic stress, anxiety, and depressive symptoms were high and comparable between patient and caregiver samples. Own psychological resilience factors and psychiatric symptoms were strongly correlated for both patients and caregivers. Depressive symptoms were interdependent between patients and their caregivers, and one's own mindfulness was independently related to one's partner's depressive symptoms. Conclusions: Rates of clinically significant psychiatric symptoms were high, equally prevalent in patients and caregivers, and interdependent between patients and their caregivers. For both patients and caregivers, psychological resiliency factors were associated with both self and partner psychiatric symptoms. Findings suggest that attending to the psychiatric health of both patients and caregivers in the neuroscience ICU is a priority and that patients and their caregivers must be considered together in a system to fully address either individual's psychiatric symptoms. C1 [Shaffer, Kelly M.; Riklin, Eric; Jacobs, Jamie M.; Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shaffer, Kelly M.] Univ Miami, Dept Psychol, Miami, FL USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM avranceanu@partners.org OI Shaffer, Kelly/0000-0002-9749-8006 FU National Cancer Institute [NCI 1 F31 CA189431-01A1]; National Institutes of Health; National Cancer Institute; Clinical Trials Methodology Course; Clinical Trials Methodology Course [5R25NS088248-02] FX Ms. Shaffer received support for this project from the National Cancer Institute (NCI 1 F31 CA189431-01A1) and from the National Institutes of Health. Her institution received funding from the National Cancer Institute and the Clinical Trials Methodology Course. Dr. Vranceanu received support from the Clinical Trials Methodology Course 5R25NS088248-02. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 50 TC 0 Z9 0 U1 12 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2016 VL 44 IS 11 BP 2028 EP 2036 DI 10.1097/CCM.0000000000001855 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA DY9TL UT WOS:000385477900010 PM 27513536 ER PT J AU Murray, MJ DeBlock, H Erstad, B Gray, A Jacobi, J Jordan, C McGee, W McManus, C Meade, M Nix, S Patterson, A Sands, MK Pino, R Tescher, A Arbour, R Rochwerg, B Murray, CF Mehta, S AF Murray, Michael J. DeBlock, Heidi Erstad, Brian Gray, Anthony Jacobi, Judi Jordan, Che McGee, William McManus, Claire Meade, Maureen Nix, Sean Patterson, Andrew Sands, M. Karen Pino, Richard Tescher, Ann Arbour, Richard Rochwerg, Bram Murray, Catherine Friederich Mehta, Sangeeta TI Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; asthma; brain death; end of life; myasthenia gravis; neuromuscular-blocking agents; obesity; sedation; therapeutic hypothermia ID INTENSIVE-CARE-UNIT; RESPIRATORY-DISTRESS-SYNDROME; MORBIDLY OBESE-PATIENTS; NICOTINIC ACETYLCHOLINE-RECEPTORS; HISTAMINE N-METHYLTRANSFERASE; PREDICT FLUID RESPONSIVENESS; ENDOTRACHEAL-TUBE HOLDERS; CARDIAC ARREST PATIENTS; IDEAL BODY-WEIGHT; BLOCKING-AGENTS AB Objective: To update the 2002 version of "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient." Design: A Task Force comprising 17 members of the Society of Critical Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided. Methods: Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions. Results: The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a Pao(2)/Fio(2) less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death. C1 [Murray, Michael J.] Geisinger Med Ctr, Danville, PA 17822 USA. [DeBlock, Heidi] Albany Med Ctr, Albany, NY USA. [Erstad, Brian] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Gray, Anthony] Clin Med Ctr, Burlington, MA USA. [Jacobi, Judi] Indiana Univ, Bloomington, IN 47405 USA. [Jordan, Che] Grand Strand Med Ctr, Myrtle Beach, SC USA. [McGee, William] Baystate Med Ctr, Springfield, MA USA. [McManus, Claire] St Elizabeths Med Ctr, Boston, MA USA. [Meade, Maureen] Univ Toronto, Toronto, ON, Canada. [Nix, Sean] Riverside Med Grp, Yorktown, VA USA. [Patterson, Andrew] Univ Nebraska Med Ctr, Omaha, NE USA. [Sands, M. Karen] Novant Hlth, Clemmons, NC USA. [Pino, Richard] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tescher, Ann] Mayo Clin, Rochester, MN USA. [Arbour, Richard] Lancaster Gen Hosp, Lancaster, PA USA. [Rochwerg, Bram] McMaster Univ, Hamilton, ON, Canada. [Murray, Catherine Friederich] Medscape, New York, NY USA. [Mehta, Sangeeta] Univ Toronto, Toronto, ON, Canada. RP Murray, MJ (reprint author), Geisinger Med Ctr, Danville, PA 17822 USA. EM mjmurray3@gmail.com FU Mallinckrodt; American College of Clinical Pharmacy; European Society of Intensive Care Medicine; Hellman Foundation FX Dr. Murray disclosed participating in healthcare professional organization activities with ASA (Committee Member) and TAS BOD. Dr. Erstad disclosed non-governmental research funding with Mallinckrodt (Research Grant) and healthcare professional organization activities with the American College of Clinical Pharmacy (Treasurer beginning in October). Dr. Jacobi disclosed family relationships with makers of healthcare products (stockholder) and disclosed healthcare professional organization activities with the American College of Clinical Pharmacy (ACCP) (President). Dr. Jordan disclosed healthcare professional organization activities (ACCP member). Dr. McGee disclosed family relationships with makers of healthcare products (Pfizer, healthcare professional organization activities with AAHPM (policy committee) and CHEST (membership committee). Dr. Nix disclosed other healthcare professional organization activities with the American College of Ostropathic Surgery committees 1 (in-service exam committee). Dr. Patterson disclosed family relationships with makers of healthcare products (he is an employee of the University of Nebraska Medical Center) and disclosed non-governmental research grant funding (Co-PI for a Surviving Sepsis in Resource Limited Environment Grant from European Society of Intensive Care Medicine and Hellman Foundation). Dr. Sands disclosed family relationships with makers of healthcare products, for-profit of healthcare services/products, and with providers of healthcare services (consultant/speaker bureau for Hospira, HillRom, and she is owner of Critical Care Learning Curves business focused on critical care continuing education) and disclosed other healthcare professional organization activities (active member of Old Salem AACN and National Member as well). Dr. Pino disclosed family relationships with makers of healthcare products (spouse employed by Genentech). Dr. Rochwerg disclosed healthcare professional organization activities (Guideline methodologist for ATS, Candian Blood services, American Hematology Society). Dr. Friederich Murray disclosed healthcare professional organization activities with the Hypersomnia Foundation (with providers of healthcare services). Dr. Mehta disclosed healthcare professional organization activities (Guideline committee membership ATS ACCP liberation from Mechanical Ventilation). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 229 TC 4 Z9 4 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2016 VL 44 IS 11 BP 2079 EP 2103 DI 10.1097/CCM.0000000000002027 PG 25 WC Critical Care Medicine SC General & Internal Medicine GA DY9TL UT WOS:000385477900016 PM 27755068 ER PT J AU Girard, TD Yende, S AF Girard, Timothy D. Yende, Sachin TI Cognitive Impairment and Critical Illness: A Chicken and an Egg SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE cognition disorders; critical illness; mild cognitive impairment C1 [Girard, Timothy D.] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Clin Res Invest & Syst Modeling Acute Illness CRI, Pittsburgh, PA 15260 USA. [Yende, Sachin] Univ Pittsburgh, Dept Crit Care Med, Clin Res Invest & Syst Modeling Acute Illness CRI, Pittsburgh, PA USA. [Yende, Sachin] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Girard, TD (reprint author), Univ Pittsburgh, Sch Med, Dept Crit Care Med, Clin Res Invest & Syst Modeling Acute Illness CRI, Pittsburgh, PA 15260 USA. NR 10 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2016 VL 44 IS 11 BP 2115 EP 2116 DI 10.1097/CCM.0000000000001934 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA DY9TL UT WOS:000385477900023 PM 27755075 ER PT J AU Thomas, JJ Lee, S Becker, AE AF Thomas, Jennifer J. Lee, Sing Becker, Anne E. TI Updates in the epidemiology of eating disorders in Asia and the Pacific SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE Asia; China; eating disorders; Pacific Islander ID MENTAL-HEALTH SURVEY; TE-RAU-HINENGARO; HIGH-SCHOOL DANCE; DSM-IV DISORDERS; ANOREXIA-NERVOSA; HONG-KONG; FEMALE STUDENTS; LATENT PROFILE; ATTITUDES TEST; POPULATION AB Purpose of reviewThis review summarizes and contextualizes the recent epidemiologic data on eating disorders in the Asia and Pacific regions.Recent findingsGaps in epidemiologic data on eating disorders from the Asia and Pacific regions stem, in part, from omission of eating disorder-specific assessments in large nationally representative cohort studies of mental disorders. Available data - often from clinical and school-going cohorts - support that the prevalence of both eating disorders and associated attitudes and behaviors in many Asian and Pacific regions studied may be comparable to those reported in Europe and North America. Moreover, the prevalence of eating disorders in some regions of Asia may be increasing. Some of the national and subnational regions with the highest annual percent increases in disability-adjusted life years per 100000 caused by eating disorders over the past two decades are located in Asia.SummaryNotwithstanding sparse epidemiologic data concerning eating disorders in Asia and the Pacific, available evidence supports comparable prevalence to other global regions and that associated health burdens in some regions of Asia may be rising. This further supports that eating disorders are trans-national in distribution and challenges the previous understanding that they were primarily culture-bound to the Global North. C1 [Thomas, Jennifer J.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.; Becker, Anne E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Lee, Sing] Chinese Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Becker, Anne E.] Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. RP Becker, AE (reprint author), Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM Anne_becker@hms.harvard.edu RI Lee, Sing/O-2136-2015 NR 52 TC 1 Z9 1 U1 10 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD NOV PY 2016 VL 29 IS 6 BP 354 EP 362 DI 10.1097/YCO.0000000000000288 PG 9 WC Psychiatry SC Psychiatry GA DZ0DW UT WOS:000385508700007 PM 27648781 ER PT J AU Mehta, S Cronkite, DA Basavappa, M Wijmenga, C Xavier, RJ Jerey, KL AF Mehta, S. Cronkite, D. A. Basavappa, M. Wijmenga, C. Xavier, R. J. Jerey, K. L. TI IMMUNE-RESTRICTED EPIGENETIC READER SP140 MAINTAINS TRANSCRIPTIONAL PROGRAMS REQUIRED FOR MACROPHAGE IDENTITY AND INTESTINAL HOMEOSTASIS SO CYTOKINE LA English DT Meeting Abstract CT 4th Annual Meeting of The International-Cytokine-and-Interferon-Society (ICIS) CY OCT 16-19, 2016 CL San Francisco, CA SP Int Cytokine & Interferon Soc C1 [Mehta, S.; Cronkite, D. A.; Basavappa, M.; Xavier, R. J.; Jerey, K. L.] Harvard, Massachusetts Gen Hosp, Med, Boston, MA USA. [Wijmenga, C.] Univ Groningen, Dept Genet, Groningen, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2016 VL 87 MA O028 BP 57 EP 57 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DY7PH UT WOS:000385321100034 ER PT J AU Sanchez, E Darvish, H Mesias, R Taghavi, S Firouzabadi, SG Walker, RH Tafakhori, A Paisan-Ruiz, C AF Sanchez, Elena Darvish, Hossein Mesias, Roxana Taghavi, Shaghyegh Firouzabadi, Saghar Ghasemi Walker, Ruth H. Tafakhori, Abbas Paisan-Ruiz, Coro TI Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism SO HUMAN MUTATION LA English DT Article DE DNAJB2; spinal muscular atrophy; Parkinsonism; DnaJ domain deletion; WGS ID HEREDITARY MOTOR NEUROPATHY; SYNAPTIC PLASTICITY; INCLUSION FORMATION; NEUROTROPHIC FACTOR; DISEASE; TAU; PROTEASOME; DIAGNOSIS; MITOPHAGY; VARIANTS AB In this study, we described the identification of a large DNAJB2 (HSJ1) deletion in a family with recessive spinal muscular atrophy and Parkinsonism. After performing homozygosity mapping and whole genome sequencing, we identified a 3.8kb deletion, spanning the entire DnaJ domain of the HSJ1 protein, as the disease-segregating mutation. By performing functional assays, we showed that HSJ1b-related DnaJ domain deletion leads to loss of HSJ1b mRNA and protein levels, increased HSJ1a mRNA and protein expressions, increased cell death, protein aggregation, and enhanced autophagy. Given the role of HSJ1 proteins in the degradation of misfolded proteins, we speculated that enhanced autophagy might be promoted by the elevated HSJ1a expression seen in HSJ1b-deficient cells. We also observed a significant reduction in both tau and brain-derived neurotrophic factor levels, which may explain the dopaminergic deficits seen in one of the affected siblings. We concluded that HSJ1b deficiency leads to a complex neurological phenotype, possibly due to the accumulation of misfolded proteins, caused by the lack of the DnaJ domain activity. We thus expand the phenotypic and genotypic spectrums associated with DNAJB2 disease and suggest relevant disease-associated mechanisms. C1 [Sanchez, Elena; Mesias, Roxana; Walker, Ruth H.; Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Dept Neurol, One Gustave L Levy Pl, New York, NY 10029 USA. [Darvish, Hossein; Taghavi, Shaghyegh] Shahid Beheshti Univ Med Sci, Sch Med, Dept Med Genet, Tehran, Iran. [Mesias, Roxana] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, One Gustave L Levy Pl, New York, NY 10029 USA. [Firouzabadi, Saghar Ghasemi] Univ Social Welf & Rehabil Sci, Genet Res Ctr, Tehran, Iran. [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Tafakhori, Abbas] Imam Khomeini Hosp, Sch Med, Dept Neurol, Tehran, Iran. [Tafakhori, Abbas] Univ Tehran Med Sci, Iranian Ctr Neurol Res, Tehran, Iran. [Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl, New York, NY 10029 USA. [Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA. [Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, One Gustave L Levy Pl, New York, NY 10029 USA. [Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Friedman Brain Inst, One Gustave L Levy Pl, New York, NY 10029 USA. RP Paisan-Ruiz, C (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, One Gustave L Levy Pl, New York, NY 10029 USA. EM coro.paisan-ruiz@mssm.edu RI Paisan-Ruiz, Coro/C-2912-2009; Sanchez, Elena/B-4140-2017; OI Sanchez, Elena/0000-0002-7041-5485; Mesias, Roxana/0000-0002-6198-6809 FU Shahid Beheshti University of Medical Sciences; National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS) [R01NS079388] FX Contract Grant Sponsor: Shahid Beheshti University of Medical Sciences; National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS; R01NS079388). NR 42 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2016 VL 37 IS 11 BP 1180 EP 1189 DI 10.1002/humu.23055 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DZ4BZ UT WOS:000385804100008 PM 27449489 ER PT J AU Dai, GP Das, A Hayashi, E Chen, Q Takahashi, E AF Dai, Guangping Das, Avilash Hayashi, Emiko Chen, Qin Takahashi, Emi TI Regional variation of white matter development in the cat brain revealed by ex vivo diffusion MR tractography SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE Development; White matter; Diffusion imaging; Tractography; Cat ID HUMAN FETAL-BRAIN; ANATOMICAL CHARACTERIZATION; TENSOR; CONNECTIVITY; ANISOTROPY; ARCHITECTURE; PATHWAYS; TRACKING; NEWBORN; CORTEX AB Three-dimensional reconstruction of developing fiber pathways is essential to assessing the developmental course of fiber pathways in the whole brain. We applied diffusion spectrum imaging (DSI) tractography to five juvenile ex vivo cat brains at postnatal day (P) 35, when the degree of myelination varies across brain regions. We quantified diffusion properties (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) and other measurements (number, volume, and voxel count) on reconstructed pathways for projection (cortico-spinal and thalamo-cortical), corpus callosal, limbic (cingulum and fornix), and association (cortico-cortical) pathways, and characterized regional differences in maturation patterns by assessing diffusion properties. FA values were significantly higher in cortico-cortical pathways within the right hemisphere compared to those within the left hemisphere, while the other measurements for the cortico-cortical pathways within the hemisphere did not show asymmetry. ADC values were not asymmetric in both types of pathways. Interestingly, tract count and volume were significantly larger in the left thalamo-cortical pathways compared to the right thalamo-cortical pathways. The bilateral thalamo-cortical pathways showed high FA values compared to the other fiber pathways. On the other hand, ADC values did not show any differences across pathways studied. These results demonstrate that DSI tractography successfully depicted regional variations of white matter tracts during development when myelination is incomplete. Low FA and high ADC values in the cingulum bundle suggest that the cingulum bundle is less mature than the others at this developmental stage. (C) 2016 ISDN. Published by Elsevier Ltd. All rights reserved. C1 [Dai, Guangping; Chen, Qin] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Dai, Guangping; Chen, Qin; Takahashi, Emi] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Das, Avilash; Hayashi, Emiko; Takahashi, Emi] Harvard Med Sch, Childrens Hosp Boston, Div Newborn Med, Dept Med, 1 Autumn St 456, Boston, MA 02115 USA. [Das, Avilash] Boston Univ, Med Sci Coll Arts & Sci, Boston, MA 02215 USA. [Takahashi, Emi] Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA USA. [Dai, Guangping] Wellesley Coll, Ctr Sci, Wellesley, MA USA. [Hayashi, Emiko] Natl Res Inst Child Hlth & Dev, Dept Human Genet, Tokyo, Japan. [Chen, Qin] Sichuan Univ, Dept Neurol, West China Hosp, Chengdu, Sichuan, Peoples R China. RP Takahashi, E (reprint author), Harvard Med Sch, Childrens Hosp Boston, Div Newborn Med, Dept Med, 1 Autumn St 456, Boston, MA 02115 USA. EM emi@nmr.mgh.harvard.edu OI Das, Avilash/0000-0002-0445-0012 FU Eunice Shriver Kennedy National Institute of Child Health and Development (NICHD) (NIH) [R01HD078561, R21HD069001]; Biomedical Technology Program of the National Center for Research Resources (NCRR); National Institutes of Health; NCRR Shared Instrumentation Grant Program (NIH) [S10RR023401, S10RR019307, S10RR023043]; High-End Instrumentation Grant Program (NIH) [S10RR016811] FX This work was supported by the Eunice Shriver Kennedy National Institute of Child Health and Development (NICHD) (NIH R01HD078561, R21HD069001) (ET). This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, NIH P41RR14075 a P41 Regional Resource supported by the Biomedical Technology Program of the National Center for Research Resources (NCRR), National Institutes of Health. This work also involved the use of instrumentation supported by the NCRR Shared Instrumentation Grant Program (NIH S10RR023401, S10RR019307, and S10RR023043) and a High-End Instrumentation Grant Program (NIH S10RR016811). We thank Kenichi Ohki for providing the specimens, and Joseph B. Mandeville and Allison C.R. Scott for technical assistance. NR 31 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 EI 1873-474X J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD NOV PY 2016 VL 54 BP 32 EP 38 DI 10.1016/j.ijdevneu.2016.08.004 PG 7 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA DY7QO UT WOS:000385324600004 PM 27568056 ER PT J AU Falit, BP Pan, HY Smith, BD Alexander, BM Zietman, AL AF Falit, Benjamin P. Pan, Hubert Y. Smith, Benjamin D. Alexander, Brian M. Zietman, Anthony L. TI The Radiation Oncology Job Market: The Economics and Policy of Workforce Regulation SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PHYSICIAN-INDUCED DEMAND; HEALTH-SERVICE-CORPS; AMERICAN SOCIETY; CARE; TRAINESS; NUMBER; SHORTAGES; MEDICARE; DESIGN; FUTURE AB Examinations of the US radiation oncology workforce offer inconsistent conclusions, but recent data raise significant concerns about an oversupply of physicians. Despite these concerns, residency slots continue to expand at an unprecedented pace. Employed radiation oncologists and professional corporations with weak contracts or loose ties to hospital administrators would be expected to suffer the greatest harm from an oversupply. The reduced cost of labor, however, would be expected to increase profitability for equipment owners, technology vendors, and entrenched professional groups. Policymakers must recognize that the number of practicing radiation oncologists is a poor surrogate for clinical capacity. There is likely to be significant opportunity to augment capacity without increasing the number of radiation oncologists by improving clinic efficiency and offering targeted incentives for geographic redistribution. Payment policy changes significantly threaten radiation oncologists' income, which may encourage physicians to care for greater patient loads, thereby obviating more personnel. Furthermore, the implementation of alternative payment models such as Medicare's Oncology Care Model threatens to decrease both the utilization and price of radiation therapy by turning referring providers into cost-conscious consumers. Medicare funds the vast majority of graduate medical education, but the extent to which the expansion in radiation oncology residency slots has been externally funded is unclear. Excess physician capacity carries a significant risk of harm to society by suboptimally allocating intellectual resources and creating comparative shortages in other, more needed disciplines. There are practical concerns associated with a market-based solution in which medical students self-regulate according to job availability, but antitrust law would likely forbid collaborative self-regulation that purports to restrict supply. Because Congress is unlikely to create one central body to govern residency controls for all specialties, we recommend better reporting of program-specific employment metrics and careful, intellectually honest re-evaluation of existing Accreditation Council for Graduate Medical Education accreditation standards. (C) 2016 Elsevier Inc. All rights reserved. C1 [Falit, Benjamin P.] Pacific Canc Inst, Wailuku, HI USA. [Pan, Hubert Y.; Smith, Benjamin D.] MD Anderson Canc Ctr, Houston, TX USA. [Alexander, Brian M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Falit, BP (reprint author), Pacific Canc Inst, Radiat Oncol, 227 Mahalani St, Wailuku, HI 96793 USA. EM bfalit2@allianceoncology.com FU Elsevier FX B.D.S. reports grants from Varian Medical Systems, outside the submitted work. A.L.Z. serves as the Editor in Chief for the International Journal of Radiation Oncology * Biology * Physics. He receives a stipend from Elsevier and is the former President and Chair of the American Society for Radiation Oncology. NR 50 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2016 VL 96 IS 3 BP 501 EP 510 DI 10.1016/j.ijrobp.2016.05.029 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0IX UT WOS:000385522900003 PM 27681745 ER PT J AU Orio, PF Nguyen, PL Buzurovic, I Cail, DW Chen, YW AF Orio, Peter F., III Nguyen, Paul L. Buzurovic, Ivan Cail, Daniel W. Chen, Yu-Wei TI Prostate Brachytherapy Case Volumes by Academic and Nonacademic Practices: Implications for Future Residency Training SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CANCER DATA-BASE; RADIATION ONCOLOGY SURVEY; UNITED-STATES; CHIEF RESIDENTS; ASSOCIATION; OUTCOMES; CARE AB Purpose: The use of prostate brachytherapy has continued to decline in the United States. We examined the national practice patterns of both academic and nonacademic practices performing prostate brachytherapy by case volume per year to further characterize the decline and postulate the effect this trend might have on training the next generation of residents. Methods and Materials: Men diagnosed with prostate cancer who had undergone radiation therapy in 2004 to 2012 were identified. The annual brachytherapy case volume at each facility was determined and further categorized into <= 12 cases per year (ie, an average of <= 1 cases per month), 13 to 52 cases per year, and >= 53 cases per year (ie, an average of >= 1 cases per week) in academic practices versus nonacademic practices. Results: In 2004 to 2012, academic practices performing an average of <= 1 brachytherapy cases per month increased from 56.4% to 73.7%. In nonacademic practices, this percentage increased from 60.2% to 77.4% (P<.0001 for both). Practices performing an average of >= 1 cases per week decreased among both academic practices (from 6.7% to 1.5%) and nonacademic practices (from 4.5% to 2.7%). Conclusions: Both academic and nonacademic radiation oncology practices have demonstrated a significant reduction in the use of prostate brachytherapy from 2004 to 2012. With the case volume continuing to decline, it is unclear whether we are prepared to train the next generation of residents in this critical modality. (C) 2016 Elsevier Inc. All rights reserved. C1 [Orio, Peter F., III; Nguyen, Paul L.; Buzurovic, Ivan; Cail, Daniel W.; Chen, Yu-Wei] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Orio, Peter F., III; Nguyen, Paul L.; Buzurovic, Ivan; Cail, Daniel W.; Chen, Yu-Wei] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Orio, Peter F., III; Nguyen, Paul L.; Buzurovic, Ivan] Harvard Med Sch, Boston, MA USA. RP Orio, PF (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM PORIO@lroc.harvard.edu OI /0000-0001-9632-3434 NR 18 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2016 VL 96 IS 3 BP 624 EP 628 DI 10.1016/j.ijrobp.2016.07.013 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DZ0IX UT WOS:000385522900018 PM 27681758 ER PT J AU Ding, SL Royall, JJ Sunkin, SM Ng, L Facer, BAC Lesnar, P Guillozet-Bongaarts, A McMurray, B Szafer, A Dolbeare, TA Stevens, A Tirrell, L Benner, T Caldejon, S Dalley, RA Dee, N Lau, C Nyhus, J Reding, M Riley, ZL Sandman, D Shen, E van der Kouwe, A Varjabedian, A Write, M Zollei, L Dang, C Knowles, JA Koch, C Phillips, JW Sestan, N Wohnoutka, P Zielke, HR Hohmann, JG Jones, AR Bernard, A Hawrylycz, MJ Hof, PR Fischl, B Lein, ES AF Ding, Song-Lin Royall, Joshua J. Sunkin, Susan M. Ng, Lydia Facer, Benjamin A. C. Lesnar, Phil Guillozet-Bongaarts, Angie McMurray, Bergen Szafer, Aaron Dolbeare, Tim A. Stevens, Allison Tirrell, Lee Benner, Thomas Caldejon, Shiella Dalley, Rachel A. Dee, Nick Lau, Christopher Nyhus, Julie Reding, Melissa Riley, Zackery L. Sandman, David Shen, Elaine van der Kouwe, Andre Varjabedian, Ani Write, Michelle Zollei, Lilla Dang, Chinh Knowles, James A. Koch, Christof Phillips, John W. Sestan, Nenad Wohnoutka, Paul Zielke, H. Ronald Hohmann, John G. Jones, Allan R. Bernard, Amy Hawrylycz, Michael J. Hof, Patrick R. Fischl, Bruce Lein, Ed S. TI Comprehensive cellular-resolution atlas of the adult human brain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE brain atlas; cerebral cortex; hippocampal formation; thalamus; hypothalamus; amygdala; cerebellum; brainstem; MRI; DWI; cytoarchitecture; parvalbumin; neurofilament protein; RRIDs: AB_10000343; AB_2314904; SCR_014329 ID HUMAN CEREBRAL-CORTEX; CALCIUM-BINDING PROTEINS; HUMAN PERIRHINAL CORTEX; HUMAN CINGULATE CORTEX; EX-VIVO; PROBABILISTIC ATLAS; PATHOLOGICAL MARKERS; TEMPORAL-LOBE; PARCELLATION; MRI AB Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole-brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high-resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and 1,356 large-format cellular resolution (1 mu m/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto- and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127-3481, 2016. (c) 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. C1 [Ding, Song-Lin; Royall, Joshua J.; Sunkin, Susan M.; Ng, Lydia; Facer, Benjamin A. C.; Lesnar, Phil; Guillozet-Bongaarts, Angie; McMurray, Bergen; Szafer, Aaron; Dolbeare, Tim A.; Caldejon, Shiella; Dalley, Rachel A.; Dee, Nick; Lau, Christopher; Nyhus, Julie; Reding, Melissa; Riley, Zackery L.; Sandman, David; Shen, Elaine; Dang, Chinh; Koch, Christof; Phillips, John W.; Wohnoutka, Paul; Hohmann, John G.; Jones, Allan R.; Bernard, Amy; Hawrylycz, Michael J.; Lein, Ed S.] Allen Inst Brain Sci, Seattle, WA 98109 USA. [Stevens, Allison; Tirrell, Lee; Benner, Thomas; van der Kouwe, Andre; Varjabedian, Ani; Write, Michelle; Zollei, Lilla; Fischl, Bruce] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Knowles, James A.] Univ Southern Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Knowles, James A.] Univ Southern Calif, Dept Psychiat, Los Angeles, CA 90033 USA. [Sestan, Nenad] Yale Univ, Sch Med, Dept Neurobiol, 333 Cedar St, New Haven, CT 06510 USA. [Sestan, Nenad] Yale Univ, Sch Med, Kavli Inst Neurosci, 333 Cedar St, New Haven, CT 06510 USA. [Zielke, H. Ronald] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 11029 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 11029 USA. RP Ding, SL; Lein, ES (reprint author), Allen Inst Brain Sci, Seattle, WA 98109 USA. EM songd@alleninstitute.org; EdL@alleninstitute.org OI Koch, Christof/0000-0001-6482-8067 FU National Institutes of Health (NIH) [RC2 MH089921]; Allen Institute for Brain Science; National Institute for Biomedical Imaging and Bioengineering [P41 EB015896, R01 EB006758, R21 EB018907, R01 EB019956]; National Institute on Aging [5R01 AG008122, R01 AG016495]; National Institute for Neurological Disorders and Stroke [R01 NS0525851, R21 NS072652, R01 NS070963, R01 NS083534, 5U01 NS086625]; Shared Instrumentation Grants [1S10 RR023401, 1S10 RR019307, 1S10 RR023043]; National Institutes of Health Blueprint for Neuroscience Research part of the multi-institutional Human Connectome Project [5U01 MH093765] FX Grant sponsor: National Institutes of Health (NIH); Grant number: RC2 MH089921 (to E. S. L. and M. J. H.); Grant sponsor: Allen Institute for Brain Science; Grant sponsor: National Institute for Biomedical Imaging and Bioengineering; Grant numbers: P41 EB015896, R01 EB006758, R21 EB018907, and R01 EB019956; Grant sponsor: National Institute on Aging; Grant numbers: 5R01 AG008122 and R01 AG016495; Grant sponsor: National Institute for Neurological Disorders and Stroke; Grant numbers: R01 NS0525851, R21 NS072652, R01 NS070963, R01 NS083534, and 5U01 NS086625; Grant sponsor: Shared Instrumentation Grants; Grant numbers: 1S10 RR023401, 1S10 RR019307, and 1S10 RR023043; Grant sponsor: National Institutes of Health Blueprint for Neuroscience Research (part of the multi-institutional Human Connectome Project); Grant number: 5U01 MH093765. NR 96 TC 6 Z9 6 U1 16 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD NOV 1 PY 2016 VL 524 IS 16 SI SI BP 3127 EP 3481 DI 10.1002/cne.24080 PG 355 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA DW4EU UT WOS:000383596100001 PM 27418273 ER PT J AU Bighamian, R Kim, CS Reisner, AT Hahn, JO AF Bighamian, Ramin Kim, Chang-Sei Reisner, Andrew T. Hahn, Jin-Oh TI Closed-Loop Fluid Resuscitation Control Via Blood Volume Estimation SO JOURNAL OF DYNAMIC SYSTEMS MEASUREMENT AND CONTROL-TRANSACTIONS OF THE ASME LA English DT Article ID SYSTOLIC PRESSURE VARIATION; ARTERIAL PULSE PRESSURE; END-DIASTOLIC VOLUME; STROKE VOLUME; CARDIAC-OUTPUT; HEART-RATE; HEMODYNAMIC OPTIMIZATION; CARDIOVASCULAR-RESPONSE; VENTRICULAR INTERACTION; MATHEMATICAL-MODEL AB This paper presents a closed-loop control of fluid resuscitation to overcome hypovolemia based on model-based estimation of relative changes in blood volume (BV). In this approach, the control system consists of a model-based relative BV (RBV) estimator and a feedback controller. The former predicts relative changes in the BV response to augmented fluid by analyzing an arterial blood pressure (BP) waveform and the electrocardiogram (ECG). Then, the latter determines the amount of fluid to be augmented by comparing target versus predicted relative changes in BV. In this way, unlike many previous methods for fluid resuscitation based on controlled variable(s) nonlinearly correlated with the changes in BV, fluid resuscitation can be guided by a controlled variable linearly correlated with the changes in BV. This paper reports initial design of the closed-loop fluid resuscitation system and its in silico evaluation in a wide range of hypovolemic scenarios. The results suggest that closed-loop fluid resuscitation guided by a controlled variable linearly correlated with the changes in BV can be effective in overcoming hypovolemia: across 100 randomly produced hypovolemia cases, it resulted in the BV regulation error of 7.98 +/- 171.6 ml, amounting to 0.18 +/- 3.04% of the underlying BV. When guided by pulse pressure (PP), a classical controlled variable nonlinearly correlated with the changes in BV; the same closed-loop fluid resuscitation system resulted in persistent under-resuscitation with the BV regulation error of -779.1 +/- 147.4 ml, amounting to -13.9 +/- 2.65% of the underlying BV. C1 [Bighamian, Ramin; Kim, Chang-Sei; Hahn, Jin-Oh] Univ Maryland, Dept Mech Engn, 2181 Glenn L Martin Hall, College Pk, MD 20742 USA. [Reisner, Andrew T.] Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St, Boston, MA 02114 USA. RP Hahn, JO (reprint author), Univ Maryland, Dept Mech Engn, 2181 Glenn L Martin Hall, College Pk, MD 20742 USA. EM rbighami@umd.edu; cskim75@umd.edu; AREISNER@mgh.harvard.edu; Jhahn12@umd.edu FU U.S. Office of Naval Research (ONR) [N000141410591, N000141512018] FX This material is based on work supported by the U.S. Office of Naval Research (ONR) under Grant Nos. N000141410591 and N000141512018. NR 75 TC 0 Z9 0 U1 3 U2 3 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0022-0434 EI 1528-9028 J9 J DYN SYST-T ASME JI J. Dyn. Syst. Meas. Control-Trans. ASME PD NOV PY 2016 VL 138 IS 11 SI SI AR 111005 DI 10.1115/1.4033833 PG 8 WC Automation & Control Systems; Instruments & Instrumentation SC Automation & Control Systems; Instruments & Instrumentation GA DY9JX UT WOS:000385451000006 ER PT J AU Siefert, CJ Stein, MB Slavin-Mulford, J Sinclair, SJ Haggerty, G Blais, MA AF Siefert, Caleb J. Stein, Michelle B. Slavin-Mulford, Jenelle Sinclair, Samuel Justin Haggerty, Greg Blais, Mark A. TI Estimating the Effects of Thematic Apperception Test Card Content on SCORS-G Ratings: Replication With a Nonclinical Sample SO JOURNAL OF PERSONALITY ASSESSMENT LA English DT Article ID OBJECT RELATIONS SCALE; SOCIAL COGNITION; INTERNAL CONSISTENCY; SIZE REQUIREMENTS; INTERVIEW DATA; TAT CARDS; RELIABILITY; VALIDITY; PRECISION AB The content of Thematic Apperception Test (TAT) cards can, in some cases, influence how respondents form narratives. This study examines how imagery from select TAT cards affects the narratives of respondents from a nonclinical setting. The Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Stein, Hilsenroth, Slavin-Mulford, & Pinsker, 2011; Westen, Lohr, Silk, Kerber, & Goodrich, 1989) was used to rate narratives. Forty-nine college students provided narratives to 6 TAT cards. Narratives were rated by two expert raters using the SCORS-G. Consistent with prior research, Card 2 exhibited the most pull for adaptive ratings on SCORS-G scales, and 3BM exhibited the most pull for maladaptive ratings. Findings for other cards were mixed. Although raters were highly reliable, internal consistency estimates were lower than desirable for 6 of the 8 SCORS-G scales. Variance component estimates indicated that card by person interactions accounted for the largest amount of variance in person-level scores. Results and limitations are discussed in light of prior research. We also make suggestions for further lines of research in this area. C1 [Siefert, Caleb J.] Univ Michigan, Dept Behav Sci, CASL Bldg,4th Floor,4901 Evergreen Rd, Dearborn, MI 48192 USA. [Stein, Michelle B.; Sinclair, Samuel Justin; Blais, Mark A.] Massachusetts Gen Hosp, Psychol Evaluat & Res Lab, Boston, MA 02114 USA. [Stein, Michelle B.; Sinclair, Samuel Justin; Blais, Mark A.] Harvard Med Sch, Boston, MA USA. [Slavin-Mulford, Jenelle] Augusta State Univ, Dept Psychol, Augusta, GA USA. [Haggerty, Greg] Nassau Univ Med Ctr, Dept Psychiat & Behav Sci, E Meadow, NY USA. RP Siefert, CJ (reprint author), Univ Michigan, Dept Behav Sci, CASL Bldg,4th Floor,4901 Evergreen Rd, Dearborn, MI 48192 USA. EM csiefert@umich.edu NR 43 TC 0 Z9 0 U1 11 U2 11 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0022-3891 EI 1532-7752 J9 J PERS ASSESS JI J. Pers. Assess. PD NOV-DEC PY 2016 VL 98 IS 6 BP 598 EP 607 DI 10.1080/00223891.2016.1167696 PG 10 WC Psychology, Clinical; Psychology, Social SC Psychology GA DZ0HW UT WOS:000385519600008 PM 27100311 ER PT J AU Xu, L Yang, KQ Wei, PO Luo, X Mo, YJ Liang, XQ Lin, H Tan, HT Mudgal, CS AF Xu, Lin Yang, Keqin Wei, Pingou Luo, Xiang Mo, Yongjun Liang, Xuquan Lin, Han Tan, Haitao Mudgal, Chaitanya S. TI Computed Tomography Angiography Allows the Classification of the First Dorsal Metatarsal Arteries SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Article DE computed tomography angiography; first dorsal metatarsal artery; finger or thumb reconstruction ID MULTISLICE CT ANGIOGRAPHY; MAGNETIC-RESONANCE ANGIOGRAPHY; DIAGNOSTIC-VALUE; DISEASE; TOE; RECONSTRUCTION; METAANALYSIS; ANKLE; BONE; FLAP AB Background Conventional angiography is an invasive technique. Submillimeter computed tomography angiography (CTA) has been shown to be an effective alternative for peripheral artery branches. This study aimed to assess the use of CTA to guide the choice and design of foot donor area for finger or thumb reconstruction. Methods This was a retrospective study of 79 patients who underwent finger or thumb reconstruction between January, 2011 and March, 2014. All these patients underwent preoperative CTA to determine the exact blood supply at the donor site. Preoperative imaging and intraoperative findings at the donor site were compared. Results Among the 79 patients (158 feet), 474 artery segments (dorsalis pedis artery [DPA], first dorsal metatarsal artery [FDMA], and toe web artery [TWA]) were evaluated using CTA. Image satisfaction rates of the vessels were 100.0 +/- 0.0%, 89.2 +/- 3.2%, and 60.1 +/- 5.0% for DPA, FDMA, and TWA, respectively. Among the 158 feet, 90 were Gilbert type I (57.0%), 52 were Gilbert type II (32.9%), 13 were Gilbert type III (8.2%), and 3 were with poor visibility and could not be classified (1.9%). In all 79 patients, the CTA image of the FDMA was consistent with the intraoperative observations. All reconstructed fingers survived. Follow-up was available for 69 patients. After a 6- to 18-month follow-up, the reconstructed fingers and donor area recovered well, and the reconstructed fingers had strong holding power, without pain. Conclusion CTA can produce three-dimensional images for extremity arteries, allowing the preoperative assessment of blood supply and planning of donor site. C1 [Xu, Lin; Yang, Keqin; Wei, Pingou; Luo, Xiang; Mo, Yongjun; Liang, Xuquan; Lin, Han; Tan, Haitao] Guigang City Peoples Hosp, Dept Hand & Foot Microsurg, Guigang 537100, Guangxi, Peoples R China. [Mudgal, Chaitanya S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Tan, HT (reprint author), Guigang City Peoples Hosp, Dept Hand & Foot Microsurg, Guigang 537100, Guangxi, Peoples R China.; Mudgal, CS (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. EM tanhaitao99@hotmail.com FU Guangxi Department of Science and Technology [1298003-5-5] FX This study was funded by the Guangxi Department of Science and Technology commissioned the research study "The research of digital medical technology assisted toe reconstruction to reconstruct thumb and finger" (Grant no.1298003-5-5). NR 23 TC 0 Z9 0 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X EI 1098-8947 J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD NOV PY 2016 VL 32 IS 9 BP 675 EP 682 DI 10.1055/s-0036-1585464 PG 8 WC Surgery SC Surgery GA DZ2SE UT WOS:000385690700006 PM 27454181 ER PT J AU Williams, EC Young, JP Achtmeyer, CE Hendershot, CS AF Williams, Emily C. Young, Jessica P. Achtmeyer, Carol E. Hendershot, Christian S. TI Primary Care Providers' Interest in Using a Genetic Test to Guide Alcohol Use Disorder Treatment SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Pharmacogenetics; Alcohol use disorders; Alcohol use; Qualitative ID CENTERED MEDICAL HOME; HEALTH-CARE; NALTREXONE RESPONSE; SMOKING-CESSATION; CLINICAL-PRACTICE; GENOMIC MEDICINE; EVIDENCE DILEMMA; HEAVY DRINKING; PUBLIC-HEALTH; UNITED-STATES AB Background: Efforts to identify genetic moderators of pharmacotherapy response have generated interest in clinical applications of pharmacogenetic tests in alcohol use disorder (AUD) treatment. To date, no research on providers' interest in using pharmacogenetic tests in the context of AUD treatment has been reported. We conducted qualitative interviews with primary care providers from 5 clinics in the Veterans Health Administration (VA) to assess their interest in using a hypothetical genetic test to inform treatment of AUD with pharmacotherapy. Methods: Key contacts were used to recruit 24 providers from 5 primary care clinics associated with a single large VA medical facility. Participants completed 30-minute in-person semi-structured interviews focused on barriers and facilitators to provision of pharmacotherapy for AUD. Interviews included a hypothetical scenario regarding the availability of a genetic test to inform AUD pharmacotherapy provision and/or selection. Provider responses to the hypothetical scenario were recorded, transcribed and analyzed qualitatively using inductive content analysis. Data were independently coded by three investigators, and themes were identified via consensus. Results: Participants were generally interested in a genetic test to aid in AUD treatment planning. Five common themes were identified, including: perceived benefits of a pharmacogenetic test (e.g., aiding with therapeutic choice, positively impacting patient motivation for and engagement with AUD treatment), perceived drawbacks (e.g., limiting potential benefits of pharmacotherapy by reducing the target population for its receipt, adverse impacts of "negative" results), caveats to clinical utility (e.g., utility would depend on prognostic accuracy and/or medication characteristics), uncertainty as to whether such a test would impact clinical decision-making, and pragmatic barriers to use (costs and other resources, such as laboratory facilities). Conclusions: Primary care providers in this study generally believed a genetic test to aid in AUD treatment planning would be useful, due to its potential to hone treatment choice as well as to influence patient motivation and adherence to treatment. However, providers acknowledged that a test's utility would depend on the strength of its prognostic characteristics, its other benefits relative to standard care, and lack of pragmatic barriers. Published by Elsevier Inc. C1 [Williams, Emily C.; Young, Jessica P.; Achtmeyer, Carol E.] Vet Affairs VA Puget Sound Hlth Care Syst, HSR&D, Ctr Innovat Vet Ctr Value Driven Care, 1660 S Columbian Way,S-152, Seattle, WA 98108 USA. [Williams, Emily C.] Univ Washington, Dept Hlth Serv, Boxes 357,660,1959 NE Pacific St, Seattle, WA 98195 USA. [Achtmeyer, Carol E.] Vet Affairs VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle Div, 1660 S Columbian Way, Seattle, WA 98108 USA. [Hendershot, Christian S.] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, 100 Stokes St,Bell Gateway Bldg, Toronto, ON M6J 1H4, Canada. [Hendershot, Christian S.] Univ Toronto, Dept Psychiat, 250 Coll St, Toronto, ON M5T 1R8, Canada. [Hendershot, Christian S.] Univ Toronto, Dept Psychol, 100 St George St,4th Floor, Toronto, ON M5S 3G3, Canada. RP Williams, EC (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-152, Seattle, WA 98108 USA. EM Emily.Williams3@va.gov; Jessica.Young@va.gov; Carol.Achtmeyer@va.gov; christian.hendershot@utoronto.ca FU VA Health Services Research Development; VA Quality Enhancement Research Initiative [RRP 12-528]; Career Development Award from VA Health Services Research Development [CDA 12-276]; Canadian Institutes of Health Research [MSH-130189]; Ontario Mental Health Foundation; Canada Research Chairs program FX The authors gratefully acknowledge the participants of this study for generously allowing us to solicit and report on their perspectives. The parent study for this project was funded by VA Health Services Research & Development and VA Quality Enhancement Research Initiative (RRP 12-528). Dr. Williams is supported by a Career Development Award from VA Health Services Research & Development (CDA 12-276). Dr. Hendershot is supported by the Canadian Institutes of Health Research (MSH-130189), the Ontario Mental Health Foundation, and the Canada Research Chairs program. NR 71 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD NOV PY 2016 VL 70 BP 14 EP 20 DI 10.1016/j.jsat.2016.07.009 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DY7UX UT WOS:000385335900003 PM 27692183 ER PT J AU Ismail, AM Lee, JS Dyer, DW Seto, D Rajaiya, J Chodosh, J AF Ismail, Ashrafali M. Lee, Ji Sun Dyer, David W. Seto, Donald Rajaiya, Jaya Chodosh, James TI Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis SO JOURNAL OF VIROLOGY LA English DT Article ID MOLECULAR EVOLUTION; STRUCTURAL-ANALYSIS; BINDING-SITES; AMINO-ACID; RECEPTOR; PROTEIN; CD46; RECOMBINATION; INFECTION; TROPISM AB Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. C1 [Ismail, Ashrafali M.; Lee, Ji Sun; Rajaiya, Jaya; Chodosh, James] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Howe Lab, Boston, MA 02115 USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Seto, Donald] George Mason Univ, Sch Syst Biol, Bioinformat & Computat Biol Program, Manassas, VA USA. RP Rajaiya, J; Chodosh, J (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Howe Lab, Boston, MA 02115 USA. EM jaya_rajaiya@meei.harvard.edu; james_chodosh@meei.harvard.edu OI Ashrafali, Mohamed Ismail/0000-0001-8694-7235 FU Research to Prevent Blindness (RPB); HHS \ NIH \ National Eye Institute (NEI) [EY013124, EY021558, EY014104]; Falk Foundation; Massachusetts Lions Eye Research Fund (MLERF) FX This work, including the efforts of James Chodosh, was funded by Research to Prevent Blindness (RPB). This work, including the efforts of Jaya Rajaiya and James Chodosh, was funded by HHS vertical bar NIH vertical bar National Eye Institute (NEI) (EY013124, EY021558, and EY014104). This work, including the efforts of James Chodosh, was funded by Falk Foundation. This work, including the efforts of Jaya Rajaiya and James Chodosh, was funded by Massachusetts Lions Eye Research Fund (MLERF). NR 62 TC 0 Z9 0 U1 7 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2016 VL 90 IS 21 BP 9598 EP 9607 DI 10.1128/JVI.01010-16 PG 10 WC Virology SC Virology GA DZ0JW UT WOS:000385525700004 PM 27512073 ER PT J AU Stroopinsky, D Kufe, D Avigan, D AF Stroopinsky, Dina Kufe, Donald Avigan, David TI MUC1 in hematological malignancies SO LEUKEMIA & LYMPHOMA LA English DT Review DE AML; MUC1; multiple myeloma; ROS ID BREAST-CANCER CELLS; CARCINOMA-ASSOCIATED ANTIGEN; CHRONIC MYELOGENOUS LEUKEMIA; MULTIPLE-MYELOMA PATIENTS; DOWN-REGULATING TIGAR; BETA-CATENIN; C-SRC; TERMINAL DIFFERENTIATION; TRANSCRIPTION FACTOR; SUBUNIT ONCOPROTEIN AB Mucin1 (MUC1) is a transmembrane oncogenic protein that plays a central role in malignant transformation and disease evolution, including cell proliferation, survival, self-renewal, and metastatic invasion. MUC1 has been shown to interact with diverse effectors such as B-catenin, receptor tyrosine kinases, and c-Abl, which are of importance in the pathogenesis of various hematological malignancies. In myeloid leukemia, MUC1 has been shown to have an essential role in leukemia stem-cell function, the induction of reactive oxygen species (ROS), and the promotion of terminal myeloid differentiation. As such, MUC1 is an attractive therapeutic target in hematologic malignancies. Targeting MUC1 has been shown to be an effective approach for inducing cell death in tumor in in vivo and in vitro models. Furthermore, MUC1 inhibition is synergistic with other therapeutic agents in the treatment of hematologic disorders. This review will explore the role of MUC1 in hematological malignancies, and strategies for targeting this oncoprotein. C1 [Stroopinsky, Dina; Avigan, David] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Kufe, Donald] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Stroopinsky, D (reprint author), Beth Israel Deaconess Med Ctr, Med, 330 Brookline Ave, Boston, MA 02215 USA. EM dstroopi@bidmc.harvard.edu NR 77 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2016 VL 57 IS 11 BP 2489 EP 2498 DI 10.1080/10428194.2016.1195500 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA DY7QM UT WOS:000385324400003 PM 27347699 ER PT J AU Castillo, JJ Ghobrial, IM Treon, SP AF Castillo, Jorge J. Ghobrial, Irene M. Treon, Steven P. TI Response to ibrutinib in a patient with IgG lymphoplasmacytic lymphoma carrying the MYD88 L265P gene mutation SO LEUKEMIA & LYMPHOMA LA English DT Letter ID WALDENSTROMS MACROGLOBULINEMIA C1 [Castillo, Jorge J.; Ghobrial, Irene M.; Treon, Steven P.] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. RP Castillo, JJ (reprint author), Dana Farber Canc Inst, Hematol Malignancies, 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 NR 11 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2016 VL 57 IS 11 BP 2699 EP 2701 DI 10.3109/10428194.2016.1157875 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA DY7QM UT WOS:000385324400032 PM 26980069 ER PT J AU Chhatwal, J Jayasuriya, S Elbasha, EH AF Chhatwal, Jagpreet Jayasuriya, Suren Elbasha, Elamin H. TI Changing Cycle Lengths in State-Transition Models: Challenges and Solutions SO MEDICAL DECISION MAKING LA English DT Article DE global health; cost-effectiveness analysis; Markov models; mathematical models; decision analysis ID MEDICAL DECISION-MAKING; COST-EFFECTIVENESS; MARKOV-MODELS; UNITED-STATES; PROBABILITIES; INFECTION; CIRRHOSIS; CANCER; CHAIN; RATES AB The choice of a cycle length in state-transition models should be determined by the frequency of clinical events and interventions. Sometimes there is need to decrease the cycle length of an existing state-transition model to reduce error in outcomes resulting from discretization of the underlying continuous-time phenomena or to increase the cycle length to gain computational efficiency. Cycle length conversion is also frequently required if a new state-transition model is built using observational data that have a different measurement interval than the model's cycle length. We show that a commonly used method of converting transition probabilities to different cycle lengths is incorrect and can provide imprecise estimates of model outcomes. We present an accurate approach that is based on finding the root of a transition probability matrix using eigendecomposition. We present underlying mathematical challenges of converting cycle length in state-transition models and provide numerical approximation methods when the eigendecomposition method fails. Several examples and analytical proofs show that our approach is more general and leads to more accurate estimates of model outcomes than the commonly used approach. MATLAB codes and a user-friendly online toolkit are made available for the implementation of the proposed methods. C1 [Chhatwal, Jagpreet] Harvard Med Sch, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA USA. [Jayasuriya, Suren] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY USA. [Elbasha, Elamin H.] Merck & Co Inc, Merck Res Labs, N Wales, PA USA. RP Chhatwal, J (reprint author), MGH Inst Technol Assessment, 101 Merrimac St,Floor 10th, Boston, MA 02114 USA. EM JagChhatwal@mgh.harvard.edu FU National Center for Advancing Translational Sciences of the National Institutes of Health [KL2TR000146]; National Institute of General Medical Sciences (MIDAS Grant) [5U54GM088491] FX Received 14 March 2015 from Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA (JC); School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA (SJ); and Merck Research Laboratories, Merck & Co., North Wales, PA, USA (EHE). JC and SJ contributed equally to the manuscript. Part of this research was presented at the 33rd and 35th Annual Meetings of the Society for Medical Decision Making. This research was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (award number KL2TR000146) and the National Institute of General Medical Sciences (MIDAS Grant 5U54GM088491). Revision accepted for publication 9 May 2016. NR 27 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD NOV PY 2016 VL 36 IS 8 BP 952 EP 964 DI 10.1177/0272989X16656165 PG 13 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DZ0AS UT WOS:000385499700003 PM 27369084 ER PT J AU Godoy, IRB Martinez-Salazar, EL Eajazi, A Genta, PR Bredella, MA Torriani, M AF Godoy, Ivan R. B. Martinez-Salazar, Edgar Leonardo Eajazi, Alireza Genta, Pedro R. Bredella, Miriam A. Torriani, Martin TI Fat accumulation in the tongue is associated with male gender, abnormal upper airway patency and whole-body adiposity SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Tongue fat; Obesity; Metabolic syndrome; Body composition ID OBSTRUCTIVE SLEEP-APNEA; METABOLIC SYNDROME; SOFT-TISSUE; INSULIN-RESISTANCE; LIPID-CONTENT; WEIGHT-LOSS; OBESITY; MEN; COLLAPSIBILITY; POPULATION AB Objective. To examine associations between tongue adiposity with upper airway measures, whole-body adiposity and gender. We hypothesized that increased tongue adiposity is higher in males and positively associated with abnormal upper airway measures and whole-body adiposity. Methods. We studied subjects who underwent whole-body positron emission tomography/computed tomography to obtain tongue attenuation (TA) values and cross-sectional area, pharyngeal length (PL) and mandibular plane to hyoid distance (MPH), as well as abdominal circumference, abdominal subcutaneous and visceral (VAT) adipose tissue areas, neck circumference (NC) and neck adipose tissue area. Metabolic syndrome was determined from available clinical and laboratory data. Results. We identified 206 patients (104 females, 102 males) with mean age 56 17 years and mean body mass index (BMI) 28 6 kg/m(2) (range 16-47 kg/m(2)). Males had lower TA values (P = 0.0002) and higher upper airway measures (P < 0.0001) independent of age and BMI (P < 0.001). In all subjects, TA was negatively associated with upper airway measures (P < 0.001). TA was negatively associated with body composition parameters (all P < 0.0001), most notably with VAT (r = -0.53) and NC (r = -0.47). TA values were lower in subjects with metabolic syndrome (P < 0.0001). Conclusion. Increased tongue adiposity is influenced by gender and is associated with abnormal upper airway patency and body composition parameters. (C) 2016 Elsevier Inc. All rights reserved. C1 [Godoy, Ivan R. B.; Martinez-Salazar, Edgar Leonardo; Eajazi, Alireza; Bredella, Miriam A.; Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. [Godoy, Ivan R. B.; Martinez-Salazar, Edgar Leonardo; Eajazi, Alireza; Bredella, Miriam A.; Torriani, Martin] Harvard Med Sch, Boston, MA USA. [Genta, Pedro R.] Univ Sao Paulo, Sch Med, Div Pulm, Heart Inst InCor,Hosp Clin, Sao Paulo, SP, Brazil. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@mgh.harvard.edu FU NIDDK NIH HHS [P30 DK040561] NR 33 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD NOV PY 2016 VL 65 IS 11 BP 1657 EP 1663 DI 10.1016/j.metabol.2016.08.008 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DZ6TB UT WOS:000385993700009 PM 27733254 ER PT J AU Yang, T Massa, SM Tran, KC Simmons, DA Rajadas, J Zeng, AY Jang, TC Carsanaro, S Longo, FM AF Yang, Tao Massa, Stephen M. Tran, Kevin C. Simmons, Danielle A. Rajadas, Jayakumar Zeng, Anne Y. Jang, Taichang Carsanaro, Sara Longo, Frank M. TI A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth SO NEUROPHARMACOLOGY LA English DT Article DE Neurotrophin receptors; Small molecule; Signaling ID NERVE GROWTH-FACTOR; TYROSINE-PHOSPHATASE RECEPTOR; PROTEIN-KINASE INHIBITION; SIGNALING PATHWAYS; NEURITE OUTGROWTH; RETT-SYNDROME; MOUSE MODEL; TRKB; LIGAND; AGONIST AB Neurotrophin (NT) receptors are coupled to numerous signaling networks that play critical roles in neuronal survival and plasticity. Several non-peptide small molecule ligands have recently been reported that bind to and activate specific tropomyosin-receptor kinase (Trk) NT receptors, stimulate their downstream signaling, and cause biologic effects similar to, though not completely overlapping, those of the native NT ligands. Here, in silico screening, coupled with low-throughput neuronal survival screening, identified a compound, LM22B-10, that, unlike prior small molecule Trk ligands, binds to and activates TrkB as well as TrkC. LM22B-10 increased cell survival and strongly accelerated neurite outgrowth, superseding the effects of brain-derived neurotrophic factor (BDNF), NT-3 or the two combined. Additionally, unlike the NTs, LM22B-10 supported substantial early neurite outgrowth in the presence of inhibiting glycoproteins. Examination of the mechanisms of these actions suggested contributions of the activation of both Trks and differential interactions with p75(NTR), as well as a requirement for involvement of the Trk extracellular domain. In aged mice, LM22B-10 activated hippocampal and striatal TrkB and TrkC, and their downstream signaling, and increased hippocampal dendritic spine density. Thus, LM22B-10 may constitute a new tool for the study of TrkB and TrkC signaling and their interactions with p75(NTR), and provides groundwork for the development of ligands that stimulate unique combinations of Trk receptors and activity patterns for application to selected neuronal populations and deficits present in various disease states. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Yang, Tao; Tran, Kevin C.; Simmons, Danielle A.; Rajadas, Jayakumar; Zeng, Anne Y.; Jang, Taichang; Carsanaro, Sara; Longo, Frank M.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, 300 Pasteur Dr,Room H3160, Stanford, CA 94305 USA. [Massa, Stephen M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Massa, Stephen M.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Lab Computat Neurochem & Drug Discovery, San Francisco, CA 94121 USA. RP Longo, FM (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, 300 Pasteur Dr,Room H3160, Stanford, CA 94305 USA.; Massa, SM (reprint author), San Francisco Vet Affairs Healthcare Syst, Dept Neurol, 4150 Clement St, San Francisco, CA 94121 USA.; Massa, SM (reprint author), Univ Calif San Francisco, 4150 Clement St, San Francisco, CA 94121 USA. EM stephen.massa@ucsf.edu; longo@stanford.edu FU Institute for the Study on Aging/Alzheimer's Drug Discovery Foundation; Eastern Chapter of the North Carolina Alzheimer's Association; Jean Perkins Foundation; Horngren Family; Department of Defense (DOD) [DAMD17-03-1-0532]; Veterans Administration, Merit Review Award [BX000267] FX These studies were supported by the Institute for the Study on Aging/Alzheimer's Drug Discovery Foundation (FML), the Eastern Chapter of the North Carolina Alzheimer's Association (FML), the Jean Perkins Foundation (FML), the Horngren Family (FML), the Department of Defense (DOD DAMD17-03-1-0532) (SMM) and the Veterans Administration, Merit Review Award (BX000267) (SMM). NR 72 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD NOV PY 2016 VL 110 BP 343 EP 361 DI 10.1016/j.neuropharm.2016.06.015 PN A PG 19 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DY7OF UT WOS:000385318100034 PM 27334657 ER PT J AU Poynter, ST Kadoch, C AF Poynter, Steven T. Kadoch, Cigall TI Polycomb and trithorax opposition in development and disease SO WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY LA English DT Review ID CHROMATIN REMODELING COMPLEX; ANTENNAPEDIA GENE-COMPLEX; TUMOR-SUPPRESSOR GENE; EXTRA-SEX-COMBS; LYSINE-4 METHYLTRANSFERASE COMPLEX; NICOLAIDES-BARAITSER SYNDROME; ADJACENT CHROMOSOMAL REGIONS; IDENTIFIES FREQUENT MUTATION; MAMMALIAN SWI/SNF COMPLEXES; DOSAGE-DEPENDENT MODIFIERS AB Early discoveries in chromatin biology and epigenetics heralded new insights into organismal development. From these studies, two mediators of cellular differentiation were discovered: the Polycomb group (PcG) of transcriptional repressors, and the trithorax group (trxG) of transcriptional activators. These protein families, while opposed in function, work together to coordinate the appropriate cellular developmental programs that allow for both embryonic stem cell self-renewal and differentiation. Recently, both the PcG and trxG chromatin modulators have been observed to be deregulated in a wide spectrum diseases including developmental disorders and cancer. To understand the impact of these findings we outline the past, present, and future. (C) 2016 Wiley Periodicals, Inc. C1 [Poynter, Steven T.] Harvard Med Sch, Chem Biol Program, Boston, MA USA. [Poynter, Steven T.; Kadoch, Cigall] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Poynter, Steven T.; Kadoch, Cigall] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Kadoch, C (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Kadoch, C (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM cigall_kadoch@dfci.harvard.edu NR 242 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7684 EI 1759-7692 J9 WIRES DEV BIOL JI Wiley Interdiscip. Rev.-Dev. Biol. PD NOV-DEC PY 2016 VL 5 IS 6 BP 659 EP 688 DI 10.1002/wdev.244 PG 30 WC Developmental Biology SC Developmental Biology GA DZ0JI UT WOS:000385524200002 PM 27581385 ER PT J AU Mnatzakanian, GN Shinagare, AB Sahni, VA Hirsch, MS Silverman, SG AF Mnatzakanian, Gevork N. Shinagare, Atul B. Sahni, V. Anik Hirsch, Michelle S. Silverman, Stuart G. TI Early-stage clear cell tubulopapillary renal cell carcinoma: imaging features and distinction from clear cell and papillary subtypes SO ABDOMINAL RADIOLOGY LA English DT Article DE Clear cell tubulopapillary renal cell carcinoma; Renal cell carcinoma subtype; Renal mass; CT and MRI features ID CT; DIFFERENTIATION; EMPHASIS; TUMOR; ONCOCYTOMA; MANAGEMENT; NEOPLASIA; PATHOLOGY; DISEASE; ENTITY AB Clear cell tubulopapillary renal cell carcinoma (CCTPRCC) is a recently described, low-grade subtype of renal cancer. We determined if imaging features could be used to distinguish early-stage CCTPRCC from stage-matched clear cell RCC (ccRCC) and papillary RCC (pRCC). This IRB-approved retrospective study included 54 stage T1a patients with pathologically confirmed CCTPRCC (n = 18), ccRCC (n = 18), and pRCC (n = 18). CT (n = 48) and MRI (n = 27) exams were reviewed and imaging features compared. Continuous variables were evaluated using ANOVA and Tukey's multiple comparison tests. Categorical variables were compared using Chi-square test or Fisher's exact test. Compared to pRCC, CCTPRCC had a lower mean attenuation value on unenhanced CT (p < 0.017), was more often hyperintense on T2-weighted images (p < 0.0001), showed an ill-defined margin (p = 0.003), and demonstrated nonenhancing areas (p = 0.0003). The presence of all three of these statistically significant features [hypoattenuation (unenhanced attenuation aecurrency sign25 HU), ill-defined margin, nonenhancing areas] yielded an area under the receiver operator curve (ROC) of 0.92 (95% CI 0.83-0.99) for differentiating CCTPRCC from pRCC. There were no significant differences in the imaging features of CCTPRCC and ccRCC. Early-stage clear cell tubulopapillary renal cell carcinoma can be distinguished from papillary RCC based on low attenuation on unenhanced CT, high intensity on T2-weighted images, an ill-defined margin, and presence of nonenhancing areas, but cannot be distinguished from clear cell RCC. C1 [Mnatzakanian, Gevork N.; Shinagare, Atul B.; Sahni, V. Anik; Silverman, Stuart G.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Mnatzakanian, Gevork N.] St Michaels Hosp, Dept Med Imaging, 3-141CC,30 Bond St, Toronto, ON M5B 1W8, Canada. [Shinagare, Atul B.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Amory 3, Boston, MA 02115 USA. RP Mnatzakanian, GN (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA.; Mnatzakanian, GN (reprint author), St Michaels Hosp, Dept Med Imaging, 3-141CC,30 Bond St, Toronto, ON M5B 1W8, Canada. EM mnatzakanian@smh.ca NR 28 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD NOV PY 2016 VL 41 IS 11 BP 2187 EP 2195 DI 10.1007/s00261-016-0830-8 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY5ZE UT WOS:000385183500013 PM 27383741 ER PT J AU Diaz-Gil, D Fintelmann, FJ Molaei, S Elmi, A Hedgire, SS Harisinghani, MG AF Diaz-Gil, Daniel Fintelmann, Florian J. Molaei, Sanaz Elmi, Azadeh Hedgire, Sandeep S. Harisinghani, Mukesh G. TI Prediction of 5-year survival in advanced-stage ovarian cancer patients based on computed tomography peritoneal carcinomatosis index SO ABDOMINAL RADIOLOGY LA English DT Article DE Ovarian cancer; Peritoneal disease; CA-125 antigen; Computed tomography; Neoadjuvant therapy; Prognosis ID INTRAPERITONEAL CHEMOTHERAPY; ENHANCED CT; CA 125; PET/CT; SURGERY; CA-125 AB To evaluate whether the quantification of peritoneal metastases in advanced-stage ovarian cancer patients using the peritoneal carcinomatosis index, detected by CT (CT-PCI), correlates with the serum levels of tumor marker CA-125 and 5-year survival. The CT-PCI was determined in 82 patients with stage III or stage IV ovarian cancer using the Sugarbaker classification prior to cytoreductive surgery. Linear regression analysis was used to correlate CT-PCI and CA-125 levels. Correlation of presurgical CT-PCI, optimal surgical cytoreduction, and 5-year survival was established using binary logistic regression analysis. A score for prediction of 5-year survival probability was established using multivariate backwards binary logistic regression. Presurgical CT-PCI correlates significantly with presurgical CA-125 serum levels (r = 0.487, P < 0.001). Multivariate binary logistic regression suggested significantly improved 5-year survival with lower CT-PCI and lower ECOG performance scores. CT-PCI allows quantification of peritoneal disease in advanced-stage ovarian cancer patients, similar to CA-125. CT-PCI in combination with ECOG performance has the potential to help evaluate the 5-year survival probability. C1 [Diaz-Gil, Daniel; Fintelmann, Florian J.; Molaei, Sanaz; Elmi, Azadeh; Hedgire, Sandeep S.; Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. RP Diaz-Gil, D (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM diazgil.daniel@gmail.com NR 26 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD NOV PY 2016 VL 41 IS 11 BP 2196 EP 2202 DI 10.1007/s00261-016-0817-5 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY5ZE UT WOS:000385183500014 PM 27338731 ER PT J AU Tanabe, K AF Tanabe, Kenneth TI What's New in Gastric and Esophageal Cancers SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material C1 [Tanabe, Kenneth] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Tanabe, Kenneth] Harvard Med Sch, Boston, MA 02115 USA. RP Tanabe, K (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA.; Tanabe, K (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM ktanabe@partners.org NR 5 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2016 VL 23 IS 12 BP 3773 EP 3773 DI 10.1245/s10434-016-5430-x PG 1 WC Oncology; Surgery SC Oncology; Surgery GA DY5QJ UT WOS:000385155900001 PM 27638669 ER PT J AU Mullen, JT Kwak, EL Hong, TS AF Mullen, John T. Kwak, Eunice L. Hong, Theodore S. TI What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID GASTROESOPHAGEAL JUNCTION; ESOPHAGOGASTRIC JUNCTION; PREOPERATIVE CHEMORADIOTHERAPY; PATHOLOGICAL RESPONSE; STAGING SYSTEM; ADENOCARCINOMA; CLASSIFICATION; ESOPHAGEAL; THERAPY; CARDIA AB The debate as to the optimal classification, staging, and treatment of gastroesophageal junction (GEJ) tumors wages on, and one must acknowledge that there is no "one-size-fits-all" approach. However, in this review we are charged with defending the position that all GEJ tumors are best treated like gastric cancer. We submit that, as stated, this is not a defensible position and that a clear definition of terms is warranted. Given the rarity of squamous cell carcinoma and the dramatic rise in incidence of adenocarcinoma of the GEJ in the West, we define GEJ "tumors" to mean adenocarcinomas of the GEJ. Furthermore, on the basis of their location, pathogenesis, and biologic behavior, we submit that few would argue with the contention that Siewert type I GEJ tumors are best treated like distal esophageal cancer and that Siewert type III GEJ tumors are best treated like gastric cancer. The real debate concerns the management of Siewert type II GEJ tumors, which arise immediately at the esophagogastric junction. Thus, for the purposes of this review, we have taken the liberty of redefining the question as what's the best way to treat adenocarcinomas of the true GEJ (i.e., Siewert type II tumors), and we submit that these tumors are in fact best treated like gastric cancer. This approach ensures that patients receive those therapies needed for the locoregional and systemic control of their disease together with a surgical procedure that optimizes complete tumor and regional lymph node resection while limiting morbidity. C1 [Mullen, John T.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Mullen, John T.; Kwak, Eunice L.; Hong, Theodore S.] Harvard Med Sch, Boston, MA 02115 USA. [Kwak, Eunice L.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Mullen, JT (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA.; Mullen, JT (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jmullen@partners.org NR 28 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2016 VL 23 IS 12 BP 3780 EP 3785 DI 10.1245/s10434-016-5426-6 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA DY5QJ UT WOS:000385155900003 PM 27459983 ER PT J AU Warren, LEG Ligibel, JA Chen, YH Truong, L Catalano, PJ Bellon, JR AF Warren, Laura E. G. Ligibel, Jennifer A. Chen, Yu-Hui Linh Truong Catalano, Paul J. Bellon, Jennifer R. TI Body Mass Index and Locoregional Recurrence in Women with Early-Stage Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID RANDOMIZED-TRIAL; WEIGHT-LOSS; POSTMENOPAUSAL WOMEN; ENDOCRINE THERAPY; SURVIVAL; OBESITY; RISK; OVERWEIGHT; ESTROGEN; PREMENOPAUSAL AB Higher body mass index (BMI) has been associated with increased distant recurrence and decreased survival for women with breast cancer. However, the relationship between BMI and locoregional recurrence (LRR) has been less well studied and was therefore the subject of this investigation. The study identified 878 women with early-stage invasive breast cancer who underwent breast-conservation therapy (BCT) between June 1997 and October 2007. Time from diagnosis to LRR was calculated using a competing risk analysis with contralateral breast cancer (CBC), distant metastases (DM), and death as the competing risks. Gray's competing risks analysis, which included an interaction term between menopausal status and BMI, was used to identify significant risk factors for the development of LRR. After a median follow-up period of 10.8 years, LRR was diagnosed as a first event for 45 women. In a multivariable analysis, BMI was positively associated with LRR but only in premenopausal women. Specifically, when these women were compared with normal- and underweight women, both the overweight women (hazard ratio (HR), 2.97; 95 % confidence interval (CI) 1.04-8.46; p = 0.04) and the obese women (HR, 3.36; 95 % CI 1.07-10.63; p = 0.04) showed a higher risk of LRR. A similar association between BMI and disease-free survival was noted for premenopausal but not postmenopausal women. For premenopausal women with invasive breast cancer who undergo BCT, BMI is an independent prognostic factor for LRR. If confirmed, these findings suggest that more aggressive treatment strategies may be warranted for these women. C1 [Warren, Laura E. G.] Harvard Radiat Oncol Program, Boston, MA USA. [Ligibel, Jennifer A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chen, Yu-Hui] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Linh Truong; Bellon, Jennifer R.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Linh Truong; Bellon, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Bellon, JR (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; Bellon, JR (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jbellon@lroc.harvard.edu NR 42 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2016 VL 23 IS 12 BP 3870 EP 3879 DI 10.1245/s10434-016-5437-3 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA DY5QJ UT WOS:000385155900015 PM 27448118 ER PT J AU Amri, R England, J Bordeianou, LG Berger, DL AF Amri, Ramzi England, Jonathan Bordeianou, Liliana G. Berger, David L. TI Risk Stratification in Patients with Stage II Colon Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; SURVIVAL; CHEMOTHERAPY; OUTCOMES AB The decision to receive adjuvant chemotherapy is far from evident and remains controversial in patients with American Joint Committee on Cancer stage II colon cancer. This study analyzes several pathological characteristics in order to assess their (combined) predictive value for outcomes in stage II colon cancer. All stage II patients treated surgically for colon cancer at our tertiary care center (2004-2011) were extracted from a prospectively maintained, Institutional Review Board-approved data repository (n = 313). Mortality and metastasis were compared, including multivariable Cox regression adjusted for stage subdivisions (IIA/IIB/IIC) and potential confounders. Colon cancer-specific mortality was substage independently increased in patients with baseline carcinoembryonic antigen (CEA) > 5 ng/L [hazard ratio (HR) 2.88; p = 0.022], large vessel invasion (LVI; HR 4.59; p < 0.001), perineural invasion (HR 3.08; p = 0.006), and extramural vascular invasion (EMVI; HR 4.96; p < 0.001). Overall mortality adjusted for substage, age, and comorbidity was also significantly higher in patients with high-grade disease (HR 2.54; p < 0.001), LVI (HR 1.74; p = 0.015), perineural (HR 2.42; p < 0.001), and EMVI (HR 2.79; p < 0.001). Metastatic recurrence adjusted for adjuvant chemotherapy status had substage-independent associations with baseline CEA > 5 ng/L (HR 2.37; p = 0.046), LVI (HR 3.07; p = 0.001), perineural invasion (HR 2.57; p = 0.010), and EMVI (HR 2.83; p = 0.002). The number of high-risk features (0, 1, 2-3, 4+) was associated with a clear incremental increase in overall and disease-specific mortality and recurrence (p aecurrency sign 0.001). The major inflection point is at two high-risk characteristics or more, whereas 5-year survival is almost halved from 77.4 % to 31.7 % (p < 0.001). The risk score introduced provides a prognostic tool based on readily available data extracted from baseline pathology and preoperative CEA, which provides an easy method to stratify risks of mortality and recurrence and may therefore help in treatment decisions after surgery in stage II patients. C1 [Amri, Ramzi; Bordeianou, Liliana G.; Berger, David L.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Boston, MA 02115 USA. [England, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. RP Berger, DL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Boston, MA 02115 USA. EM dberger@partners.org NR 21 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2016 VL 23 IS 12 BP 3907 EP 3914 DI 10.1245/s10434-016-5387-9 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DY5QJ UT WOS:000385155900019 PM 27380640 ER PT J AU Carpenter, JS Jones, SMW Studts, CR Heiman, JR Reed, SD Newton, KM Guthrie, KA Larson, JC Cohen, LS Freeman, EW Lau, RJ Learman, LA Shifren, JL AF Carpenter, Janet S. Jones, Salene M. W. Studts, Christina R. Heiman, Julia R. Reed, Susan D. Newton, Katherine M. Guthrie, Katherine A. Larson, Joseph C. Cohen, Lee S. Freeman, Ellen W. Lau, R. Jane Learman, Lee A. Shifren, Jan L. TI Female Sexual Function Index Short Version: A MsFLASH Item Response Analysis SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Menopause; Psychometrics; Female Sexual Function Index ID RANDOMIZED-CONTROLLED-TRIAL; VASOMOTOR SYMPTOMS; MENOPAUSAL SYMPTOMS; WOMEN; VALIDATION; FSFI; EFFICACY; ESCITALOPRAM; VENLAFAXINE; POPULATION AB The Female Sexual Function Index (FSFI) is a psychometrically sound and popular 19-item self-report measure, but its length may preclude its use in studies with multiple outcome measures, especially when sexual function is not a primary endpoint. Only one attempt has been made to create a shorter scale, resulting in the Italian FSFI-6, later translated into Spanish and Korean without further psychometric analysis. Our study evaluated whether a subset of items on the 19-item English-language FSFI would perform as well as the full-length FSFI in peri- and postmenopausal women. We used baseline data from 898 peri- and postmenopausal women recruited from multiple communities, ages 42-62 years, and enrolled in randomized controlled trials for vasomotor symptom management. Goals were to (1) create a psychometrically sound, shorter version of the FSFI for use in peri- and postmenopausal women as a continuous measure and (2) compare it to the Italian FSFI-6. Results indicated that a 9-item scale provided more information than the FSFI-6 across a spectrum of sexual functioning, was able to capture sample variability, and showed sufficient range without floor or ceiling effects. All but one of the items from the Italian 6-item version were included in the 9-item version. Most omitted FSFI items focused on frequency of events or experiences. When assessment of sexual function is a secondary endpoint and subject burden related to questionnaire length is a priority, the 9-item FSFI may provide important information about sexual function in English-speaking peri- and postmenopausal women. C1 [Carpenter, Janet S.] Indiana Univ, Sch Nursing, Dept Sci Nursing Care, Indianapolis, IN 46204 USA. [Jones, Salene M. W.; Newton, Katherine M.] Grp Hlth Res Inst, Seattle, WA USA. [Studts, Christina R.] Univ Kentucky, Coll Publ Hlth, Dept Hlth Behav, Lexington, KY USA. [Heiman, Julia R.] Indiana Univ, Kinsey Inst, Psychol & Brain Sci, Bloomington, IN USA. [Reed, Susan D.] Univ Washington, Sch Med, Dept Obstet Gynecol, Seattle, WA USA. [Reed, Susan D.] Univ Washington, Sch Med, Dept Epidemiol, Seattle, WA USA. [Guthrie, Katherine A.; Larson, Joseph C.] Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Cohen, Lee S.] Massachusetts Gen Hosp, Ctr Womens Mental Hlth, Boston, MA 02114 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Obstet Gynecol, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Lau, R. Jane; Learman, Lee A.] Indiana Univ, Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Shifren, Jan L.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Carpenter, Janet S.] Indiana Univ, Sch Nursing, 600 Barnhill Dr NU 340G, Indianapolis, IN 46202 USA. RP Carpenter, JS (reprint author), Indiana Univ, Sch Nursing, Dept Sci Nursing Care, Indianapolis, IN 46204 USA.; Carpenter, JS (reprint author), Indiana Univ, Sch Nursing, 600 Barnhill Dr NU 340G, Indianapolis, IN 46202 USA. EM carpentj@iu.edu OI Carpenter, Janet/0000-0003-3988-8855 FU National Institutes of Health by National Institute on Aging (NIA); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Complementary and Alternative Medicine (NCCAM); Office of Research on Women's Health (ORWH); NIA [U01AG032656, U01AG032659, U01AG03 2669, U01AG032682, U01AG032699, U01AG032700]; Indiana Clinical and Translational Sciences Institute from NIH, National Center for Research Resources, Clinical and Translational Sciences Award [UL1RR02571] FX This study was funded by the National Institutes of Health as a cooperative agreement issued by the National Institute on Aging (NIA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM), the Office of Research on Women's Health (ORWH), and Grants U01AG032656, U01AG032659, U01AG03 2669, U01AG032682, U01AG032699, and U01AG032700 from the NIA. At Indiana University, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, Grant UL1RR02571 from the NIH, National Center for Research Resources, Clinical and Translational Sciences Award. NR 41 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD NOV PY 2016 VL 45 IS 8 BP 1897 EP 1905 DI 10.1007/s10508-016-0804-5 PG 9 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA DY5WM UT WOS:000385175100005 PM 27502350 ER PT J AU Gilpin, SE Charest, JM Ren, X Tapias, LF Wu, T Evangelista-Leite, D Mathisen, DJ Ott, HC AF Gilpin, Sarah E. Charest, Jonathan M. Ren, Xi Tapias, Luis F. Wu, Tong Evangelista-Leite, Daniele Mathisen, Douglas J. Ott, Harald C. TI Regenerative potential of human airway stem cells in lung epithelial engineering SO BIOMATERIALS LA English DT Article DE Lung tissue engineering; Regeneration; Epithelial repair; Extracellular matrix; Decellularization; Recellularization ID OBSTRUCTIVE PULMONARY-DISEASE; TRACHEAL BASAL-CELLS; IN-VITRO; PERFUSION DECELLULARIZATION; EXTRACELLULAR-MATRIX; BRONCHIAL EPITHELIUM; NATURES PLATFORM; CLINICAL-SCALE; ADULT LUNG; MULTIPOTENT AB Bio-engineered organs for transplantation may ultimately provide a personalized solution for end-stage organ failure, without the risk of rejection. Building upon the process of whole organ perfusion decellularization, we aimed to develop novel, translational methods for the recellularization and regeneration of transplantable lung constructs. We first isolated a proliferative KRT5+TP63+ basal epithelial stem cell population from human lung tissue and demonstrated expansion capacity in conventional 2D culture. We then repopulated acellular rat scaffolds in ex vivo whole organ culture and observed continued cell proliferation, in combination with primary pulmonary endothelial cells. To show clinical scalability, and to test the regenerative capacity of the basal cell population in a human context, we then recellularized and cultured isolated human lung scaffolds under biomimetic conditions. Analysis of the regenerated tissue constructs confirmed cell viability and sustained metabolic activity over 7 days of culture. Tissue analysis revealed extensive recellularization with organized tissue architecture and morphology, and preserved basal epithelial cell phenotype. The recellularized lung constructs displayed dynamic compliance and rudimentary gas exchange capacity. Our results underline the regenerative potential of patient-derived human airway stem cells in lung tissue engineering. We anticipate these advances to have clinically relevant implications for whole lung bioengineering and ex vivo organ repair. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Gilpin, Sarah E.; Charest, Jonathan M.; Ren, Xi; Tapias, Luis F.; Wu, Tong; Evangelista-Leite, Daniele; Mathisen, Douglas J.; Ott, Harald C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Gilpin, Sarah E.; Ren, Xi; Tapias, Luis F.; Wu, Tong; Mathisen, Douglas J.; Ott, Harald C.] Harvard Med Sch, Boston, MA USA. [Gilpin, Sarah E.; Charest, Jonathan M.; Ren, Xi; Tapias, Luis F.; Wu, Tong; Evangelista-Leite, Daniele; Ott, Harald C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Ott, HC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 185 Cambridge St,CPZN 4812, Boston, MA 02114 USA. FU National Institutes of Health Director's New Innovator Award [DP2-OD008749-01]; NHLBI [R01 HL108678]; United Therapeutics Inc. FX This study was supported by the National Institutes of Health Director's New Innovator Award (DP2-OD008749-01), the NHLBI R01 HL108678, and by the United Therapeutics Inc. NR 52 TC 0 Z9 0 U1 33 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2016 VL 108 BP 111 EP 119 DI 10.1016/j.biomaterials.2016.08.055 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DY1MW UT WOS:000384860100009 PM 27622532 ER PT J AU Sun, LM Ahlfors, SP Hinrichs, H AF Sun, Limin Ahlfors, Seppo P. Hinrichs, Hermann TI Removing Cardiac Artefacts in Magnetoencephalography with Resampled Moving Average Subtraction SO BRAIN TOPOGRAPHY LA English DT Article DE Cardiac artefact; Moving average subtraction; Resampling; MEG ID INDEPENDENT COMPONENT ANALYSIS; SIMULTANEOUS EEG-FMRI; FUNCTIONAL MRI; MEG; BRAIN; IDENTIFICATION; ACQUISITION; ALGORITHMS; REJECTION AB Magnetoencephalography (MEG) signals are commonly contaminated by cardiac artefacts (CAs). Principle component analysis and independent component analysis have been widely used for removing CAs, but they typically require a complex procedure for the identification of CA-related components. We propose a simple and efficient method, resampled moving average subtraction (RMAS), to remove CAs from MEG data. Based on an electrocardiogram (ECG) channel, a template for each cardiac cycle was estimated by a weighted average of epochs of MEG data over consecutive cardiac cycles, combined with a resampling technique for accurate alignment of the time waveforms. The template was subtracted from the corresponding epoch of the MEG data. The resampling reduced distortions due to asynchrony between the cardiac cycle and the MEG sampling times. The RMAS method successfully suppressed CAs while preserving both event-related responses and high-frequency (> 45 Hz) components in the MEG data. C1 [Sun, Limin; Ahlfors, Seppo P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sun, Limin] Harvard Med Sch, Boston Childrens Hosp, Div Newborn Med, Dept Med, Boston, MA 02115 USA. [Hinrichs, Hermann] Otto Von Guericke Univ, Dept Neurol, Leipziger Str 44, D-39120 Magdeburg, Germany. [Hinrichs, Hermann] LIN, Dept Behav Neurol, Magdeburg, Germany. [Hinrichs, Hermann] DZNE, Magdeburg, Germany. [Hinrichs, Hermann] Forsch Campus STIMULATE, Magdeburg, Germany. RP Sun, LM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Sun, LM (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Newborn Med, Dept Med, Boston, MA 02115 USA. EM liminsun@nmr.mgh.harvard.edu OI Sun, Limin/0000-0002-2004-0777 FU National Institutes of Health [NS037462]; National Center for Research Resources [P41RR14075] FX Experimental data were collected while Dr. -Ing. Sun worked in Max Planck Institute for brain research, Frankfurt am Main, Germany. This work was supported in part by the National Institutes of Health Grant NS037462 and by The National Center for Research Resources (P41RR14075). NR 36 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 EI 1573-6792 J9 BRAIN TOPOGR JI Brain Topogr. PD NOV PY 2016 VL 29 IS 6 BP 783 EP 790 DI 10.1007/s10548-016-0513-3 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY5RU UT WOS:000385160600001 PM 27503196 ER PT J AU Scaccianoce, E Lagana, MM Baglio, F Preti, MG Bergsland, N Cecconi, P Clerici, M Baselli, G Papadimitriou, G Makris, N AF Scaccianoce, Elisa Lagana, Maria Marcella Baglio, Francesca Preti, Maria Giulia Bergsland, Niels Cecconi, Pietro Clerici, Mario Baselli, Giuseppe Papadimitriou, George Makris, Nikos TI Combined DTI-fMRI Analysis for a Quantitative Assessment of Connections Between WM Bundles and Their Peripheral Cortical Fields in Verbal Fluency SO BRAIN TOPOGRAPHY LA English DT Article DE Diffusion tensor imaging (DTI); Functional magnetic resonance imaging (fMRI); Mapping brain connectivity; Language; Multimodal imaging ID STATE FUNCTIONAL CONNECTIVITY; INFERIOR FRONTAL-CORTEX; TRAUMATIC BRAIN-INJURY; STRUCTURAL CONNECTIVITY; IMAGING TRACTOGRAPHY; DEFAULT MODE; REGISTRATION; PATHWAYS; NETWORK; STROKE AB Diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) are powerful techniques to elucidate the anatomical and functional aspects of brain connectivity. However, integrating these approaches to describe the precise link between structure and function within specific brain circuits remains challenging. In this study, a novel DTI-fMRI integration method is proposed, to provide the topographical characterization and the volumetric assessment of the functional and anatomical connections within the language circuit. In a group of 21 healthy elderly subjects (mean age 68.5 +/- 5.8 years), the volume of connection between the cortical activity elicited by a verbal fluency task and the cortico-cortical fiber tracts associated with this function are mapped and quantified. An application of the method to a case study in neuro-rehabilitation context is also presented. Integrating structural and functional data within the same framework, this approach provides an overall view of white and gray matter when studying specific brain circuits. C1 [Scaccianoce, Elisa; Lagana, Maria Marcella; Baglio, Francesca; Bergsland, Niels; Cecconi, Pietro; Clerici, Mario] IRCCS S Maria Nascente, Magnet Resonance Lab, Fdn Don Carlo Gnocchi ONLUS, Via Capecelatro 66, I-20148 Milan, Italy. [Scaccianoce, Elisa; Bergsland, Niels; Baselli, Giuseppe] Politecn Milan, Dept Elect Informat & Bioengn, I-20133 Milan, Italy. [Preti, Maria Giulia] Ecole Polytech Fed Lausanne, Inst Bioengn, CH-1015 Lausanne, Switzerland. [Preti, Maria Giulia] Univ Geneva, Dept Radiol & Med Informat, CH-1211 Geneva, Switzerland. [Bergsland, Niels] SUNY Buffalo, Buffalo Neuroimaging Anal Ctr, Sch Med & Biomed Sci, Dept Neurol, Buffalo, NY USA. [Clerici, Mario] Univ Milan, I-20122 Milan, Italy. [Papadimitriou, George; Makris, Nikos] Harvard Med Sch, A Martinos Ctr Biomed Imaging, Dept Psychiat Neurol & Radiol Serv, Massachusetts Gen Hosp,Ctr Morphometr Anal, Boston, MA 02129 USA. RP Scaccianoce, E; Lagana, MM (reprint author), IRCCS S Maria Nascente, Magnet Resonance Lab, Fdn Don Carlo Gnocchi ONLUS, Via Capecelatro 66, I-20148 Milan, Italy.; Scaccianoce, E (reprint author), Politecn Milan, Dept Elect Informat & Bioengn, I-20133 Milan, Italy. EM elisa.scaccianoce@gmail.it; mlagana@dongnocchi.it OI scaccianoce, elisa/0000-0002-4001-0954 FU Ricerca Corrente (Italian Ministry of Health) [R21NS077059, R21NS079905, R01AG042512, R21EB016449] FX This work was supported by 2014-2015 Ricerca Corrente (Italian Ministry of Health) (ES, MML, MGP, NB, PC, MC) and by the following funds: R21NS077059, R21NS079905, R01AG042512, R21EB016449 (NM). NR 56 TC 1 Z9 1 U1 11 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 EI 1573-6792 J9 BRAIN TOPOGR JI Brain Topogr. PD NOV PY 2016 VL 29 IS 6 BP 814 EP 823 DI 10.1007/s10548-016-0516-0 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY5RU UT WOS:000385160600003 PM 27509899 ER PT J AU Mashaghi, A Marmalidou, A Tehrani, M Grace, PM Pothoulakis, C Dana, R AF Mashaghi, Alireza Marmalidou, Anna Tehrani, Mohsen Grace, Peter M. Pothoulakis, Charalabos Dana, Reza TI Neuropeptide substance P and the immune response SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Immune regulation; Neuropeptides; Cell-to-cell communication; Signaling; Cellular dynamics ID VASOACTIVE-INTESTINAL-PEPTIDE; GENE-RELATED PEPTIDE; NF-KAPPA-B; CORNEAL EPITHELIAL-CELLS; NEUROKININ 1 RECEPTOR; MELANOCYTE-STIMULATING HORMONE; REGULATORY T-CELLS; MICROVASCULAR ENDOTHELIAL-CELLS; GROWTH-FACTOR-I; PSEUDOMONAS-AERUGINOSA INFECTION AB Substance P is a peptide mainly secreted by neurons and is involved in many biological processes, including nociception and inflammation. Animal models have provided insights into the biology of this peptide and offered compelling evidence for the importance of substance P in cell-to-cell communication by either paracrine or endocrine signaling. Substance P mediates interactions between neurons and immune cells, with nerve-derived substance P modulating immune cell proliferation rates and cytokine production. Intriguingly, some immune cells have also been found to secrete substance P, which hints at an integral role of substance P in the immune response. These communications play important functional roles in immunity including mobilization, proliferation and modulation of the activity of immune cells. This review summarizes current knowledge of substance P and its receptors, as well as its physiological and pathological roles. We focus on recent developments in the immunobiology of substance P and discuss the clinical implications of its ability to modulate the immune response. C1 [Mashaghi, Alireza; Marmalidou, Anna; Tehrani, Mohsen; Dana, Reza] Harvard Med Sch, Schepens Eye Res Inst, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Grace, Peter M.] Univ Colorado, Dept Psychol & Neurosci, Ctr Neurosci, Boulder, CO 80309 USA. [Pothoulakis, Charalabos] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90095 USA. RP Dana, R (reprint author), Harvard Med Sch, Schepens Eye Res Inst, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu OI Grace, Peter/0000-0002-8999-1220 FU National Institute of Health [R01 DK047343, P30 DK 41301, EY020889, EY012963] FX CP was supported by grants from the National Institute of Health (R01 DK047343, and P30 DK 41301). The work in the RD laboratory was supported by the National Institute of Health (EY020889 and EY012963). We thank Dr. Susanne Leeman, Dr. Susanne Eiglmeier, and Dr. Ilya Leskov for their helpful comments on our manuscript. NR 250 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2016 VL 73 IS 22 BP 4249 EP 4264 DI 10.1007/s00018-016-2293-z PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DY5SO UT WOS:000385163300006 PM 27314883 ER PT J AU Konermann, A Kantarci, A Wilbert, S Van Dyke, T Jager, A AF Konermann, Anna Kantarci, Alpdogan Wilbert, Steven Van Dyke, Thomas Jaeger, Andreas TI Verification of gamma-Amino-Butyric Acid (GABA) Signaling System Components in Periodontal Ligament Cells In Vivo and In Vitro SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE gamma-Amino-butyric acid (GABA); L-Glutamic acid decarboxylase (GAD)65; Inflammation; Neurotransmitter; Periodontal ligament cells; Periodontal pathophysiology ID ORTHODONTIC TOOTH MOVEMENT; CREVICULAR FLUID; RECEPTORS; EXPRESSION; STRESS; MICE; RAT; FIBROBLASTS; ACTIVATION; CYTOKINES AB CNS key neurotransmitter gamma-amino-butyric acid (GABA) and its signaling components are likewise detectable in non-neuronal tissues displaying inter alia immunomodulatory functions. This study aimed at identifying potential glutamate decarboxylase (GAD)65 and GABA receptor expression in periodontal ligament (PDL) cells in vivo and in vitro, with particular regard to inflammation and mechanical loading. Gene expression was analyzed in human PDL cells at rest or in response to IL-1 (5 ng/ml) or TNF alpha (5 ng/ml) challenge via qRT-PCR. Western blot determined constitutive receptor expression, and confocal laser scanning fluorescence microscopy visualized expression changes induced by inflammation. ELISA quantified GAD65 release. Immunocytochemistry was performed for GABA component detection in vitro on mechanically loaded PDL cells, and in vivo on rat upper jaw biopsies with mechanically induced root resorptions. Statistical significance was set at p < 0.05. GABA(B1), GABA(B2), GABA(A1), and GABA(A3) were ubiquitously expressed both on gene and protein level. GABA(A2) and GAD65 were undetectable in resting cells, but induced by inflammation. GABA(B1) exhibited the highest basal gene expression (6.97 % +/- 0.16). IL-1 markedly increased GABA(B2) on a transcriptional (57.28-fold +/- 12.40) and protein level seen via fluorescence microscopy. TNF alpha-stimulated PDL cells released GAD65 (3.68 pg/ml +/- 0.17 after 24 h, 5.77 pg/ml +/- 0.65 after 48 h). Immunocytochemistry revealed GAD65 expression in mechanically loaded PDL cells. In vivo, GABA components were varyingly expressed in an inflammatory periodontal environment. PDL cells differentially express GABA signaling components and secrete GAD65. Inflammation and mechanical loading regulate these neurotransmitter molecules, which are also detectable in vivo and are potentially involved in periodontal pathophysiology. C1 [Konermann, Anna; Jaeger, Andreas] Univ Bonn, Fac Med, Dept Orthodont, Welschnonnenstr 17, D-53111 Bonn, Germany. [Kantarci, Alpdogan; Wilbert, Steven; Van Dyke, Thomas] Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. RP Konermann, A (reprint author), Univ Bonn, Fac Med, Dept Orthodont, Welschnonnenstr 17, D-53111 Bonn, Germany. EM anna.konermann@gmx.de FU Deutsche Gesellschaft fur Kieferorthopadie (DGKFO); NIH/NIDCR [DE020906] FX We thank D. Nguyen and D. Stephens from the Forsyth Institute as much as I. Bay-Muler K. Reifenrath and S. van Dyk from the Department of Orthodontics, University of Bonn for technical support. This research received Grant Support by the Deutsche Gesellschaft fur Kieferorthopadie (DGKFO) and NIH/NIDCR Grant DE020906. NR 34 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 EI 1573-6830 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD NOV PY 2016 VL 36 IS 8 BP 1353 EP 1363 DI 10.1007/s10571-016-0335-6 PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA DY5VX UT WOS:000385173600012 PM 26865191 ER PT J AU Fuchs, CH West, LM Graham, JR Kalill, KS Morgan, LPK Hayes-Skelton, SA Orsillo, SM Roemer, L AF Fuchs, Cara H. West, Lindsey M. Graham, Jessica R. Kalill, Kathleen Sullivan Morgan, Lucas P. K. Hayes-Skelton, Sarah A. Orsillo, Susan M. Roemer, Lizabeth TI Reactions to an Acceptance-Based Behavior Therapy for GAD: Giving Voice to the Experiences of Clients From Marginalized Backgrounds SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE Mindfulness; Marginalized identities; Treatment acceptability; Valued action; Cultural adaptations ID MENTAL-HEALTH; CLINICAL CONSIDERATIONS; VIETNAMESE REFUGEES; ANXIETY DISORDERS; AMERICAN ADULTS; DISCRIMINATION; METAANALYSIS; CULTURE; MINDFULNESS; DEPRESSION AB There is emerging evidence supporting the acceptability of mindfulness and acceptance-based therapies with individuals from marginalized backgrounds. The current phenomenological study aimed to understand the extent to which clients from marginalized backgrounds who had completed an acceptance-based behavioral therapy (ABBT) for GAD felt that their identities affected their experience of the treatment and the therapist. Purposeful sampling methods were used to identify seven clients from a larger RCT who identified with one or more marginalized identities. Nine themes related to the treatment components, treatment focus and/or delivery, and the therapist emerged. Themes reflected aspects of treatment that clients were satisfied with and areas where they experienced some discord with treatment. Clinical implications for working with marginalized individuals include the importance of inviting conversations about barriers to valued actions, balancing the need to maintain treatment fidelity with the need to be responsive to clients' concerns, the utility of assessing responses to mindfulness exercises as they are presented, and making client-centered adjustments to either the content or delivery of mindfulness practice to help make connections between exercises and clients' lives. C1 [Fuchs, Cara H.] Harvard Med Sch, Boston, MA USA. [Fuchs, Cara H.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Fuchs, Cara H.] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. [West, Lindsey M.] Augusta Univ, Med Coll Georgia, Dept Psychiat & Hlth Behav, Augusta, GA USA. [Graham, Jessica R.] Salem State Univ, Dept Psychol, Salem, MA USA. [Kalill, Kathleen Sullivan] VA Boston Healthcare Syst, Boston, MA USA. [Morgan, Lucas P. K.] I Ola Lahui Rural Hawaii Behav Hlth, Honolulu, HI USA. [Hayes-Skelton, Sarah A.; Roemer, Lizabeth] Univ Massachusetts Boston, Dept Psychol, Boston, MA USA. [Orsillo, Susan M.] Suffolk Univ, Dept Psychol, Boston, MA USA. RP Fuchs, CH (reprint author), Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Box G BH,Duncan Bldg, Providence, RI 02912 USA. EM Cara_Fuchs@Brown.edu OI Roemer, Lizabeth/0000-0002-2453-5435 FU National Institute of Mental Health [MH074589] FX This work was supported by National Institute of Mental Health Grant MH074589, awarded to the last two authors. NR 67 TC 0 Z9 0 U1 12 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD NOV PY 2016 VL 23 IS 4 BP 473 EP 484 PG 12 WC Psychology, Clinical SC Psychology GA DY1RT UT WOS:000384872800013 ER PT J AU Tripathi, A Kaymakcalan, MD LeBoeuf, NR Harshman, LC AF Tripathi, Abhishek Kaymakcalan, Marina D. LeBoeuf, Nicole R. Harshman, Lauren C. TI Programmed cell death-1 pathway inhibitors in genitourinary malignancies: specific side-effects and their management SO CURRENT OPINION IN UROLOGY LA English DT Review DE checkpoint blockade; immune-related adverse events; immunotherapy; renal cell carcinoma; urothelial carcinoma ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; METASTATIC MELANOMA; ADVERSE EVENTS; IPILIMUMAB THERAPY; LUNG-CANCER; T-CELLS; CARCINOMA; NIVOLUMAB; B7-H1; IMMUNOTHERAPY AB Purpose of review Immune checkpoint inhibitors such as those that target the programmed cell death (PD)-1 pathway harness the host immune system to elicit an antitumor response. Their remarkable clinical benefit has led to regulatory approvals in several malignancies including the genitourinary cancers, renal cell carcinoma, and urothelial carcinoma. This review will focus on the management of the toxicities encountered with these agents. Recent findings Although generally well tolerated, a small proportion of patients (10-20%) treated with PD-1 directed agents as monotherapy can develop severe autoimmune manifestations, also known as, immune-related adverse events. These include but are not limited to rashes, pneumonitis, endocrinopathy, colitis, and immune-mediated hepatic dysfunction. Combining these agents with the anti-CTLA-4 antibody ipilimumab can be associated with a higher incidence of these toxicities. Early initiation of immunosuppression with corticosteroids and other agents when needed can help mitigate these toxicities and to date has not been shown to compromise their clinical benefit. Summary The development of immune checkpoint inhibitors represents significant advances in anticancer therapy but their efficacy may come at the cost of autoimmune toxicities secondary to their induction of the immune system. Early recognition of these effects and aggressive upfront management is essential to safely administer these agents in routine clinical practice. C1 [Tripathi, Abhishek; Kaymakcalan, Marina D.; Harshman, Lauren C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02215 USA. [LeBoeuf, Nicole R.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Cutaneous Oncol,Dept Dermatol, Boston, MA USA. RP Harshman, LC (reprint author), Dana Farber Canc Inst, Med, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM LaurenC_Harshman@dfci.harvard.edu NR 46 TC 0 Z9 0 U1 10 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0963-0643 EI 1473-6586 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD NOV PY 2016 VL 26 IS 6 BP 548 EP 555 DI 10.1097/MOU.0000000000000332 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DY1FF UT WOS:000384839600009 PM 27517638 ER PT J AU Mullane, SA Bellmunt, J AF Mullane, Stephanie A. Bellmunt, Joaquim TI Cancer immunotherapy: new applications in urologic oncology SO CURRENT OPINION IN UROLOGY LA English DT Review DE inventive immunotherapy combinations; new biomarkers; novel immunotherapy ID RENAL-CELL CARCINOMA; RESISTANT PROSTATE-CANCER; RANDOMIZED CONTROLLED-TRIAL; PERSONALIZED PEPTIDE VACCINE; DOSE-ESCALATION TRIAL; REGULATORY T-CELLS; LONG-TERM SAFETY; CTLA-4 BLOCKADE; UROTHELIAL CARCINOMA; CLINICAL ACTIVITY AB Purpose of review Immunotherapy in urological cancer has made substantial progress during the last 20 years, but recent advances in immunotherapy have completely transformed the present treatment landscape. In this review, we summarize major clinical achievements of immunotherapy in genitourinary cancers, as well as address potential new directions for these therapies, including new agents, combinations, and biomarkers. Recent findings Recently, nivolumab and atezolizumab have joined sipuleucel-T as Food and Drug Administration-approved therapies in urological malignancies. Additional checkpoint inhibitors and vaccines are being tested in clinical trials. Furthermore, significant work has been done exploring predictors of response to therapy. Summary Immunotherapy has changed the treatment of urologic malignancies. New immunotherapies and novel combinations will continue to create new treatment options in urologic tumors. C1 [Mullane, Stephanie A.; Bellmunt, Joaquim] Harvard Med Sch, Bladder Canc Ctr, Dana Farber Canc Inst, Boston, MA USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, Bladder Canc Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu FU Jimmy Fund Whole Foods Golf Tournament for Bladder Cancer Research FX This work was supported by The Jimmy Fund Whole Foods Golf Tournament for Bladder Cancer Research. NR 116 TC 0 Z9 0 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0963-0643 EI 1473-6586 J9 CURR OPIN UROL JI Curr. Opin. Urol. PD NOV PY 2016 VL 26 IS 6 BP 556 EP 563 DI 10.1097/MOU.0000000000000337 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DY1FF UT WOS:000384839600010 PM 27584023 ER PT J AU Maher, DP Woo, P Wong, W Zhang, X Yumul, R Louy, C AF Maher, Dermot P. Woo, Pauline Wong, Waylan Zhang, Xiao Yumul, Roya Louy, Charles TI Perioperative factors associated with Hospital Consumer Assessment of Healthcare Providers and Systems responses of total hip arthroplasty patients SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE Patient satisfaction; HCAHPS; Preoperative medications; Opioids; NSAIDs ID POSTOPERATIVE PAIN; ANESTHESIA; EXPERIENCE; ANALGESIA; IMPROVE; TRIAL AB Objective: To determine perioperative treatments and events associated with Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) responses among patients who undergo total hip arthroplasties (THAs) and total knee arthroplasties (TKAs). Design: Retrospective analysis. Setting: Single tertiary care, academic, urban, level 1 trauma center. Participants: Final cohort represents 301 consecutive surgical inpatients meeting criteria for evaluation by HCAHPS survey. Exposures: Responses to 4 HCAHPS questions were analyzed against perioperative treatments and events. Measures: Positive and negative responses to HCAHPS questions. Results: THA patients responding affirmatively to both pain specific and general satisfaction were associated with preoperative use of chronic nonsteroidal anti-inflammatory drugs. In addition, THA patients responding affirmatively "how often was your pain well controlled" were also associated decreased post-anesthesia care unit (PACU) opioid requirement. TKA patients responding affirmatively to "what number would you use to rate this hospital" were associated with shorter PACU stays and lower final pain scores. TKA patients responding affirmatively to "would you recommend this hospital to your family" were associated with shorter lengths of stay in the hospital and in the PACU. TKA patients responding affirmatively to "How often did the hospital staff do everything to help with your pain" were not associated with any measured perioperative event. TKA patients responding affirmatively to "how often was your pain well controlled" were associated with older age, decreased use of preoperative chronic benzodiazepines, and increased use of preoperative midazolam. Conclusions: These data suggest that chronic use of nonsteroidal anti-inflammatory drugs is associated with improved overall satisfaction and satisfaction with pain in THA patients. Furthermore, increased PACU opioid use was negatively associated satisfaction with pain management. Age, lengths of stay preadmission medications, anxiolytic medications, and PACU pain scores are associated with patient satisfaction with regards to both pain management and overall satisfaction in TKA patients. (C) 2016 Elsevier Inc. All rights reserved. C1 [Maher, Dermot P.] Harvard Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Woo, Pauline; Wong, Waylan; Zhang, Xiao; Yumul, Roya; Louy, Charles] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Maher, DP (reprint author), Wang Ambulatory Care Ctr, Ctr Pain Med, Suite 340,15 Parkman St, Boston, MA 02114 USA. EM dpmaher@mgh.harvard.edu NR 23 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD NOV PY 2016 VL 34 BP 232 EP 238 DI 10.1016/j.jclinane.2016.03.047 PG 7 WC Anesthesiology SC Anesthesiology GA DY2WL UT WOS:000384952700046 PM 27687381 ER PT J AU Buckley, RF Villemagne, VL Masters, CL Ellis, KA Rowe, CC Johnson, K Sperling, R Amariglio, R AF Buckley, Rachel F. Villemagne, Victor L. Masters, Colin L. Ellis, Kathryn A. Rowe, Christopher C. Johnson, Keith Sperling, Reisa Amariglio, Rebecca TI A Conceptualization of the Utility of Subjective Cognitive Decline in Clinical Trials of Preclinical Alzheimer's Disease SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Cognition; Subjective cognitive decline; Preclinical; Alzheimer's disease; Amyloid; Tau ID MEMORY COMPLAINTS; AMYLOID DEPOSITION; OLDER INDIVIDUALS; HEALTHY-ADULTS; IMPAIRMENT; BIOMARKERS; DEMENTIA; BRAIN; SELF; STAGE AB This commentary outlines a conceptual model for subjective cognitive decline (SCD) in relation to Alzheimer's disease (AD) biomarkers in the preclinical stages of disease and a framework for effectively utilizing SCD in secondary prevention clinical trials. Mounting evidence supports the notion that SCD is sensitive to encroaching A beta-amyloid and neurodegeneration. SCD has also been shown to provide additive information of AD-dementia risk beyond what is known about the biomarker status of the individual. Thus, we provide recommendations for the implementing SCD measurement in clinical trials. We argue that SCD can be measured at three catch points within the course of the clinical trial: firstly, at the initial recruitment and screening phase; secondly, to create more robust estimates of rates of AD-dementia progression; and finally, to measure subjective experiences of cognitive change and quality of life over the course of the trial as a proxy of clinically meaningful functional improvement. We provide recommendations of how SCD can be approached at each of these points. SCD is an important component of the preclinical AD-dementia trajectory. Future studies need to elucidate the interactive influence of A beta-amyloid and tau on SCD from a spatiotemporal perspective. Even as this evidence accrues, it is clear that SCD can provide unique and additive information about rates of progression and subjectively experienced cognitive change within clinical trials. C1 [Buckley, Rachel F.; Villemagne, Victor L.; Masters, Colin L.; Ellis, Kathryn A.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia. [Buckley, Rachel F.] Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia. [Buckley, Rachel F.; Johnson, Keith; Sperling, Reisa; Amariglio, Rebecca] Harvard Med Sch, Brigham Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Buckley, Rachel F.] Massachusetts Gen Hosp, Dept Neurol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Melbourne, Vic, Australia. [Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Ctr PET, Melbourne, Vic, Australia. [Villemagne, Victor L.; Rowe, Christopher C.] Univ Melbourne, Austin Hlth, Dept Med, Melbourne, Vic, Australia. [Ellis, Kathryn A.] Univ Melbourne, Dept Psychiat, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia. [Johnson, Keith; Sperling, Reisa; Amariglio, Rebecca] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Johnson, Keith] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Buckley, RF (reprint author), Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia.; Buckley, RF (reprint author), Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia.; Buckley, RF (reprint author), Harvard Med Sch, Brigham Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA.; Buckley, RF (reprint author), Massachusetts Gen Hosp, Dept Neurol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM rfbuckley@mgh.harvard.edu FU National Medical and Health Research Council (NHMRC) Dementia Research Fellowship [APP1105576] FX Dr. Buckley is funded by the National Medical and Health Research Council (NHMRC) Dementia Research Fellowship (APP1105576). NR 70 TC 1 Z9 1 U1 15 U2 15 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2016 VL 60 IS 3 BP 354 EP 361 DI 10.1007/s12031-016-0810-z PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DY6GU UT WOS:000385205200010 PM 27514526 ER PT J AU Feder, A Mota, N Salim, R Rodriguez, J Singh, R Schaffer, J Schechter, CB Cancelmo, LM Bromet, EJ Katz, CL Reissman, DB Ozbay, F Kotov, R Crane, M Harrison, DJ Herbert, R Levin, SM Luft, BJ Moline, JM Stellman, JM Udasin, IG Landrigan, PJ Zvolensky, MJ Yehuda, R Southwick, SM Pietrzak, RH AF Feder, Adriana Mota, Natalie Salim, Ryan Rodriguez, Janice Singh, Ritika Schaffer, Jamie Schechter, Clyde B. Cancelmo, Leo M. Bromet, Evelyn J. Katz, Craig L. Reissman, Dori B. Ozbay, Fatih Kotov, Roman Crane, Michael Harrison, Denise J. Herbert, Robin Levin, Stephen M. Luft, Benjamin J. Moline, Jacqueline M. Stellman, Jeanne M. Udasin, Iris G. Landrigan, Philip J. Zvolensky, Michael J. Yehuda, Rachel Southwick, Steven M. Pietrzak, Robert H. TI Risk, coping and PTSD symptom trajectories in World Trade Center responders SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Posttraumatic stress disorder; World Trade Center; Responders; Trajectories; Risk; Coping ID POSTTRAUMATIC-STRESS-DISORDER; CENTER TERRORIST ATTACK; POLICE RESPONDERS; CENTER DISASTER; CENTER RESCUE; ENVIRONMENTAL-INFLUENCES; PROSPECTIVE COHORT; RECOVERY WORKERS; CLEANUP WORKERS; SOCIAL SUPPORT AB Trajectories of disaster-related posttraumatic stress disorder (PTSD) symptoms are often heterogeneous, and associated with common and unique risk factors, yet little is known about potentially modifiable psychosocial characteristics associated with low-symptom and recovering trajectories in disaster responders. A total of 4487 rescue and recovery workers (1874 police and 2613 non-traditional responders) involved during and in the aftermath of the unprecedented World Trade Center (WTC) attacks, were assessed an average of 3, 6, 8, and 12 years post-9/11/2001. Among police responders, WTC-related PTSD symptoms were characterized by four trajectories, including no/low-symptom (76.1%), worsening (12.1%), improving (7.5%), and chronic (4.4%) trajectories. In non-traditional responders, a five-trajectory solution was optimal, with fewer responders in a no/low-symptom trajectory (55.5%), and the remainder in subtly worsening (19.3%), chronic (10.8%), improving (8.5%), and steeply worsening (5.9%) trajectories. Consistent factors associated with symptomatic PTSD trajectories across responder groups included Hispanic ethnicity, pre-9/11 psychiatric history, greater WTC exposure, greater medical illness burden, life stressors and post-9/11 traumas, and maladaptive coping (e.g., substance use, avoidance coping). Higher perceived preparedness, greater sense of purpose in life, and positive emotion-focused coping (e.g., positive reframing, acceptance) were negatively associated with symptomatic trajectories. Findings in this unique cohort indicate considerable heterogeneity in WTC-related PTSD symptom trajectories over 12 years post-9/11/2001, with lower rates of elevated PTSD symptoms in police than in non-traditional responders. They further provide a comprehensive risk prediction model of PTSD symptom trajectories, which can inform prevention, monitoring, and treatment efforts in WTC and other disaster responders. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Feder, Adriana; Salim, Ryan; Rodriguez, Janice; Singh, Ritika; Schaffer, Jamie; Cancelmo, Leo M.; Katz, Craig L.; Ozbay, Fatih; Yehuda, Rachel] Icahn Sch Med, Dept Psychiat, New York, NY USA. [Mota, Natalie; Southwick, Steven M.; Pietrzak, Robert H.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, VA Connecticut Healthcare Syst, West Haven, CT USA. [Mota, Natalie; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Schechter, Clyde B.] Yeshiva Univ, Dept Family & Social Med, Albert Einstein Coll Med, Bronx, NY USA. [Bromet, Evelyn J.; Kotov, Roman] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. [Reissman, Dori B.] NIOSH, Off Director, Washington, DC USA. [Crane, Michael; Herbert, Robin; Levin, Stephen M.; Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Harrison, Denise J.] NYU, Dept Med, Div Pulm Crit Care & Sleep Med, New York, NY 10003 USA. [Luft, Benjamin J.] SUNY Stony Brook, Div Infect Dis, Dept Med, Stony Book, NY USA. [Moline, Jacqueline M.] Hofstra North Shore Long Isl Jewish Sch Med, Dept Occupat Med Epidemiol & Prevent, Great Neck, NY USA. [Stellman, Jeanne M.] Columbia Univ, Dept Hlth Policy & Management, Mailman Sch Publ Hlth, New York, NY 10027 USA. [Udasin, Iris G.] UMDNJ Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ USA. [Zvolensky, Michael J.] Univ Houston, Dept Psychol, Houston, TX USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Feder, A (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM adriana.feder@mssm.edu FU CDC/National Institute for Occupational Safety and Health (NIOSH) [200-2011-41919] FX This work was supported by the CDC/National Institute for Occupational Safety and Health (NIOSH) (A.F., R.H.P. and S.M.S., research contract # 200-2011-41919). The CDC/NIOSH did not contribute to study design; data collection, analysis or interpretation; writing of the report; or decision to submit the manuscript for publication. NR 51 TC 0 Z9 0 U1 17 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2016 VL 82 BP 68 EP 79 DI 10.1016/j.jpsychires.2016.07.003 PG 12 WC Psychiatry SC Psychiatry GA DY1KN UT WOS:000384854000010 PM 27468166 ER PT J AU Park, JM Samuels, JF Grados, MA Riddle, MA Bienvenu, OJ Goes, FS Cullen, B Wang, Y Krasnow, J Murphy, DL Rasmussen, SA McLaughlin, NC Piacentini, J Pauls, DL Stewart, SE Shugart, YY Maher, B Pulver, AE Knowles, JA Greenberg, BD Fyer, AJ McCracken, JT Nestadt, G Geller, DA AF Park, Jennifer M. Samuels, Jack F. Grados, Marco A. Riddle, Mark A. Bienvenu, O. Joseph Goes, Fernando S. Cullen, Bernadette Wang, Ying Krasnow, Janice Murphy, Dennis L. Rasmussen, Steven A. McLaughlin, Nicole C. Piacentini, John Pauls, David L. Stewart, S. Evelyn Shugart, Yin-Yao Maher, Brion Pulver, Ann E. Knowles, James A. Greenberg, Benjamin D. Fyer, Abby J. McCracken, James T. Nestadt, Gerald Geller, Daniel A. TI ADHD and executive functioning deficits in OCD youths who hoard SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Hoarding; Obsessive compulsive disorder; Children; Adolescents; Executive functioning; ADHD ID OBSESSIVE-COMPULSIVE DISORDER; COGNITIVE-BEHAVIORAL THERAPY; SYMPTOM DIMENSIONS; NEUROPSYCHOLOGICAL PERFORMANCE; ANXIETY DISORDERS; COLLABORATIVE GENETICS; CHILDREN; SCALE; ADOLESCENTS; VALIDITY AB Hoarding is common among youth with obsessive compulsive disorder (OCD), with up to 26% of OCD youth exhibiting hoarding symptoms. Recent evidence from adult hoarding and OCD cohorts suggests that hoarding symptoms are associated with executive functioning deficits similar to those observed in subjects with attention deficit hyperactivity disorder (ADHD). However, while hoarding behavior often onsets during childhood, there is little information about executive function deficits and ADHD in affected children and adolescents. The study sample included 431 youths (ages 6-17 years) diagnosed with OCD who participated in the OCD Collaborative Genetics Study and the OCD Collaborative Genetics Association Study and completed a series of clinician-administered and parent report assessments, including diagnostic interviews and measures of executive functioning (Behavior Rating Inventory of Executive Functioning; BRIEF) and hoarding severity (Hoarding Rating Scale-Interview; HRS-I). 113 youths (26%) had clinically significant levels of hoarding compulsions. Youths with and without hoarding differed significantly on most executive functioning subdomains and composite indices as measured by the parent-rated BRIEF. Groups did not differ in the frequency of full DSM-IV ADHD diagnoses; however, the hoarding group had significantly greater number of inattention and hyperactivity symptoms compared to the non-hoarding group. In multivariate models, we found that overall BRIEF scores were related to hoarding severity, adjusting for age, gender and ADHD symptoms. These findings suggest an association between hoarding and executive functioning deficits in youths with OCD, and assessing executive functioning may be important for investigating the etiology and treatment of children and adolescents with hoarding and OCD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Park, Jennifer M.] Stanford Univ, Sch Med, Dept Child & Adolescent Psychiatiy, 1195 W Fremont Ave, Sunnyvale, CA 94087 USA. [Samuels, Jack F.; Grados, Marco A.; Riddle, Mark A.; Bienvenu, O. Joseph; Goes, Fernando S.; Cullen, Bernadette; Wang, Ying; Krasnow, Janice; Pulver, Ann E.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 1800 Orleans St, Baltimore, MD 21287 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, 6001 Execut Blvd,Rm 6200,MSC 9663, Bethesda, MD 20892 USA. [Rasmussen, Steven A.; McLaughlin, Nicole C.; Greenberg, Benjamin D.] Brown Med Sch, Dept Psychiat & Human Behav, Box G-A1, Providence, RI 02912 USA. [Piacentini, John; McCracken, James T.] Univ Calif Los Angeles, Los Angeles Sch Med, Dept Psychiat & Biobehav Sci, 757 Westwood Plaza, Los Angeles, CA 90095 USA. [Stewart, S. Evelyn] Univ British Columbia, Fac Med, Dept Psychiat, Detwiller Pavil,2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. [Shugart, Yin-Yao] NIMH, Unit Stat Genom, Div Intramural Res, 6001 Execut Blvd,Rm 6200,MSC 9663, Bethesda, MD 20892 USA. [Maher, Brion] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. [Knowles, James A.] Univ Southern Calif, Keck Sch Med, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Fyer, Abby J.] Columbia Univ, Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Fyer, Abby J.] New York State Psychiat Inst & Hosp, Dept Psychiat, 630 W 168th St, New York, NY 10032 USA. [Pauls, David L.; Geller, Daniel A.] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Pauls, David L.; Geller, Daniel A.] Harvard Med Sch, Dept Psychiatty, 55 Fruit St, Boston, MA 02114 USA. RP Park, JM (reprint author), Massachusetts Gen Hosp, Child CBT Program, 151 Merrimac St,3rd Floor, Boston, MA 02114 USA. EM jmpark05@stanford.edu FU IRP of NIMH FX Dr. Yin-Yao Shugart is supported by the IRP of NIMH. NR 61 TC 1 Z9 1 U1 11 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2016 VL 82 BP 141 EP 148 DI 10.1016/j.jpsychires.2016.07.024 PG 8 WC Psychiatry SC Psychiatry GA DY1KN UT WOS:000384854000018 PM 27501140 ER PT J AU Okita, K Petersen, N Robertson, CL Dean, AC Mandelkern, MA London, ED AF Okita, Kyoji Petersen, Nicole Robertson, Chelsea L. Dean, Andy C. Mandelkern, Mark A. London, Edythe D. TI Sex Differences in Midbrain Dopamine D2-Type Receptor Availability and Association with Nicotine Dependence SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID REFERENCE TISSUE MODEL; SMOKING-CESSATION; BEHAVIORAL SENSITIZATION; CIGARETTE-SMOKING; MENSTRUAL-CYCLE; RELEASE; BRAIN; NEURONS; BINDING; PET AB Women differ from men in smoking-related behaviors, among them a greater difficulty in quitting smoking. Unlike female smokers, male smokers have lower striatal dopamine D2-type receptor availability (binding potential, BPND) than nonsmokers and exhibit greater smoking-induced striatal dopamine release. Because dopamine D2-type autoreceptors in the midbrain influence striatal dopamine release, a function that has been linked to addiction, we tested for sex differences in midbrain dopamine D2-type receptor BPND and in relationships between midbrain BPND, nicotine dependence and striatal dopamine D2-type receptor BPND. Positron emission tomography was used with [F-18]fallypride to measure BPND in a midbrain region, encompassing the substantia nigra and ventral tegmental area, in 18 daily smokers (7 women, 11 men) and 19 nonsmokers (10 women, 9 men). A significant sex-by-group interaction reflected greater midbrain BPND in female but not male smokers than in corresponding nonsmokers (F-1,F- 32 = 5.089, p = 0.03). Midbrain BPND was positively correlated with BPND in the caudate nucleus and putamen in nonsmokers and female smokers but not in male smokers and with nicotine dependence in female but not in male smokers. Striatal BPND was correlated negatively with nicotine dependence and smoking exposure. These findings extend observations on dopamine D2-type receptors in smokers and suggest a sex difference in how midbrain dopamine D2-type autoreceptors influence nicotine dependence. C1 [Okita, Kyoji; Petersen, Nicole; Dean, Andy C.; London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Okita, Kyoji; Robertson, Chelsea L.; Mandelkern, Mark A.; London, Edythe D.] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA USA. [Robertson, Chelsea L.; London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Dean, Andy C.; London, Edythe D.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP London, ED (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 740 Westwood Plaza,POB 175919, Los Angeles, CA 90024 USA. EM elondon@mednet.ucla.edu FU National Institute on Drug Abuse [R01 DA015179, R01 DA020726, P20 DA022539, K23 DA027734]; National Center for Research Resources [M01 RR00865]; Thomas P and Katherine K Pike Chair in Addiction Studies; Marjorie M Greene Trust; Department of Psychiatry, Graduate School of Medicine, Chiba University; [T32 DA024635] FX This research was supported, in part, by grants from the National Institute on Drug Abuse (R01 DA015179, R01 DA020726, P20 DA022539, EDL; K23 DA027734, ACD) and the National Center for Research Resources (M01 RR00865) and endowments from the Thomas P and Katherine K Pike Chair in Addiction Studies (EDL) and the Marjorie M Greene Trust. KO was partly supported by the Department of Psychiatry, Graduate School of Medicine, Chiba University, DOMONKAI fund. CLR was supported by T32 DA024635. The authors declare no conflict of interest. NR 57 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2016 VL 41 IS 12 BP 2913 EP 2919 DI 10.1038/npp.2016.105 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DY6JR UT WOS:000385212700013 PM 27329684 ER PT J AU Handa, A Tham, E Wang, Z Horemuzova, E Grigelioniene, G AF Handa, Atsuhiko Tham, Emma Wang, Zheng Horemuzova, Eva Grigelioniene, Giedre TI Autosomal recessive brachyolmia: early radiological findings SO SKELETAL RADIOLOGY LA English DT Article DE Skeletal dysplasia; Autosomal recessive brachyolmia; PAPSS2; Platyspondyly; Dumbbell deformity ID PAPSS2 MUTATIONS; SPONDYLOEPIMETAPHYSEAL DYSPLASIA; DOMINANT BRACHYOLMIA; FEATURES; FORM AB Brachyolmia (BO) is a heterogeneous group of skeletal dysplasias with skeletal changes limited to the spine or with minimal extraspinal features. BO is currently classified into types 1, 2, 3, and 4. BO types 1 and 4 are autosomal recessive conditions caused by PAPSS2 mutations, which may be merged together as an autosomal recessive BO (AR-BO). The clinical and radiological signs of AR-BO in late childhood have already been reported; however, the early manifestations and their age-dependent evolution have not been well documented. We report an affected boy with AR-BO, whose skeletal abnormalities were detected in utero and who was followed until 10 years of age. Prenatal ultrasound showed bowing of the legs. In infancy, radiographs showed moderate platyspondyly and dumbbell deformity of the tubular bones. Gradually, the platyspondyly became more pronounced, while the bowing of the legs and dumbbell deformities of the tubular bones diminished with age. In late childhood, the overall findings were consistent with known features of AR-BO. Genetic testing confirmed the diagnosis. Being aware of the initial skeletal changes may facilitate early diagnosis of PAPSS2-related skeletal dysplasias. C1 [Handa, Atsuhiko] MassGen Hosp Children, 175 Cambridge St,5th Floor, Boston, MA 02114 USA. [Handa, Atsuhiko; Grigelioniene, Giedre] Harvard Med Sch, 175 Cambridge St,5th Floor, Boston, MA 02114 USA. [Handa, Atsuhiko] St Lukess Int Hosp, Dept Radiol, Tokyo, Japan. [Tham, Emma; Grigelioniene, Giedre] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Tham, Emma; Grigelioniene, Giedre] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. [Tham, Emma; Grigelioniene, Giedre] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Wang, Zheng] RIKEN, Ctr Integrat Med Sci, Lab Bone & Joint Dis, Tokyo, Japan. [Wang, Zheng] Chinese Acad Med Sci, McKusick Zhang Ctr Genet Med, Beijing, Peoples R China. [Wang, Zheng] Chinese Acad Med Sci, State Key Lab Med Mol Biol, Inst Basic Med Sci, Beijing, Peoples R China. [Wang, Zheng] Peking Union Med Coll, Beijing, Peoples R China. [Horemuzova, Eva] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Horemuzova, Eva] Karolinska Univ Hosp, Astrid Lindgren Childrenss Hosp, Dept Pediat Endocrinol, Stockholm, Sweden. [Grigelioniene, Giedre] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. RP Handa, A (reprint author), MassGen Hosp Children, 175 Cambridge St,5th Floor, Boston, MA 02114 USA.; Handa, A (reprint author), Harvard Med Sch, 175 Cambridge St,5th Floor, Boston, MA 02114 USA.; Handa, A (reprint author), St Lukess Int Hosp, Dept Radiol, Tokyo, Japan. EM handa-tky@umin.ac.jp NR 11 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD NOV PY 2016 VL 45 IS 11 BP 1557 EP 1560 DI 10.1007/s00256-016-2458-8 PG 4 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA DY5XI UT WOS:000385177400014 PM 27544198 ER PT J AU Ambrus, A Wang, JJ Mizsei, R Zambo, Z Torocsik, B Jordan, F Adam-Vizi, V AF Ambrus, Attila Wang, Junjie Mizsei, Reka Zambo, Zsofia Torocsik, Beata Jordan, Frank Adam-Vizi, Vera TI Structural alterations induced by ten disease-causing mutations of human dihydrolipoamide dehydrogenase analyzed by hydrogen/deuterium-exchange mass spectrometry: Implications for the structural basis of E3 deficiency SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Dihydrolipoamide dehydrogenase; Pathogenic mutation; E3 deficiency; Hydrogen/deuterium exchange; Mass spectrometry ID ALPHA-KETOGLUTARATE DEHYDROGENASE; OXYGEN SPECIES GENERATION; PYRUVATE-DEHYDROGENASE; 2-OXOGLUTARATE DEHYDROGENASE; LIPOAMIDE DEHYDROGENASE; MULTIENZYME COMPLEXES; OXIDATIVE STRESS; LEIGH-SYNDROME; PARKINSONS-DISEASE; MOLECULAR-DYNAMICS AB Pathogenic amino acid substitutions of the common E3 component (hE3) of the human alpha-ketoglutarate dehydrogenase and the pyruvate dehydrogenase complexes lead to severe metabolic diseases (E3 deficiency), which usually manifest themselves in cardiological and/or neurological symptoms and often cause premature death. To date, 14 disease-causing amino acid substitutions of the hE3 component have been reported in the clinical literature. None of the pathogenic protein variants has lent itself to high-resolution structure elucidation by X-ray or NMR. Hence, the structural alterations of the hE3 protein caused by the disease-causing mutations and leading to dysfunction, including the enhanced generation of reactive oxygen species by selected disease-causing variants, could only be speculated. Here we report results of an examination of the effects on the protein structure of ten pathogenic mutations of hE3 using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), a new and state-of-the-art approach of solution structure elucidation. On the basis of the results, putative structural and mechanistic conclusions were drawn regarding the molecular pathogenesis of each disease-causing hE3 mutation addressed in this study. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ambrus, Attila; Mizsei, Reka; Zambo, Zsofia; Torocsik, Beata; Adam-Vizi, Vera] Semmelweis Univ, Dept Med Biochem, MTA SE Lab Neurobiochem, Budapest, Hungary. [Wang, Junjie; Jordan, Frank] Rutgers State Univ, Dept Chem, Newark, NJ 08901 USA. [Wang, Junjie] Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, New York, NY 10021 USA. [Mizsei, Reka] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. RP Ambrus, A; Adam-Vizi, V (reprint author), Semmelweis Univ, Dept Med Biochem, MTA SE Lab Neurobiochem, Budapest, Hungary.; Jordan, F (reprint author), Rutgers State Univ, Dept Chem, Newark, NJ 08901 USA. EM ambrus.attila@med.semmelweis-univ.hu; frjordan@rutgers.edu; adam.veronika@med.semmelweis-univ.hu FU Hungarian Academy of Sciences (MTA grant) [02001]; Hungarian Scientific Research Fund (OTKA) [112230]; Hungarian Brain Research Program [KTIA_13_NAP-A-III/6]; Bolyai Fellowship; Fulbright Fellowship; [NIH-R15GM116077]; [NSF-CHE-1402675] FX We are grateful to Drs. Oliver Ozohanics, Karoly Vekey (both from the Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary) and Arpad Somogyi (Ohio State University, Columbus, OH, USA) for their contributions to the method development in mass spectrometry. Financial support is gratefully acknowledged from the Hungarian Academy of Sciences (MTA grant 02001 to V.A.-V.), the Hungarian Scientific Research Fund (OTKA, grant 112230 to V.A.-V.), the Hungarian Brain Research Program (grant KTIA_13_NAP-A-III/6 to V.A.-V.), the Bolyai and the Fulbright Fellowships (to A.A.), NIH-R15GM116077 and NSF-CHE-1402675 (to F.J.). NR 72 TC 0 Z9 0 U1 20 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD NOV PY 2016 VL 1862 IS 11 BP 2098 EP 2109 DI 10.1016/j.bbadis.2016.08.013 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DY1MX UT WOS:000384860200008 PM 27544700 ER PT J AU Jiang, X Peng, FH Liu, QQ Zhao, QH He, J Jiang, R Wang, L Xu, XQ Li, JH Ebrahimi, R Jing, ZC AF Jiang, Xin Peng, Fu-Hua Liu, Qian-Qian Zhao, Qin-Hua He, Jing Jiang, Rong Wang, Lan Xu, Xi-Qi Li, Jing-Hui Ebrahimi, Ramin Jing, Zhi-Cheng TI Optical coherence tomography for hypertensive pulmonary vasculature SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Chronic thromboembolic pulmonary hypertension; Optical coherence tomography; Pulmonary arterial hypertension ID INTRAVASCULAR ULTRASOUND; ARTERIAL-HYPERTENSION; MORPHOLOGY; PATHOLOGY AB Background: Optical coherence tomography (OCT) is an intravascular imaging modality capable of providing in situ images of tissues at near histologic resolution. In this study we examine the utility of OCT in identifying vascular changes related to pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results: OCT of four different distal pulmonary arteries was performed during right heart catheterization in 87 patients, 64 patients with PAH and 23 patients with CTEPH. The mean luminal diameter measured by OCT for all patients was 2.26 mm. Intimal thickening was significantly increased in all PAH patients (0.26 +/- 0.05 mm in idiopathic PAH, 0.24 +/- 0.03 mm in connective tissue disease related PAH, 0.26 +/- 0.06 mm in congenital heart disease related PAH and 0.22 +/- 0.04 mm in CTEPH, respectively) compared with controls (0.13 +/- 0.03 mm) (all p < 0.05). An intimal thickness of >= 0.176 mm had a 91% positive predictive value for pulmonary hypertension. The anatomic abnormalities revealed by OCT tended to be severe in the idiopathic PAH group and mild in the CTEPH group. Signs of intravascular webs were found in 60.9% of CTEPH patients, but no other patients. Intimal thickness was moderately correlated with pulmonary arterial pressure and pulmonary vascular resistance (r = 0.423 and 0.439, respectively, p < 0.001). Conclusions: OCT provides important information for assessment of pulmonary arterial remodeling in patients with PAH and improves diagnostic capability of angiographically undetected distal-thrombotic lesions in patients with CTEPH. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Jiang, Xin; Peng, Fu-Hua; Liu, Qian-Qian; Xu, Xi-Qi; Li, Jing-Hui; Jing, Zhi-Cheng] Peking Union Med Coll, FuWai Hosp, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China. [Jiang, Xin; Peng, Fu-Hua; Liu, Qian-Qian; Xu, Xi-Qi; Li, Jing-Hui; Jing, Zhi-Cheng] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Zhao, Qin-Hua; He, Jing; Jiang, Rong; Wang, Lan; Jing, Zhi-Cheng] Tongji Univ, Shanghai Pulm Hosp, Dept Cardiopulm Circulat, Sch Med, Shanghai 200433, Peoples R China. [Ebrahimi, Ramin] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Ebrahimi, Ramin] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Jing, ZC (reprint author), Chinese Acad Med Sci, FuWai Hosp, Peking Union Med Coll, State Key Lab Cardiovasc Dis, 167 Beilishi Rd, Beijing 100037, Peoples R China. EM jingzhicheng@vip.163.com FU Capital Medicine Developing Research Foundation [2014-SHF01] FX This study was partly supported by the Capital Medicine Developing Research Foundation (2014-SHF01). The sponsors had no involvement in the study design, data analysis, data interpretation, and writing or revision of the manuscript. All the authors have no relationships relevant to the contents of this paper to disclose. NR 18 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD NOV 1 PY 2016 VL 222 BP 494 EP 498 DI 10.1016/j.ijcard.2016.07.215 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9FF UT WOS:000384698300090 PM 27505340 ER PT J AU Jacobsen, E Nicotra, A Patterson, V Redd, R Virchick, B AF Jacobsen, Eric Nicotra, Alyssa Patterson, Victoria Redd, Robert Virchick, Barbara TI A Phase II Trial of Lenalidomide in Adults with Histiocyte Disorders SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Jacobsen, Eric; Nicotra, Alyssa; Patterson, Victoria; Virchick, Barbara] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Redd, Robert] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2016 VL 63 SU 2 BP S21 EP S22 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DW3ZH UT WOS:000383581100029 ER PT J AU Kantor, ED Zhang, XH Wu, KN Signorello, LB Chan, AT Fuchs, CS Giovannucci, EL AF Kantor, Elizabeth D. Zhang, Xuehong Wu, Kana Signorello, Lisa B. Chan, Andrew T. Fuchs, Charles S. Giovannucci, Edward L. TI Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses' Health Study and Health Professionals follow-up study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE chemoprevention; chondroitin; colorectal cancer; epidemiology; glucosamine ID DEXTRAN SULFATE SODIUM; C-REACTIVE PROTEIN; KNEE OSTEOARTHRITIS; DIETARY-SUPPLEMENTS; PROSTAGLANDIN E-2; DOWN-REGULATION; NITRIC-OXIDE; INFLAMMATION; ARTHRITIS; CHONDROCYTES AB Recent epidemiologic evidence has emerged to suggest that use of glucosamine and chondroitin supplements may be associated with reduced risk of colorectal cancer (CRC). We therefore evaluated the association between use of these non-vitamin, non-mineral supplements and risk of CRC in two prospective cohorts, the Nurses' Health Study and Health Professionals Follow-up Study. Regular use of glucosamine and chondroitin was first assessed in 2002 and participants were followed until 2010, over which time 672 CRC cases occurred. Cox proportional hazards regression was used to estimate relative risks (RRs) within each cohort, and results were pooled using a random effects meta-analysis. Associations were comparable across cohorts, with a RR of 0.79 (95% CI: 0.63-1.00) observed for any use of glucosamine and a RR of 0.77 (95% CI: 0.59-1.01) observed for any use of chondroitin. Use of glucosamine in the absence of chondroitin was not associated with risk of CRC, whereas use of glucosamine+chondroitin was significantly associated with risk (RR: 0.77; 95% CI: 0.58-0.999). The association between use of glucosamine+chondroitin and risk of CRC did not change markedly when accounting for change in exposure status over follow-up (RR: 0.75; 95% CI: 0.58-0.96), nor did the association significantly vary by sex, aspirin use, body mass index, or physical activity. The association was comparable for cancers of the colon and rectum. Results support a protective association between use of glucosamine and chondroitin and risk of CRC. Further study is needed to better understand the chemopreventive potential of these supplements. C1 [Kantor, Elizabeth D.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA. [Kantor, Elizabeth D.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Zhang, Xuehong; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Wu, Kana; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Signorello, Lisa B.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.] Harvard Med Sch, 181 Longwood Ave,Room 355, Boston, MA 02115 USA. RP Kantor, ED (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 485 Lexington Ave,2nd Floor, New York, NY 10017 USA.; Zhang, XH (reprint author), Harvard Med Sch, 181 Longwood Ave,Room 355, Boston, MA 02115 USA.; Zhang, XH (reprint author), Brigham & Womens Hosp, 181 Longwood Ave,Room 355, Boston, MA 02115 USA. EM kantore@mskcc.org; poxue@channing.harvard.edu FU National Cancer Institute of the National Institutes of Health [P50CA127003, UM1CA167552, UM1CA186107, P01CA87969, P01 CA55075] FX Grant sponsor: National Cancer Institute of the National Institutes of Health; Grant numbers: P50CA127003, UM1CA167552, UM1CA186107, P01CA87969, and P01 CA55075 NR 40 TC 0 Z9 0 U1 19 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2016 VL 139 IS 9 BP 1949 EP 1957 DI 10.1002/ijc.30250 PG 9 WC Oncology SC Oncology GA DV9TM UT WOS:000383285100008 PM 27357024 ER PT J AU Biondi, M Boas, DA Wilcox, T AF Biondi, Marisa Boas, David A. Wilcox, Teresa TI On the other hand: Increased cortical activation to human versus mechanical hands in infants SO NEUROIMAGE LA English DT Article DE Infants; fNIRS; Temporal cortex; Object processing; Human hands; Functional events ID NEAR-INFRARED SPECTROSCOPY; BIOLOGICAL MOTION PERCEPTION; GOAL-DIRECTED ACTIONS; MANIPULATABLE OBJECTS; INDIVIDUATION TASK; INTENDED ACTS; YOUNG INFANTS; BRAIN; RESPONSES; INTENTIONS AB There is a large body of work demonstrating that infants are sensitive to the distinction between human and mechanical entities from the early months of life, and have different expectations for the way these entities move and interact. The current work investigates the extent to which the functional organization of the immature brain reflects these early emerging sensitivities. Infants aged 8 months watched two kinds of hands (human or mechanical) engage in two kinds of events (one with a functional outcome and one without). Using functional near-infrared spectroscopy (fNIRS), we assessed hemodynamic activation in the left and right temporal and temporal-occipital cortex in response to these events. The neuroimaging data revealed a significantly greater increase in activation in the right middle-posterior temporal cortex to events executed by the human than the mechanical hand; the event in which the hand engaged (function or non-function) did not significantly influence hemodynamic responses. In comparison, the left middle-temporal cortex showed significantly greater activation to events executed by the human than mechanical hand, but only when the events were functionally relevant. That is, the left middle-posterior temporal cortex responded selectively to human (as compared to mechanical) agents, but only in the context of functionally relevant actions on objects. These results reveal that the immature brain is functionally specialized to support infants' processing of human and non-human agents as distinct entities. These results also shed light on the cognitive and cortical mechanisms that guide infants' learning about agentive action and object function. (C) 2016 Elsevier Inc. All rights reserved. C1 [Biondi, Marisa; Wilcox, Teresa] Texas A&M Univ, College Stn, TX 77843 USA. [Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Biondi, M (reprint author), Texas A&M Univ, College Stn, TX 77843 USA. OI Biondi, Marisa/0000-0002-1847-3637 FU [R01-HD057999]; [P41-RR14075] FX We thank Melissa Wallace Klapuch, Amy Hirshkowitz, Laura Hawkins, and the staff of the Infant Cognition Lab at Texas A&M University for help with data collection and management, and the infants and parents who so graciously participated in the research. Preparation of this manuscript was supported by grant R01-HD057999 to TW and grant P41-RR14075 to DAB. NR 84 TC 0 Z9 0 U1 7 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV PY 2016 VL 141 BP 143 EP 153 DI 10.1016/j.neuroimage.2016.07.021 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DX0SF UT WOS:000384074500014 PM 27417344 ER PT J AU Guo, YK Zhou, IY Chan, ST Wang, Y Mandeville, ET Igarashi, T Lo, EH Ji, XM Sun, PZ AF Guo, Yingkun Zhou, Iris Yuwen Chan, Suk-Tak Wang, Yu Mandeville, Emiri T. Igarashi, Takahiro Lo, Eng H. Ji, Xunming Sun, Phillip Zhe TI pH-sensitive MRI demarcates graded tissue acidification during acute stroke - pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI SO NEUROIMAGE LA English DT Article ID SATURATION-TRANSFER CEST; FOCAL CEREBRAL-ISCHEMIA; CHEMICAL-EXCHANGE RATE; RF IRRADIATION; HUMAN BRAIN; BLOOD-FLOW; QUANTITATIVE DESCRIPTION; INTRACELLULAR PH; REPETITION TIME; RAT-BRAIN AB pH-sensitive amide proton transfer (APT) MRI provides a surrogate metabolic biomarker that complements the widely-used perfusion and diffusion imaging. However, the endogenous APT MRI is often calculated using the asymmetry analysis (MTRasym), which is susceptible to an inhomogeneous shift due to concomitant semisolid magnetization transfer (MT) and nuclear overhauser (NOE) effects. Although the intact brain tissue has little pH variation, white and gray matter appears distinct in the MTRasym image. Herein we showed that the heterogeneous MTRasym shift not related to pH highly correlates with MT ratio (MTR) and longitudinal relaxation rate (R-1w), which can be reasonably corrected using the multiple regression analysis. Because there are relatively small MT and R-1w changes during acute stroke, we postulate that magnetization transfer and relaxation-normalized APT (MRAPT) analysis increases MRI specificity to acidosis over the routine MTRasym image, hence facilitates ischemic lesion segmentation. We found significant differences in perfusion, pH and diffusion lesion volumes (P < 0.001, ANOVA). Furthermore, MRAPT MRI depicted graded ischemic acidosis, with the most severe acidosis in the diffusion lesion (-1.05 +/- 0.29%/s), moderate acidification within the pH/diffusion mismatch (i.e., metabolic penumbra, -0.67 +/- 0.27%/s) and little pH change in the perfusion/pH mismatch (i.e., benign oligemia, -0.04 +/- 0.14%/s), providing refined stratification of ischemic tissue injury. (C) 2016 Elsevier Inc. All rights reserved. C1 [Guo, Yingkun; Zhou, Iris Yuwen; Chan, Suk-Tak; Wang, Yu; Igarashi, Takahiro; Sun, Phillip Zhe] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Wang, Yu; Ji, Xunming; Sun, Phillip Zhe] Capital Med Univ, China Amer Joint Neurosci Inst, Xuanwu Hosp, Beijing, Peoples R China. [Mandeville, Emiri T.; Lo, Eng H.; Sun, Phillip Zhe] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol & Neurol, Neuroprotect Res Lab, Charlestown, MA USA. [Guo, Yingkun] Sichuan Univ, West China Univ Hosp 2, Dept Radiol, Chengdu, Sichuan, Peoples R China. RP Sun, PZ (reprint author), MGH, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Rm 2301,CNY 149 13th St, Charlestown, MA 02129 USA.; Sun, PZ (reprint author), Harvard Med Sch, Rm 2301,CNY 149 13th St, Charlestown, MA 02129 USA. EM pzhesun@mgh.harvard.edu RI Zhou, Iris Yuwen/A-2089-2017 OI Zhou, Iris Yuwen/0000-0002-4351-7398 FU National Natural Science Foundation of China [81471721]; National Science Foundation for Distinguished Young Scholars; National Institutes of Health [R21NS085574, R01NS083654] FX This study was supported by research grants from the National Natural Science Foundation of China 81471721 (to Guo), National Science Foundation for Distinguished Young Scholars (to Ji), and the National Institutes of Health R21NS085574 and R01NS083654 (to Sun). NR 51 TC 5 Z9 5 U1 18 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV PY 2016 VL 141 BP 242 EP 249 DI 10.1016/j.neuroimage.2016.07.025 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DX0SF UT WOS:000384074500020 PM 27444569 ER PT J AU Chung, AW Schirmer, MD Krishnan, ML Ball, G Aljabar, P Edwards, AD Montana, G AF Chung, A. W. Schirmer, M. D. Krishnan, M. L. Ball, G. Aljabar, P. Edwards, A. D. Montana, G. TI Characterising brain network topologies: A dynamic analysis approach using heat kernels SO NEUROIMAGE LA English DT Article DE Brain connectivity networks; Connectome; Structural network; Heat kernel; Diffusion kernel; Synthetic networks; Preterm; Developing brain; Classification; Motor function; Diffusion MRI ID STATE FUNCTIONAL CONNECTIVITY; RICH-CLUB ORGANIZATION; SMALL-WORLD; HUMAN CONNECTOME; PRETERM BIRTH; MULTIPLE-SCLEROSIS; SPATIAL STATISTICS; ALZHEIMERS-DISEASE; CHILDREN BORN; DIFFUSION MRI AB Network theory provides a principled abstraction of the human brain: reducing a complex system into a simpler representation from which to investigate brain organisation. Recent advancement in the neuroimaging field is towards representing brain connectivity as a dynamic process in order to gain a deeper understanding of how the brain is organised for information transport. In this paper we propose a network modelling approach based on the heat kernel to capture the process of heat diffusion in complex networks. By applying the heat kernel to structural brain networks, we define new features which quantify change in heat propagation. Identifying suitable features which can classify networks between cohorts is useful towards understanding the effect of disease on brain architecture. We demonstrate the discriminative power of heat kernel features in both synthetic and clinical preterm data. By generating an extensive range of synthetic networks with varying density and randomisation, we investigate heat diffusion in relation to changes in network topology. We demonstrate that our proposed features provide a metric of network efficiency and may be indicative of organisational principles commonly associated with, for example, small-world architecture. In addition, we show the potential of these features to characterise and classify between network topologies. We further demonstrate our methodology in a clinical setting by applying it to a large cohort of preterm babies scanned at term equivalent age from which diffusion networks were computed. We show that our heat kernel features are able to successfully predict motor function measured at two years of age (sensitivity, specificity, F-score, accuracy = 75.0, 82.5, 78.6, and 82.3%, respectively). (C) 2016 Elsevier Inc. All rights reserved. C1 [Chung, A. W.; Montana, G.] Kings Coll London, Div Imaging Sci & Biomed Engn, Dept Biomed Engn, London, England. [Schirmer, M. D.] Harvard Med Sch, J Philip Kistler Stroke Res Ctr, Stroke Div, Boston, MA USA. [Schirmer, M. D.] Harvard Med Sch, J Philip Kistler Stroke Res Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Krishnan, M. L.; Ball, G.; Aljabar, P.; Edwards, A. D.] Kings Coll London, Ctr Dev Brain, Div Imaging Sci & Biomed Engn, London, England. RP Montana, G (reprint author), Kings Coll London, Div Imaging Sci & Biomed Engn, Dept Biomed Engn, London, England. EM giovanni.montana@kcl.ac.uk OI Ball, Gareth/0000-0003-3509-1435 FU NIHR Biomedical Research Centers at Guy's and St Thomas' NHS Trust; Imperial College Healthcare Trust; NIHR Programme Grants for Applied Research Programme [RP-PG-0707-10154] FX Data on preterm infants used in the paper was obtained as part of independent research commissioned by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRIC, CCF, NETSCC, the Programme Grants for Applied Research programme or the Department of Health. The programme of research funded by the NIHR Programme Grants for Applied Research Programme (RP-PG-0707-10154.) and in the future a compendium report of the whole programme will be published in the NIHR Journal. The work was also supported by the NIHR Biomedical Research Centers at Guy's and St Thomas' NHS Trust and Imperial College Healthcare Trust. NR 84 TC 1 Z9 1 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV PY 2016 VL 141 BP 490 EP 501 DI 10.1016/j.neuroimage.2016.07.006 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DX0SF UT WOS:000384074500042 PM 27421183 ER PT J AU Iglesias, JE Van Leemput, K Augustinack, J Insausti, R Fischl, B Reuter, M AF Iglesias, Juan Eugenio Van Leemput, Koen Augustinack, Jean Insausti, Ricardo Fischl, Bruce Reuter, Martin CA Alzheimer's Dis Neuroimaging Initi TI Bayesian longitudinal segmentation of hippocampal substructures in brain MRI using subject-specific atlases SO NEUROIMAGE LA English DT Article DE Hippocampal subfields; Longitudinal modeling; Segmentation; Bayesian modeling ID MILD COGNITIVE IMPAIRMENT; SURFACE-BASED ANALYSIS; HIGH-RESOLUTION MRI; IN-VIVO MRI; ALZHEIMERS-DISEASE; EPISODIC MEMORY; ATROPHY; SUBFIELDS; REGISTRATION; AD AB The hippocampal formation is a complex, heterogeneous structure that consists of a number of distinct, interacting subregions. Atrophy of these subregions is implied in a variety of neurodegenerative diseases, most prominently in Alzheimer's disease (AD). Thanks to the increasing resolution of MR images and computational atlases, automatic segmentation of hippocampal subregions is becoming feasible in MRI scans. Here we introduce a generative model for dedicated longitudinal segmentation that relies on subject-specific atlases. The segmentations of the scans at the different time points are jointly computed using Bayesian inference. All time points are treated the same to avoid processing bias. We evaluate this approach using over 4700 scans from two publicly available datasets (ADNI and MIRIAD). In test-retest reliability experiments, the proposed method yielded significantly lower volume differences and significantly higher Dice overlaps than the cross-sectional approach for nearly every subregion (average across subregions: 4.5% vs. 6.5%, Dice overlap: 81.8% vs. 75.4%). The longitudinal algorithm also demonstrated increased sensitivity to group differences: in MIRIAD (69 subjects: 46 with AD and 23 controls), it found differences in atrophy rates between AD and controls that the cross sectional method could not detect in a number of subregions: right parasubiculum, left and right presubiculum, right subiculum, left dentate gyrus, left CA4, left HATA and right tail. In ADNI (836 subjects: 369 with AD, 215 with early cognitive impairment - eMCI - and 252 controls), all methods found significant differences between AD and controls, but the proposed longitudinal algorithm detected differences between controls and eMCI and differences between eMCI and AD that the cross sectional method could not find: left presubiculum, right subiculum, left and right parasubiculum, left and right HATA. Moreover, many of the differences that the cross-sectional method already found were detected with higher significance. The presented algorithm will be made available as part of the open-source neuroimaging package FreeSurfer. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license C1 [Iglesias, Juan Eugenio] Basque Ctr Cognit Brain & Language, San Sebastian, Gipuzkoa, Spain. [Iglesias, Juan Eugenio] UCL, Translat Imaging Grp, London WC1E 6BT, England. [Van Leemput, Koen; Augustinack, Jean; Fischl, Bruce; Reuter, Martin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Van Leemput, Koen; Augustinack, Jean; Fischl, Bruce; Reuter, Martin] Harvard Med Sch, Boston, MA USA. [Van Leemput, Koen] Tech Univ Denmark, Dept Appl Math & Comp Sci, Lyngby, Denmark. [Insausti, Ricardo] Univ Castilla La Mancha, Human Neuroanat Lab, E-13071 Ciudad Real, Spain. [Fischl, Bruce; Reuter, Martin] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Iglesias, JE (reprint author), UCL, Translat Imaging Grp, London WC1E 6BT, England. EM e.iglesias@bcbl.eu FU European Union's Horizon research and innovation program under the Marie Sklodowska-Curie grant [654911]; Spanish Ministry of Economy and Competitiveness (MINECO) [TEC2014-51882-P]; National Cancer Institute [1K25-CA181632-01]; Genentech Foundation [G-40819]; Nvidia corporation; A.A. Martinos Center for Biomedical Imaging [P41RR014075, P41EB015896, U24RR021382]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758, R21EB018907, R01EB019956]; National Institute on Aging [5R01AG008122, R01AG016495]; National Institute for Neurological Disorders and Stroke [R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625]; Lundbeck Foundation [R141-2013-13117]; NIH Blueprint for Neuroscience Research, multi-institutional Human Connectome Project [5U01-MH093765]; CorticoMetrics; Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health) [U01 AG024904]; DOD ADNI (U.S. Department of Defense) [W81XWH-12-2-0012)]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 654911 (project "THALAMODEL"), and also from the Spanish Ministry of Economy and Competitiveness (MINECO, reference TEC2014-51882-P). Support for this research was also provided in part by the National Cancer Institute (1K25-CA181632-01), the Genentech Foundation (G-40819) and the Nvidia corporation, which donated a Titan X GPU. Further support was provided by the A.A. Martinos Center for Biomedical Imaging (P41RR014075, P41EB015896, U24RR021382), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Support was also provided by the National Institute for Biomedical Imaging and Bioengineering (R01EB006758, R21EB018907, R01EB019956), the National Institute on Aging (5R01AG008122, R01AG016495), the National Institute for Neurological Disorders and Stroke (R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625) and the Lundbeck Foundation (R141-2013-13117), Additional support was provided by the NIH Blueprint for Neuroscience Research (5U01-MH093765), as part of the multi-institutional Human Connectome Project. In addition, BF has a financial interest in CorticoMetrics, a company whose medical pursuits focus on brain imaging and measurement technologies. BF's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.; The collection and sharing of the MRI data used in the group study based on ADNI was funded by the Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904) and DOD ADNI (U.S. Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 59 TC 1 Z9 1 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV PY 2016 VL 141 BP 542 EP 555 DI 10.1016/j.neuroimage.2016.07.020 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DX0SF UT WOS:000384074500046 PM 27426838 ER PT J AU Varkanitsa, M Kasselimis, D Fugard, AJB Evdokimidis, I Druks, J Potagas, C Van de Koot, H AF Varkanitsa, Maria Kasselimis, Dimitrios Fugard, Andrew J. B. Evdokimidis, Ioannis Druks, Judit Potagas, Constantin Van de Koot, Hans TI Syntactic predictions and asyntactic comprehension in aphasia: Evidence from scope relations SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Aphasia; Sentence comprehension deficits; Syntactic predictions; Contrastive focus; Scope ambiguity ID SENTENCE COMPREHENSION; AGRAMMATIC APHASIA; EYE-MOVEMENTS; WORKING-MEMORY; INTEGRATION; ACTIVATION; RESOLUTION; DISTANCE; SUBJECT; CLAUSES AB People with aphasia (PWA) often fail to understand syntactically complex sentences. This phenomenon has been described as asyntactic comprehension and has been explored in various studies cross-linguistically in the past decades. However, until now there has been no consensus among researchers as to the nature of sentence comprehension failures in aphasia. Impaired representations accounts ascribe comprehension deficits to loss of syntactic knowledge, whereas processing/resource reduction accounts assume that PWA are unable to use syntactic knowledge in comprehension due to resource limitation resulting from the brain damage. The aim of this paper is to use independently motivated psycholinguistic models of sentence processing to test a variant of the processing/resource reduction accounts that we dub the Complexity Threshold Hypothesis. According to this hypothesis, PWA are capable of building well-formed syntactic representations, but, because their resources for language processing are limited, their syntactic parser fails when processing complexity exceeds a certain threshold. The source of complexity investigated in the experiments reported in this paper is syntactic prediction. We conducted two experiments involving comprehension of sentences with different types of syntactic dependencies, namely dependencies that do not require syntactic prediction (i.e. unpredictable dependencies in sentences that require Quantifier Raising) and dependencies whose resolution requires syntactic predictions at an early stage of processing based on syntactic cues (i.e. predictable dependencies in movement-derived sentences). In line with the predictions of the Complexity Threshold Hypothesis, the results show that the agrammatic patients that participated in this study had no difficulties comprehending sentences with the former type of dependencies, whereas their comprehension of sentences with the latter type of dependencies was impaired. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Varkanitsa, Maria; Druks, Judit; Van de Koot, Hans] UCL, Dept Linguist, London WC1E 6BT, England. [Kasselimis, Dimitrios] Univ Crete, Dept Psychol, Rethimnon, Greece. [Kasselimis, Dimitrios; Evdokimidis, Ioannis; Potagas, Constantin] Univ Athens, Sch Med, Dept Neurol, Athens, Greece. [Fugard, Andrew J. B.] UCL, Dept Clin Educ & Hlth Psychol, London WC1E 6BT, England. [Varkanitsa, Maria] Harvard Med Sch, Massachusetts Gen Hosp, Neuropsychol Lab, 100 Cambridge St 2057, Boston, MA 02114 USA. RP Varkanitsa, M (reprint author), Room 102,Chandler House 2,Wakefield St, London WC1N 1PF, England. EM maria.varkanitsa.09@ucl.ac.uk OI Varkanitsa, Maria/0000-0001-6040-6254; Fugard, Andrew/0000-0001-6507-2054 FU Greek State Scholarship Foundation (IKY); Alexander Onassis Public Benefit Foundation; A.G. Leventis Foundation; "IRAKLITOS II - University of Crete" of the Operational Program for Education and Lifelong Learning of the NSRF; European Union (European Social Fund); National Resources FX We would like to thank the individuals who participated in this study, especially the patients with aphasia. We would also like to thank Gordon Craig for an earlier version of statistical analysis of the data presented here. Special thanks also to Mike Coleman for creating the software used in the experiment. The first author received research funding from the Greek State Scholarship Foundation (IKY), the Alexander Onassis Public Benefit Foundation and the A.G. Leventis Foundation. The second author was supported by "IRAKLITOS II - University of Crete" of the Operational Program for Education and Lifelong Learning 2007-2013 of the NSRF (2007-2013), co-funded by the European Union (European Social Fund) and National Resources. NR 40 TC 0 Z9 0 U1 16 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD NOV PY 2016 VL 40 BP 15 EP 36 DI 10.1016/j.jneuroling.2016.04.001 PG 22 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA DW0DN UT WOS:000383311200002 ER PT J AU Christofferson, DE Hertzberg, JS Beckham, JC Dennis, PA Hamlett-Berry, K AF Christofferson, Dana E. Hertzberg, Jeffrey S. Beckham, Jean C. Dennis, Paul A. Hamlett-Berry, Kim TI Engagement and abstinence among users of a smoking cessation text message program for veterans SO ADDICTIVE BEHAVIORS LA English DT Article DE Smoking; Tobacco; Cessation; mHealth; Engagement; Veteran ID RANDOMIZED-TRIAL; HEALTH-PROMOTION; UNITED-STATES; INTERVENTIONS; SMOKERS; METAANALYSIS; ATTRITION; TEXT2QUIT; EFFICACY; HISTORY AB Background: SmokefreeVET is a text messaging smoking cessation program available to veterans enrolled in the Veterans Health Administration. SmokefreeVET was developed in collaboration with the National Cancer Institute as part of the SmokefreeTXT initiative. Purpose: To evaluate the real world use of and effectiveness of the SmokefreeVET program for SmokefreeVET users who enrolled between 2013 and 2014. Methods: Demographics and smoking behavior of 1470 SmokefreeVET users who enrolled between 2013 and 2014 were analyzed. Latent growth mixture modeling was used to identify discrete classes of SmokefreeVET users based on engagement patterns. Multi-level modeling determined class differences in abstinence. Results: The average age of the SmokefreeVET user was 48, 75% of users were male, and 84% were daily smokers. After five weeks, 13% of all users reported abstinence from smoking. Five statistically distinct engagement classes of SmokefreeVET users were identified. Highly engaged classes were significantly less likely to opt-out and more likely to report abstinence. Over 60% of users who were classified as high engagers throughout the program reported abstinence 5 weeks after their quit date. Users were more likely to report abstinence after two weeks if they used smoking cessation medication than those that did not use medication (OR = 9.01, p < 0.001). Conclusions: SmokefreeVET may be effective at supporting abstinence among a real world group of highly engaged users. Smoking cessation medication use was also associated with abstinence in SmokefreeVET users. Engagement appears to be a critical component when assessing the efficacy of a text messaging smoking cessation intervention. Published by Elsevier Ltd. C1 [Christofferson, Dana E.; Hamlett-Berry, Kim] Vet Hlth Adm, Off Patient Care Serv, US Dept Vet Affairs, 810 Vermont Ave NW, Washington, DC 20420 USA. [Hertzberg, Jeffrey S.; Beckham, Jean C.; Dennis, Paul A.] Durham VA Med Ctr, 508 Fulton St, Durham, NC 27705 USA. [Beckham, Jean C.] VA Mid Atlantic Mental Illness Res Educ & Clin Ct, 508 Fulton St, Durham, NC 27705 USA. [Beckham, Jean C.; Dennis, Paul A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, 2301 Erwin Rd, Durham, NC 27705 USA. RP Christofferson, DE (reprint author), Vet Hlth Adm, Tobacco & Hlth Policy & Programs, Off Patient Care Serv, US Dept Vet Affairs, 810 Vermont Ave NW 10P4M, Washington, DC 20420 USA. EM dana.christofferson@va.gov FU Department of Veterans Affairs, Veterans Health Administration (VHA): Office of Public Health; Office of Research and Development, Clinical Science Research and Development; Durham Veterans Affairs Medical Center; VISN 6 Mid-Atlantic Mental Illness Research, Education and Clinical Center, Office of Mental Health Services FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration (VHA): Office of Public Health; Office of Research and Development, Clinical Science Research and Development; the Durham Veterans Affairs Medical Center; and the VISN 6 Mid-Atlantic Mental Illness Research, Education and Clinical Center, Office of Mental Health Services. VHA had no role in the design, analysis and interpretation of data, drafting of the manuscript, or the decision to submit for publication. NR 43 TC 0 Z9 0 U1 14 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD NOV PY 2016 VL 62 BP 47 EP 53 DI 10.1016/j.addbeh.2016.06.016 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DT2QQ UT WOS:000381325900008 PM 27318948 ER PT J AU Fayette, J Wirth, L Oprean, C Udrea, A Jimeno, A Rischin, D Nutting, C Harari, PM Csoszi, T Cernea, D O'Brien, P Hanley, WD Kapp, AV Anderson, M Penuel, E McCall, B Pirzkall, A Vermorken, JB AF Fayette, Jerome Wirth, Lori Oprean, Cristina Udrea, Anghel Jimeno, Antonio Rischin, Danny Nutting, Christopher Harari, Paul M. Csoszi, Tibor Cernea, Dana O'Brien, Paul Hanley, William D. Kapp, Amy V. Anderson, Maria Penuel, Elicia McCall, Bruce Pirzkall, Andrea Vermorken, Jan B. TI Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study) SO FRONTIERS IN ONCOLOGY LA English DT Article DE NRG1; HER3; EGFR; SCCHN; HPV; duligotuzumab; MEHD7945A; cetuximab ID PLATINUM-BASED THERAPY; ACQUIRED-RESISTANCE; OPEN-LABEL; RECEPTOR; ANTIBODY; CANCER; EGFR; RECURRENT; DOCETAXEL; AFATINIB AB Background: Duligotuzumab, a novel dual -action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody -dependent cell -mediated cytotoxicity. High tumor -expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Methods: This multicenter, open -label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1 high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1 w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status]. Results: Patients (N =121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression -free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (Cl): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% Cl: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients with NRG/ -high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade >3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash -related events were less with duligotuzumab (49 vs. 67%). Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRGI, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab. C1 [Fayette, Jerome] Univ Lyon, Ctr Leon Berard, Lyon, France. [Wirth, Lori] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Oprean, Cristina] Oncomed SRL, Timisoara, Romania. [Udrea, Anghel] Medisprof SRL, Cluj Napoca, Romania. [Jimeno, Antonio] Univ Colorado, Ctr Canc, Aurora, CO USA. [Rischin, Danny] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Nutting, Christopher] Royal Marsden NHS Trust, Inst Canc Res London, Sutton, Surrey, England. [Harari, Paul M.] Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. [Csoszi, Tibor] Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz, Szolnok, Hungary. [Cernea, Dana] Inst Oncol Prof Dr Ion Chiricuta Cluj Napoca, Cluj Napoca, Romania. [O'Brien, Paul] Med Univ South Carolina, Charleston, SC USA. [Hanley, William D.; Kapp, Amy V.; Anderson, Maria; Penuel, Elicia; McCall, Bruce; Pirzkall, Andrea] Genentech Inc, San Francisco, CA USA. [Vermorken, Jan B.] Univ Antwerp Hosp, Edegem, Belgium. RP Fayette, J (reprint author), Univ Lyon, Ctr Leon Berard, Lyon, France. EM jerome.fayette@lyon.unicancer.fr FU Genentech, Inc., South San Francisco, CA, USA; Cancer Research UK [A13407]; RM/ICR NIHR Biomedical Research Centre FX This work was supported by Genentech, Inc., South San Francisco, CA, USA. CN was supported by Cancer Research UK Programme Grant A13407 and the RM/ICR NIHR Biomedical Research Centre. NR 26 TC 1 Z9 1 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD OCT 31 PY 2016 VL 6 AR 232 DI 10.3389/fonc.2016.00232 PG 12 WC Oncology SC Oncology GA EA3UR UT WOS:000386531300001 PM 27843803 ER PT J AU Villar, RF Patel, J Weaver, GC Kanekiyo, M Wheatley, AK Yassine, HM Costello, CE Chandler, KB McTamney, PM Nabel, GJ McDermott, AB Mascola, JR Carr, SA Lingwood, D AF Villar, Rina F. Patel, Jinal Weaver, Grant C. Kanekiyo, Masaru Wheatley, Adam K. Yassine, Hadi M. Costello, Catherine E. Chandler, Kevin B. McTamney, Patrick. M. Nabel, Gary J. McDermott, Adrian B. Mascola, John R. Carr, Steven A. Lingwood, Daniel TI Reconstituted B cell receptor signaling reveals carbohydrate-dependent mode of activation SO SCIENTIFIC REPORTS LA English DT Article ID INFLUENZA-VIRUS HEMAGGLUTININ; ANTIGEN RECEPTOR; NEUTRALIZING EPITOPE; BINDING-PROPERTIES; HUMORAL IMMUNITY; T-CELLS; ANTIBODY; EXPRESSION; RECOGNITION; DIVERSITY AB Activation of immune cells (but not B cells) with lectins is widely known. We used the structurally defined interaction between influenza hemagglutinin (HA) and its cell surface receptor sialic acid (SA) to identify a B cell receptor (BCR) activation modality that proceeded through non-cognate interactions with antigen. Using a new approach to reconstitute antigen-receptor interactions in a human reporter B cell line, we found that sequence-defined BCRs from the human germline repertoire could be triggered by both complementarity to influenza HA and a separate mode of signaling that relied on multivalent ligation of BCR sialyl-oligosaccharide. The latter suggested a new mechanism for priming naive B cell responses and manifested as the induction of SA-dependent pan-activation by peripheral blood B cells. BCR crosslinking in the absence of complementarity is a superantigen effect induced by some microbial products to subvert production of antigen-specific immune responses. B cell superantigen activity through affinity for BCR carbohydrate is discussed. C1 [Villar, Rina F.; Weaver, Grant C.; Lingwood, Daniel] Ragon Inst Massachusetts Gen Hosp Massachusetts I, 400 Technol Sq, Cambridge, MA 02139 USA. [Patel, Jinal; Carr, Steven A.] Broad Inst Massachusetts Inst Technol & Harvard U, 415 Main St, Cambridge, MA 02142 USA. [Kanekiyo, Masaru; McDermott, Adrian B.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20814 USA. [Wheatley, Adam K.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, 792 Elizabeth St, Melbourne, Vic 3000, Australia. [Yassine, Hadi M.] Qatar Univ, Biomed Res Ctr, QU NRC, POB 2713 Doha Qatar, Doha, Qatar. [Costello, Catherine E.; Chandler, Kevin B.] Boston Univ, Sch Med, 670 Albany St, Boston, MA 02118 USA. [McTamney, Patrick. M.] Medimmune LLC, One MedImmune Way, Gaithersburg, MD 20878 USA. [Nabel, Gary J.] Sanofi, 640 Mem Dr, Cambridge, MA 02139 USA. RP Lingwood, D (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, 400 Technol Sq, Cambridge, MA 02139 USA. EM dlingwood@mgh.harvard.edu OI Chandler, Kevin/0000-0001-5514-9652 FU Harvard University CFAR grant [P30 AI060354]; William F. Milton Fund; Gilead Sciences Research Scholars Program in HIV; Broad-Ragon ENDHIV Catalytic Grant; [P41 GM104602]; [S10 OD010724] FX This work was supported by the following awards to D.L.: a Harvard niversity CFAR grant (P30 AI060354); the William F. Milton Fund; the Gilead Sciences Research Scholars Program in HIV; and an Broad-Ragon ENDHIV Catalytic Grant (jointly awarded to D.L. and S.A.C.). C.E.C and K.B.C. were supported by P41 GM104602 and S10 OD010724 grants. NR 64 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 31 PY 2016 VL 6 AR 36298 DI 10.1038/srep36298 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA3MP UT WOS:000386507200001 PM 27796362 ER PT J AU Wang, B Abraham, N Gao, GD Yang, Q AF Wang, Bao Abraham, Neeta Gao, Guodong Yang, Qian TI Dysregulation of autophagy and mitochondrial function in Parkinson's disease SO TRANSLATIONAL NEURODEGENERATION LA English DT Review DE Parkinson's disease; Autophagy; Macroautophagy; Mitophagy; Chaperone-mediated autophagy; Mitochondria; alpha-synuclein; PINK/Parkin; LRRK2; DJ-1 ID CHAPERONE-MEDIATED AUTOPHAGY; PROTEIN ALPHA-SYNUCLEIN; SURVIVAL FACTOR MEF2D; IPSC-DERIVED NEURONS; COMPLEX-I ACTIVITY; PINK1/PARKIN PATHWAY; MOLECULAR-MECHANISMS; REGULATES AUTOPHAGY; CALCIUM HOMEOSTASIS; INHIBITS AUTOPHAGY AB Parkinson's disease (PD) is the second most common neurodegenerative disease. Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis. In this review, we briefly summarized autophagy pathway, which consists of macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Then, we discussed the involvement of mitochondrial dysfunction in PD pathogenesis. We specifically reviewed the recent developments in the relationship among several PD related genes, autophagy and mitochondrial dysfunction, followed by the therapeutic implications of these pathways. In conclusion, we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD. Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration. C1 [Wang, Bao; Gao, Guodong; Yang, Qian] Fourth Mil Med Univ, Tangdu Hosp, Dept Neurosurg, 569 Xinsi Rd, Xian 710038, Shaanxi Provinc, Peoples R China. [Wang, Bao; Abraham, Neeta] Harvard Med Sch, Dept Neurol, Beth Isreal Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. RP Yang, Q (reprint author), Fourth Mil Med Univ, Tangdu Hosp, Dept Neurosurg, 569 Xinsi Rd, Xian 710038, Shaanxi Provinc, Peoples R China. EM qianyang@fmmu.edu.cn NR 103 TC 0 Z9 0 U1 20 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-9158 J9 TRANSL NEURODEGENER JI Transl. Neurodegener. PD OCT 31 PY 2016 VL 5 AR 19 DI 10.1186/s40035-016-0065-1 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EA3PS UT WOS:000386516600001 PM 27822367 ER PT J AU Tian, F Yang, WL Mordes, DA Wang, JY Salameh, JS Mok, J Chew, J Sharma, A Leno-Duran, E Suzuki-Uematsu, S Suzuki, N Han, SS Lu, FK Ji, MBA Zhang, R Liu, Y Strominger, J Shneider, NA Petrucelli, L Xie, XS Eggan, K AF Tian, Feng Yang, Wenlong Mordes, Daniel A. Wang, Jin-Yuan Salameh, Johnny S. Mok, Joanie Chew, Jeannie Sharma, Aarti Leno-Duran, Ester Suzuki-Uematsu, Satomi Suzuki, Naoki Han, Steve S. Lu, Fa-Ke Ji, Minbiao Zhang, Rosanna Liu, Yue Strominger, Jack Shneider, Neil A. Petrucelli, Leonard Xie, X. Sunney Eggan, Kevin TI Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging SO NATURE COMMUNICATIONS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DEGENERATION; IN-VIVO; TRANSGENIC MICE; MOUSE MODEL; MICROSCOPY; PATHOGENESIS; SOD1(G93A); SURVIVAL; TISSUE AB The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics. C1 [Tian, Feng; Mordes, Daniel A.; Wang, Jin-Yuan; Mok, Joanie; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Eggan, Kevin] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Tian, Feng; Mordes, Daniel A.; Wang, Jin-Yuan; Mok, Joanie; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Eggan, Kevin] Harvard Univ, Dept Mol & Cellular Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tian, Feng; Mordes, Daniel A.; Wang, Jin-Yuan; Mok, Joanie; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Zhang, Rosanna; Liu, Yue; Eggan, Kevin] Broad Inst MITand Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Yang, Wenlong; Lu, Fa-Ke; Ji, Minbiao; Xie, X. Sunney] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Mordes, Daniel A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Salameh, Johnny S.] Univ Massachusetts, Dept Neurol, Mem Med Ctr, Worcester, MA 01655 USA. [Chew, Jeannie; Petrucelli, Leonard] Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Sharma, Aarti; Shneider, Neil A.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10032 USA. [Lu, Fa-Ke] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02215 USA. [Suzuki-Uematsu, Satomi] Tohuku Univ, Div Adv Surg Sci & Technol, Dept Transplantat Reconstruct & Endoscop Surg, Sendai, Miyagi 9808572, Japan. [Suzuki, Naoki] Tohoku Univ, Dept Neurol, Sch Med, Sendai, Miyagi 9808574, Japan. [Han, Steve S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ji, Minbiao] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Liu, Yue] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. RP Eggan, K (reprint author), Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Eggan, K (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Eggan, K (reprint author), Broad Inst MITand Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.; Xie, XS (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM xie@chemistry.harvard.edu; eggan@mcb.harvard.edu FU Howard Hughes Medical Institute; Target ALS; NINDS [RO1NS01NS089742, R01NS07377]; National Institute of Health/National Institute of Biomedical Imaging and Bioengineering [5R01EB010244]; Massachusetts Alzheimer's Disease Research Center [NIA P50 AG005134]; NCI [5T32CA009216-34]; Mochida Memorial Foundation for Medical and Pharmaceutical Research; National Institutes of Health/National Institute on Aging [P50AG016574]; National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS084528, R01NS088689, R01NS063964, R01NS077402, P01NS084974]; National Institute of Environmental Health Services [R01ES20395]; Mayo Clinic Foundation; Mayo Graduate School; ALS Association; Robert Packard Center for ALS Research at Johns Hopkins FX We thank P. Arlotta, A. Cohen, F. Engert and J. Lichtman for informative suggestions on this work. We also thank A. Huang for the discussion on spectral reconstruction and S. Oh for the help on SRS signal measurement. This work was supported by the Howard Hughes Medical Institute, Target ALS, NINDS grant RO1NS01NS089742 to KE and National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (Award #: 5R01EB010244). D.A.M. was supported by the Massachusetts Alzheimer's Disease Research Center (NIA P50 AG005134) and NCI 5T32CA009216-34. N.S. was a 2011 Lilly Scientific Fellow and received grant from The Mochida Memorial Foundation for Medical and Pharmaceutical Research. N.A.S and A.S. were supported by the National Institute of Neurological Disorders and Stroke (NINDS) (Award#: R01NS07377). This work was supported by the National Institutes of Health/National Institute on Aging (P50AG016574 (L.P.)), National Institutes of Health/National Institute of Neurological Disorders and Stroke (R21NS084528 (L.P.), R01NS088689 (L.P.), R01NS063964 (L.P.); R01NS077402 (L.P.); P01NS084974 (L.P.)), National Institute of Environmental Health Services (R01ES20395 (L.P.)), Mayo Clinic Foundation (L.P.), Mayo Graduate School (J.C.), ALS Association (L.P.) and Robert Packard Center for ALS Research at Johns Hopkins (L.P.), Target ALS (L.P.). NR 64 TC 2 Z9 2 U1 20 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 31 PY 2016 VL 7 AR 13283 DI 10.1038/ncomms13283 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA2WB UT WOS:000386455400001 PM 27796305 ER PT J AU Zou, J Valiant, G Valiant, P Karczewski, K Chan, SO Samocha, K Lek, M Sunyaev, S Daly, M MacArthur, DG AF Zou, James Valiant, Gregory Valiant, Paul Karczewski, Konrad Chan, Siu On Samocha, Kaitlin Lek, Monkol Sunyaev, Shamil Daly, Mark MacArthur, Daniel G. TI Quantifying unobserved protein-coding variants in human populations provides a roadmap for large-scale sequencing projects SO NATURE COMMUNICATIONS LA English DT Article ID HUMAN GENOME; NUMBER AB As new proposals aim to sequence ever larger collection of humans, it is critical to have a quantitative framework to evaluate the statistical power of these projects. We developed a new algorithm, UnseenEst, and applied it to the exomes of 60,706 individuals to estimate the frequency distribution of all protein-coding variants, including rare variants that have not been observed yet in the current cohorts. Our results quantified the number of new variants that we expect to identify as sequencing cohorts reach hundreds of thousands of individuals. With 500K individuals, we find that we expect to capture 7.5% of all possible loss-of-function variants and 12% of all possible missense variants. We also estimate that 2,900 genes have loss-of-function frequency of <0.00001 in healthy humans, consistent with very strong intolerance to gene inactivation. C1 [Zou, James] Stanford Univ, Dept Biomed Data Sci, Palo Alto, CA 94305 USA. [Valiant, Gregory] Stanford Univ, Dept Comp Sci, Palo Alto, CA 94305 USA. [Valiant, Paul] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Karczewski, Konrad; Samocha, Kaitlin; Lek, Monkol; Daly, Mark; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Karczewski, Konrad; Samocha, Kaitlin; Lek, Monkol; Sunyaev, Shamil; Daly, Mark; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Chan, Siu On] Chinese Univ Hong Kong, Comp Sci & Engn, Hong Kong, Hong Kong, Peoples R China. [Sunyaev, Shamil] Harvard Med Sch, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA. [Daly, Mark; MacArthur, Daniel G.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Zou, J (reprint author), Stanford Univ, Dept Biomed Data Sci, Palo Alto, CA 94305 USA.; MacArthur, DG (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; MacArthur, DG (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; MacArthur, DG (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM jamesz@stanford.edu; danmac@broadinstitute.org FU NSF CAREER Award [CCF-1351108]; Sloan Research Fellowship; NSF [IIS-1562657]; NIH [U54DK105566, R01GM104371] FX We wish to acknowledge Simon Gravel and Iuliana Ionita-Laza for helpful discussion and feedback. We also like to thank the Exome Aggregation Consortium for generating the data used in this paper. This work was supported in part by NSF CAREER Award CCF-1351108 to G.V., a Sloan Research Fellowship and NSF Grant IIS-1562657, and NIH Grants U54DK105566 and R01GM104371 to D.M. NR 21 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 31 PY 2016 VL 7 AR 13293 DI 10.1038/ncomms13293 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA2WH UT WOS:000386456100001 PM 27796292 ER PT J AU Coutinho, J Goncalves, OF Soares, JM Marques, P Sampaio, A AF Coutinho, Joana Goncalves, Oscar Filipe Soares, Jose Miguel Marques, Paulo Sampaio, Adriana TI Alterations of the default mode network connectivity in obsessive-compulsive personality disorder: A pilot study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Obsessive-compulsive personality disorder; Neuroimaging; Functional MRI; Default-mode network; Functional connectivity ID MAJOR DEPRESSION; EPISODIC MEMORY; POSTERIOR CINGULATE; BRAIN ACTIVITY; CORTEX; SELF; INVENTORY; EMOTION; FUTURE; MIND AB Obsessive-compulsive personality (OCPD) disorder is characterized by a pattern of excessive self-control, perfectionism and behavioral and cognitive rigidity. Despite the fact that OCPD is the most common personality disorder in the general population, published studies looking at the brain correlates of this disorder are practically nonexistent. The main goal of this study was to analyze the presence of brain alterations in OCPD when compared to healthy controls, specifically at the level of the Default Mode Network (DMN). The DMN is a well-established resting state network which was found to be associated with psychological processes that may play a key role in OCPD (e.g., self-awareness, episodic future thinking and mental simulation). Ten individuals diagnosed with OCPD and ten healthy controls underwent a clinical assessment interview and a resting-state functional magnetic resonance imaging (fMRI) acquisition. The results show that OCPD patients presented an increased functional connectivity in the precuneus (i.e., a posterior node of the DMN), known to be involved in the retrieval manipulation of past events in order to solve current problems and develop plans for the future. These results suggest that this key node of the DMN may play an important role in the pathophysiology of OCPD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Coutinho, Joana; Goncalves, Oscar Filipe; Sampaio, Adriana] Univ Minho, Sch Psychol, Neuropsychophysiol Lab, CIPsi, Campus Gualtar, P-4710057 Braga, Portugal. [Soares, Jose Miguel; Marques, Paulo] Univ Minho, Life & Hlth Sci Res Inst, Braga, Portugal. [Soares, Jose Miguel; Marques, Paulo] ICVS 3Bs PT Govt Associate Lab, Braga, Guimaraes, Portugal. [Goncalves, Oscar Filipe] Northeastern Univ, Bouve Coll Hlth Sci, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. [Goncalves, Oscar Filipe] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Spaulding Ctr Neuromodulat, Boston, MA USA. [Goncalves, Oscar Filipe] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Coutinho, J (reprint author), Univ Minho, Sch Psychol, Neuropsychophysiol Lab, CIPsi, Campus Gualtar, P-4710057 Braga, Portugal. EM joanafpc@gmail.com RI Goncalves, Oscar/G-5278-2010; OI Goncalves, Oscar/0000-0003-2735-9155; Marques, Paulo/0000-0002-6304-4989 FU Portuguese Foundation for Science and Technology; Portuguese Ministry of Education and Science; FEDER through COMPETE under the PTPartnership Agreement [POCI-01-0145-FEDER-007653]; FCT postdoctoral grant [SFRH/BPD/75014/2010]; Bial Foundation [87/12] FX This study was conducted at Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653).; Joana Coutinho was funded by a FCT postdoctoral grant (number: SFRH/BPD/75014/2010) and Bial Foundation (grant number 87/12). NR 68 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 30 PY 2016 VL 256 BP 1 EP 7 DI 10.1016/j.pscychresns.2016.08.007 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ9HX UT WOS:000386187000001 PM 27591486 ER PT J AU Monteith, LL Bahraini, NH Matarazzo, BB Gerber, HR Soberay, KA Forster, JE AF Monteith, Lindsey L. Bahraini, Nazanin H. Matarazzo, Bridget B. Gerber, Holly R. Soberay, Kelly A. Forster, Jeri E. TI The influence of gender on suicidal ideation following military sexual trauma among Veterans in the Veterans Health Administration SO PSYCHIATRY RESEARCH LA English DT Article DE Suicidal ideation; Military; Gender; Sexual assault; Sexual harassment; Sexual violence; Posttraumatic stress disorder ID POSTTRAUMATIC-STRESS-DISORDER; PSYCHOMETRIC PROPERTIES; OEF/OIF VETERANS; CLINICAL-SAMPLE; RISK-FACTORS; DEPLOYMENT; PERSONNEL; EXPERIENCES; BARRIERS; ASSAULT AB No studies have examined whether military sexual trauma, as measured and defined within the Veterans Health Administration (VHA), is associated with suicidal ideation among Veterans in VHA care, when taking prior suicide attempts into account. Research regarding the role of gender in this association is also limited. The present study examined: (1) whether military sexual trauma was associated with the presence of past-week suicidal ideation among 354 Veterans in VHA (310 men, 44 women); (2) whether gender moderated the association between military sexual trauma and suicidal ideation. Information regarding military sexual trauma, suicidal ideation, suicide attempt, and psychiatric diagnoses was obtained from self-report instruments and medical records. Adjusting for age, gender, combat, posttraumatic stress disorder, depressive disorders, negative affect, and lifetime suicide attempt, Veterans with military sexual trauma were significantly more likely to report suicidal ideation, compared to Veterans without military sexual trauma. Furthermore, the association between military sexual trauma and suicidal ideation was stronger for men compared to women. These results contribute to a growing literature identifying military sexual trauma as a risk factor for suicidal thoughts and behaviors among Veterans in VHA care and emphasize the importance of screening for suicidal ideation among survivors of military sexual trauma. Published by Elsevier Ireland Ltd. C1 [Monteith, Lindsey L.; Bahraini, Nazanin H.; Matarazzo, Bridget B.; Gerber, Holly R.; Soberay, Kelly A.; Forster, Jeri E.] Rocky Mt Mental Illness Res Educ & Clin Ctr, Denver Vet Affairs Med Ctr, 1055 Clermont St, Denver, CO USA. [Monteith, Lindsey L.; Bahraini, Nazanin H.; Matarazzo, Bridget B.] Univ Colorado, Dept Psychiat, Anschutz Med Campus, Aurora, CO USA. [Bahraini, Nazanin H.; Forster, Jeri E.] Univ Colorado, Dept Phys Med & Rehabil, Anschutz Med Campus, Aurora, CO USA. [Forster, Jeri E.] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. RP Monteith, LL (reprint author), Rocky Mt Mental Illness Res Educ & Clin Ctr, Denver Vet Affairs Med Ctr, 1055 Clermont St, Denver, CO USA. EM Lindsey.Monteith@va.gov NR 46 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD OCT 30 PY 2016 VL 244 BP 257 EP 265 DI 10.1016/j.psychres.2016.07.036 PG 9 WC Psychiatry SC Psychiatry GA DY0HA UT WOS:000384776700039 PM 27504921 ER PT J AU Habeck, M Tokhtaeva, E Nadav, Y Ben Zeev, E Ferris, SP Kaufman, RJ Bab-Dinitz, E Kaplan, JH Dada, LA Farfel, Z Tal, DM Katz, A Sachs, G Vagin, O Karlish, SJD AF Habeck, Michael Tokhtaeva, Elmira Nadav, Yotam Ben Zeev, Efrat Ferris, Sean P. Kaufman, Randal J. Bab-Dinitz, Elizabeta Kaplan, Jack H. Dada, Laura A. Farfel, Zvi Tal, Daniel M. Katz, Adriana Sachs, George Vagin, Olga Karlish, Steven J. D. TI Selective Assembly of Na,K-ATPase alpha(2)beta(2) Heterodimers in the Heart DISTINCT FUNCTIONAL PROPERTIES AND ISOFORM-SELECTIVE INHIBITORS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SODIUM-POTASSIUM PUMP; CARDIAC NA/K ATPASE; NA+/K+-ATPASE; PICHIA-PASTORIS; K-ATPASE; ADHESION MOLECULE; CRYSTAL-STRUCTURE; ALPHA-2 ISOFORM; BETA-SUBUNIT; INTRAOCULAR-PRESSURE AB The Na, K-ATPase alpha(2) subunit plays a key role in cardiac muscle contraction by regulating intracellular Ca2+, whereas alpha(1) has a more conventional role of maintaining ion homeostasis. The beta subunit differentially regulates maturation, trafficking, and activity of alpha-beta heterodimers. It is not known whether the distinct role of alpha(2) in the heart is related to selective assembly with a particular one of the three beta isoforms. We show here by immunofluorescence and co-immunoprecipitation that alpha(2) is preferentially expressed with beta(2) in T-tubules of cardiac myocytes, forming alpha(2)beta(2) heterodimers. We have expressed human alpha(1)beta(1), alpha(2)beta(1), alpha(2)beta(2), and alpha(2)beta(3) in Pichia pastoris, purified the complexes, and compared their functional properties. alpha(2)beta(2) and alpha(2)beta(3) differ significantly from both alpha(2)beta(1) and alpha(1)beta(1) in having a higher K0.5K+ and lower K0.5Na+ for activating Na, K-ATPase. These features are the result of a large reduction in binding affinity for extracellular K+ and shift of the E1P-E2P conformational equilibrium toward E1P. A screen of perhydro-1,4-oxazepine derivatives of digoxin identified several derivatives (e.g. cyclobutyl) with strongly increased selectivity for inhibition of alpha(2)beta(2) and alpha(2)beta(3) over alpha(1)beta(1) (range 22-33-fold). Molecular modeling suggests a possible basis for isoform selectivity. The preferential assembly, specific T-tubular localization, and low K+ affinity of alpha(2)beta(2) could allow an acute response to raised ambient K+ concentrations in physiological conditions and explain the importance of alpha(2)beta(2) for cardiac muscle contractility. The high sensitivity of alpha(2)beta(2) to digoxin derivatives explains beneficial effects of cardiac glycosides for treatment of heart failure and potential of alpha(2)beta(2)-selective digoxin derivatives for reducing cardiotoxicity. C1 [Bab-Dinitz, Elizabeta; Farfel, Zvi; Tal, Daniel M.; Katz, Adriana; Karlish, Steven J. D.] Weizmann Inst Sci, Dept Biomol Sci, IL-7610001 Rehovot, Israel. [Ben Zeev, Efrat] Weizmann Inst Sci, Israel Natl Ctr Personalized Med, IL-7610001 Rehovot, Israel. [Farfel, Zvi] Tel Aviv Univ, Sch Med, IL-6997801 Tel Aviv, Israel. [Tokhtaeva, Elmira; Sachs, George; Vagin, Olga] Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA. [Tokhtaeva, Elmira; Sachs, George; Vagin, Olga] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Ferris, Sean P.; Kaufman, Randal J.] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Kaplan, Jack H.] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Dada, Laura A.] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60611 USA. [Ferris, Sean P.] Univ Calif San Francisco, Dept Pathol, 513 Parnassus Ave,Hlth Sci West 451,Box 0102, San Francisco, CA 94143 USA. [Kaufman, Randal J.] Sanford Burnham Prebys Med Discovery Inst, Rm 7103,10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. RP Karlish, SJD (reprint author), Weizmann Inst Sci, Dept Biomol Sci, IL-7610001 Rehovot, Israel.; Vagin, O (reprint author), Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90073 USA.; Vagin, O (reprint author), Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. EM olgav@ucla.edu; Steven.Karlish@weizmann.ac.il OI Habeck, Michael/0000-0002-4586-0499 FU Israel Science Foundation [789/12]; US-Israel Binational Science Foundation [711993]; National Institutes of Health [R37-HL48129, RO1HL113350]; USVA [2I01BX001006, 1RO1DK105156-01] FX This work was supported by Israel Science Foundation (789/12) and US-Israel Binational Science Foundation (711993, to S. J. D. K.) and, in part, by National Institutes of Health Grants R37-HL48129 (to L. A. D.), RO1HL113350 (to L. A. D. and O. V.), USVA 2I01BX001006 (to G. S.), and 1RO1DK105156-01 (to G. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 76 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 28 PY 2016 VL 291 IS 44 BP 23159 EP 23174 DI 10.1074/jbc.M116.751735 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EB2XB UT WOS:000387224800026 PM 27624940 ER PT J AU Karna, SLR D'Arpa, P Chen, T Qian, LW Fourcaudot, AB Yamane, K Chen, P Abercrombie, JJ You, T Leung, KP AF Karna, S. L. Rajasekhar D'Arpa, Peter Chen, Tsute Qian, Li-Wu Fourcaudot, Andrea B. Yamane, Kazuyoshi Chen, Ping Abercrombie, Johnathan J. You, Tao Leung, Kai P. TI RNA-Seq Transcriptomic Responses of FullThickness Dermal Excision Wounds to Pseudomonas aeruginosa Acute and Biofilm Infection SO PLOS ONE LA English DT Article ID ALTERNATIVE SIGMA-FACTOR; GENE-EXPRESSION DATA; RABBIT-EAR; METABOLIC STRESS; OXIDATIVE STRESS; IN-VITRO; MODEL; ACTIVATION; PVDS; REGULATORS AB Pseudomonas aeruginosa infections of wounds in clinical settings are major complications whose outcomes are influenced by host responses that are not completely understood. Herein we evaluated transcriptomic changes of wounds as they counter P. aeruginosa infection D first active infection, and then chronic biofilm infection. We used the dermal fullthickness, rabbit ear excisional wound model. We studied the wound response: towards acute infection at 2, 6, and 24 hrs after inoculating 10(6) bacteria into day-3 wounds; and, towards more chronic biofilm infection of wounds similarly infected for 24 hrs but then treated with topical antibiotic to coerce biofilm growth and evaluated at day 5 and 9 postinfection. The wounds were analyzed for bacterial counts, expression of P. aeruginosa virulence and biofilm-synthesis genes, biofilm morphology, infiltrating immune cells, re-epithelialization, and genome-wide gene expression (RNA-Seq transcriptome). This analysis revealed that 2 hrs after bacterial inoculation into day-3 wounds, the down-regulated genes (infected vs. non-infected) of the wound edge were nearly all non-coding RNAs (ncRNAs), comprised of snoRNA, miRNA, and RNU6 pseudogenes, and their down-regulation preceded a general down-regulation of skin-enriched coding gene expression. As the active infection intensified, ncRNAs remained overrepresented among down-regulated genes; however, at 6 and 24 hrs they changed to a different set, which overlapped between these times, and excluded RNU6 pseudogenes but included snRNA components of the major and minor spliceosomes. Additionally, the raw counts of multiple types of differentiallyexpressed ncRNAs increased on post-wounding day 3 in control wounds, but infection suppressed this increase. After 5 and 9 days, these ncRNA counts in control wounds decreased, whereas they increased in the infected, healing-impaired wounds. These data suggest a sequential and coordinated change in the levels of transcripts of multiple major classes of ncRNAs in wound cells transitioning from inflammation to the proliferation phase of healing. C1 [Karna, S. L. Rajasekhar; Qian, Li-Wu; Fourcaudot, Andrea B.; Yamane, Kazuyoshi; Chen, Ping; Abercrombie, Johnathan J.; You, Tao; Leung, Kai P.] US Army Inst Surg Res, Dent & Craniofacial Trauma Res & Tissue Regenerat, Jbsa Ft Sam Houston, TX USA. [D'Arpa, Peter] US Army Ctr Environm Hlth Res, Ft Detrick, MD USA. [D'Arpa, Peter] Geneva Fdn, Tacoma, WA USA. [Chen, Tsute] Forsyth Inst, Cambridge, MA USA. RP Leung, KP (reprint author), US Army Inst Surg Res, Dent & Craniofacial Trauma Res & Tissue Regenerat, Jbsa Ft Sam Houston, TX USA. EM kai.p.leung.civ@mail.mil FU US Army Medical Research and Materiel Command; Combat Casualty Care Research Directorate; Naval Medical Research Center's Advanced Medical Development program [MIPR N3239815MHX040]; Research Associateship Program from the National Research Council; U. S. Army Research Laboratory; U.S. Army Research Office [W911NF1310376] FX This work was supported in part by the US Army Medical Research and Materiel Command, Combat Casualty Care Research Directorate and the Naval Medical Research Center's Advanced Medical Development program (MIPR N3239815MHX040) (KPL)and the Research Associateship Program from the National Research Council (SLRK). P. D'Arpa is supported by the U. S. Army Research Laboratory and the U.S. Army Research Office under contract/grant number W911NF1310376 to The Geneva Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2016 VL 11 IS 10 DI 10.1371/journal.pone.0165312 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3YA UT WOS:000389537000017 ER PT J AU Shah, R Pico, AR Freedman, JE AF Shah, Ravi Pico, Alexander R. Freedman, Jane E. TI Translational Epidemiology: Entering a Brave New World of Team Science SO CIRCULATION RESEARCH LA English DT Editorial Material DE genomics; metabolomics; research; risk factors; science ID BODY-MASS INDEX; CARDIOVASCULAR-DISEASE; RISK; VARIANTS; PATHWAYS; LOCI C1 [Shah, Ravi] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Pico, Alexander R.] Univ Calif San Francisco, Dept Bioinformat, Gladstone Inst, San Francisco, CA 94143 USA. [Freedman, Jane E.] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. RP Shah, R (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA.; Freedman, JE (reprint author), Univ Massachusetts, Sch Med, Plantat St, Worcester, MA 01605 USA. EM rvshah@partners.org; jane.freedman@umassmed.edu FU NCATS NIH HHS [UH2 TR000921, UH3 TR000921]; NHLBI NIH HHS [K23 HL127099, U01 HL126495] NR 13 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 28 PY 2016 VL 119 IS 10 BP 1060 EP 1062 DI 10.1161/CIRCRESAHA.116.309881 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EB3FN UT WOS:000387248800007 PM 27789584 ER PT J AU Fujiwara, N Som, AT Pham, LDD Lee, BJ Mandeville, ET Lo, EH Arai, K AF Fujiwara, Norio Som, Angel T. Pham, Loc-Duyen D. Lee, Brian J. Mandeville, Emiri T. Lo, Eng H. Arai, Ken TI A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model SO NEUROSCIENCE LETTERS LA English DT Article DE Stroke; Edaravone; Oxidative stress; Pro-inflammatory cytokine; Middle cerebral artery occlusion; Protein array ID CEREBRAL-ARTERY OCCLUSION; OXIDATIVE STRESS; BRAIN-DAMAGE; MITOCHONDRIAL DYSFUNCTION; NEURONAL DEATH; STROKE; INJURY; MCI-186; NEUROPROTECTION; MECHANISMS AB A free radical scavenger edaravone is clinically used in Japan for acute stroke, and several basic researches have carefully examined the mechanisms of edaravone's protective effects. However, its actions on pro-inflammatory responses under stroke are still understudied. In this study, we subjected adult male Sprague-Dawley rats to 90-min middle cerebral artery (MCA) occlusion followed by reperfusion. Edaravone was treated twice via tail vein; after MCA occlusion and after reperfusion. As expected, edaravone-treated group showed less infarct volume and edema formation compared with control group at 24-h after an ischemic onset. Furthermore, edaravone reduced the levels of plasma interleukin (IL)-1 beta and matrix metalloproteinase-9 at 3-h after ischemic onset. Several molecules besides IL-1 beta and MMP-9 are involved in inflammatory responses under stroke conditions. Therefore, we also examined whether edaravone treatment could decrease a wide range of pro-inflammatory cytokines/chemokines by testing rat plasma samples with a rat cytokine array. MCAO rats showed elevations in plasma levels of CINC-1, Fractalkine, IL-l alpha, IL-lra, IL-6, IL-10, IP-10, MIG, MIP-l alpha, and MIP-3 alpha, and all these increases were reduced by edaravone treatment. These data suggest that free radical scavengers may reduce systemic inflammatory responses under acute stroke conditions, and therefore, oxidative stress can be still a viable target for acute stroke therapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Lo, EH; Arai, K (reprint author), Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM lo@helix.mgh.harvard.edu; karai@partners.org FU National Institutes of Health [R37 NS037074, P01 NS055104, R01 NS065089] FX This study was funded by National Institutes of Health (grant numbers: R37 NS037074, P01 NS055104, R01 NS065089). NR 47 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 28 PY 2016 VL 633 BP 7 EP 13 DI 10.1016/j.neulet.2016.08.048 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EA8BY UT WOS:000386861500002 PM 27589890 ER PT J AU Cherry, JD Tripodis, Y Alvarez, VE Huber, B Kiernan, PT Daneshvar, DH Mez, J Montenigro, PH Solomon, TM Alosco, ML Stern, RA Mckee, AC Stein, TD AF Cherry, Jonathan D. Tripodis, Yorghos Alvarez, Victor E. Huber, Bertrand Kiernan, Patrick T. Daneshvar, Daniel H. Mez, Jesse Montenigro, Philip H. Solomon, Todd M. Alosco, Michael L. Stern, Robert A. McKee, Ann C. Stein, Thor D. TI Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE CTE; Neuroinflammation; Microglia; Repetitive head impacts; Mild traumatic brain injury; American football ID BETA-AMYLOID DEPOSITION; BRAIN-INJURY; ALZHEIMERS-DISEASE; AXONAL INJURY; MOUSE MODEL; HEAD-INJURY; NEURODEGENERATION; PATHOLOGY; INFLAMMATION; TAUOPATHY AB The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran's Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE. C1 [Cherry, Jonathan D.; Alvarez, Victor E.; Huber, Bertrand; Kiernan, Patrick T.; Daneshvar, Daniel H.; Mez, Jesse; Montenigro, Philip H.; Solomon, Todd M.; Alosco, Michael L.; Stern, Robert A.; McKee, Ann C.; Stein, Thor D.] Boston Univ, Alzheimers Dis, Boston, MA 02215 USA. [Cherry, Jonathan D.; Alvarez, Victor E.; Huber, Bertrand; Kiernan, Patrick T.; Daneshvar, Daniel H.; Mez, Jesse; Montenigro, Philip H.; Solomon, Todd M.; Alosco, Michael L.; Stern, Robert A.; McKee, Ann C.; Stein, Thor D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Cherry, Jonathan D.; Alvarez, Victor E.; Huber, Bertrand; Kiernan, Patrick T.; Mez, Jesse; Alosco, Michael L.; Stern, Robert A.; McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Tripodis, Yorghos] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Montenigro, Philip H.; Stern, Robert A.; McKee, Ann C.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [McKee, Ann C.; Stein, Thor D.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [McKee, Ann C.; Stein, Thor D.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [McKee, Ann C.; Stein, Thor D.] Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. RP Stein, TD (reprint author), Boston Univ, Alzheimers Dis, Boston, MA 02215 USA.; Stein, TD (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA.; Stein, TD (reprint author), Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA.; Stein, TD (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Stein, TD (reprint author), Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. EM tdstein@bu.edu FU CSRD VA [I01 CX001038]; NHLBI NIH HHS [N01HC25195]; NIA NIH HHS [P30 AG013846, R01 AG008122, K23 AG046377]; NINDS NIH HHS [F32 NS096803, U01 NS086659] NR 38 TC 3 Z9 3 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD OCT 28 PY 2016 VL 4 AR 112 DI 10.1186/s40478-016-0382-8 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EA2RN UT WOS:000386442500001 PM 27793189 ER PT J AU White, MC Horner, KC Lai, PS AF White, Michelle C. Horner, Katherine C. Lai, Peggy S. TI Retrospective Review of the Anaesthetic Management of Maxillectomies and Mandibulectomies for Benign Tumours in Sub-Saharan Africa SO PLoS One LA English DT Review ID NATIONAL AUDIT PROJECT; DEVELOPING-COUNTRIES; MAJOR COMPLICATIONS; AIRWAY MANAGEMENT; ROYAL-COLLEGE; AMELOBLASTOMA; SURGERY; RISK AB Background Safe anaesthesia is a crucial component of safe surgical care, yet anaesthetic complications are common in resource-limited settings. We describe differences in anaesthetic needs for Mandibulectomy vs. Maxillectomy in three sub-Saharan African countries. Materials and Methods Retrospective review of patients undergoing minor Mandibulectomy, major Mandibulectomy, or Maxillectomy in Togo, Guinea and Republic of the Congo. Surgeries were performed on the Africa Mercy, an international non-governmental hospital ship. Primary outcomes were need for advanced airway management and intra-operative blood loss. Secondary outcomes were time under general anaesthesia and hospital length of stay. Multivariate regression determined the association between operation type and each outcome measure. Results 105 patients were included (25 minor Mandibulectomy, 58 major Mandibulectomy, 22 Maxillectomy procedures). In-hospital mortality was 0%. 44/105 (41.9%) required an advanced airway management technique to achieve intubation, although in all cases this was anticipated prior to the procedure; no differences were noted between surgical procedure (p = 0.72). Operative procedure was a significant risk factor for intra-operative blood loss. Patients undergoing Maxillectomy lost on average 851.5 (413.3, 1289.8, p = 0.0003) mL more blood than patients undergoing minor Mandibulectomy, and 507.3 (150.3, 864.3, p = 0.007) mL more blood than patients undergoing major Mandibulectomy. Patients undergoing Maxillectomy had a significantly higher time under general anaesthesia than those undergoing minor Mandibulectomy. There was no significant difference in hospital length of stay between operation type. Conclusion Anaesthetic considerations for minor Mandibulectomy, major Mandibulectomy, and Maxillectomy differ with respect to intra-operative blood loss and time under general anaesthesia, but not need for advanced airway management or length of stay. Although advanced airway management was required in 41.9% of patients, there were no unanticipated difficult airways. With appropriate training and resources, safe anaesthesia can be delivered to patients from low-income countries requiring major head and neck surgery. C1 [White, Michelle C.; Horner, Katherine C.] Mercy Ships, Dept Anaesthesia, Reg 12, Port Au Toamasina, Madagascar. [Lai, Peggy S.] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. RP White, MC (reprint author), Mercy Ships, Dept Anaesthesia, Reg 12, Port Au Toamasina, Madagascar. EM doctormcw@gmail.com FU US National Institutes of Health [K23 ES023700] FX The authors received no specific funding for this work. PSL reports receiving salary support from the US National Institutes of Health (K23 ES023700). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2016 VL 11 IS 10 DI 10.1371/journal.pone.0165090 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4VY UT WOS:000389604900042 ER PT J AU Albert, RK Au, DH Blackford, AL Casaburi, R Cooper, JA Criner, GJ Diaz, P Fuhlbrigge, AL Gay, SE Kanner, RE MacIntyre, N Martinez, FJ Panos, RJ Piantadosi, S Sciurba, F Shade, D Stibolt, T Stoller, JK Wise, R Yusen, RD Tonascia, J Sternberg, AL Bailey, W AF Albert, Richard K. Au, David H. Blackford, Amanda L. Casaburi, Richard Cooper, J. Allen, Jr. Criner, Gerard J. Diaz, Philip Fuhlbrigge, Anne L. Gay, Steven E. Kanner, Richard E. MacIntyre, Neil Martinez, Fernando J. Panos, Ralph J. Piantadosi, Steven Sciurba, Frank Shade, David Stibolt, Thomas Stoller, James K. Wise, Robert Yusen, Roger D. Tonascia, James Sternberg, Alice L. Bailey, William CA Long-Term Oxygen Treatment Trial TI A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; 60 MM HG; EXERCISE; THERAPY; SCALE; VALIDITY; QUALITY; DYSPNEA; INDEX AB BACKGROUND Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation. METHODS We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo(2)], 89 to 93%). After 7 months and the randomization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo(2) >= 80% for >= 5 minutes and < 90% for >= 10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1: 1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked. RESULTS A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = 0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes. CONCLUSIONS In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198.) C1 [Albert, Richard K.] Univ Colorado, Denver, CO 80202 USA. [Au, David H.] Vet Affairs VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Au, David H.] Univ Washington, Seattle, WA 98195 USA. [Blackford, Amanda L.; Casaburi, Richard] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Shade, David; Tonascia, James; Sternberg, Alice L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Casaburi, Richard] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Piantadosi, Steven] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Cooper, J. Allen, Jr.] Birmingham VA Med Ctr, Birmingham, AL USA. [Cooper, J. Allen, Jr.; Bailey, William] Univ Alabama Birmingham, Birmingham, AL USA. [Criner, Gerard J.] Temple Univ, Lewis Katz Sch Med, Philadelphia, PA 19122 USA. [Sciurba, Frank] Univ Pittsburgh, Pittsburgh, PA USA. [Diaz, Philip] Ohio State Univ, Columbus, OH 43210 USA. [Panos, Ralph J.] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Panos, Ralph J.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Stoller, James K.] Cleveland Clin, Cleveland, OH 44106 USA. [Fuhlbrigge, Anne L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Fuhlbrigge, Anne L.] Harvard Med Sch, Boston, MA USA. [Gay, Steven E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Kanner, Richard E.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [MacIntyre, Neil] Duke Univ, Med Ctr, Durham, NC USA. [Martinez, Fernando J.] Weill Cornell Med Ctr, New York, NY USA. [Stibolt, Thomas] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Yusen, Roger D.] Washington Univ, Sch Med, St Louis, MO 63130 USA. RP Wise, R (reprint author), Johns Hopkins Asthma & Allergy Ctr, Div Pulm & Crit Care, 4B-72,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM rwise@jhmi.edu FU National Heart, Lung, and Blood Institute; Centers for Medicare and Medicaid Services FX Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198. NR 29 TC 2 Z9 2 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 27 PY 2016 VL 375 IS 17 BP 1617 EP 1627 DI 10.1056/NEJMoa1604344 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EB2DX UT WOS:000387168900008 ER PT J AU Simmons, LH Goldstein, AJ Boruta, DM Stall, JN AF Simmons, Leigh H. Goldstein, Alan J. Boruta, David M., II Stall, Jennifer N. TI Case 33-2016: A 30-Year-Old Woman with Severe Lower Abdominal Pain and Chills ANATOMICAL DIAGNOSIS SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUBOOVARIAN-ABSCESS; OVARIAN ABSCESS C1 [Simmons, Leigh H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Goldstein, Alan J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Boruta, David M., II] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Stall, Jennifer N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Simmons, LH (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 27 PY 2016 VL 375 IS 17 BP 1672 EP 1681 DI 10.1056/NEJMcpc1609308 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EB2DX UT WOS:000387168900014 PM 27783909 ER PT J AU Luther, J Pierce, VM AF Luther, Jay Pierce, Virginia M. TI Case 21-2016: A Man in an Unresponsive State REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Luther, Jay; Pierce, Virginia M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Luther, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 27 PY 2016 VL 375 IS 17 BP 1697 EP 1697 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EB2DX UT WOS:000387168900023 PM 27783904 ER PT J AU Pham, TD Pham, PQ Li, JF Letai, AG Wallace, DC Burke, PJ AF Pham, Ted D. Pham, Phi Q. Li, Jinfeng Letai, Anthony G. Wallace, Douglas C. Burke, Peter J. TI Cristae remodeling causes acidification detected by integrated graphene sensor during mitochondrial outer membrane permeabilization SO SCIENTIFIC REPORTS LA English DT Article ID CYTOCHROME-C RELEASE; FIELD-EFFECT TRANSISTORS; CELL-DEATH; CULTURED-CELLS; APOPTOSIS; PH; ACTIVATION; CANCER; BAX; PHOSPHORYLATION AB The intrinsic apoptotic pathway and the resultant mitochondrial outer membrane permeabilization (MOMP) via BAK and BAX oligomerization, cytochrome c (cytc) release, and caspase activation are well studied, but their effect on cytosolic pH is poorly understood. Using isolated mitochondria, we show that MOMP results in acidification of the surrounding medium. BAK conformational changes associated with MOMP activate the OMA1 protease to cleave OPA1 resulting in remodeling of the cristae and release of the highly concentrated protons within the cristae invaginations. This was revealed by utilizing a nanomaterial graphene as an optically clear and ultrasensitive pH sensor that can measure ionic changes induced by tethered mitochondria. With this platform, we have found that activation of mitochondrial apoptosis is accompanied by a gradual drop in extra-mitochondrial pH and a decline in membrane potential, both of which can be rescued by adding exogenous cytc. These findings have importance for potential pharmacological manipulation of apoptosis, in the treatment of cancer. C1 [Pham, Ted D.; Burke, Peter J.] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92697 USA. [Pham, Phi Q.; Li, Jinfeng; Burke, Peter J.] Univ Calif Irvine, Dept Chem Engn & Mat Sci, Irvine, CA 92697 USA. [Letai, Anthony G.] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Wallace, Douglas C.] Univ Penn, Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Wallace, Douglas C.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Burke, Peter J.] Univ Calif Irvine, Dept Elect Engn & Comp Sci, Irvine, CA 92697 USA. RP Burke, PJ (reprint author), Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92697 USA.; Burke, PJ (reprint author), Univ Calif Irvine, Dept Chem Engn & Mat Sci, Irvine, CA 92697 USA.; Burke, PJ (reprint author), Univ Calif Irvine, Dept Elect Engn & Comp Sci, Irvine, CA 92697 USA. EM pburke@uci.edu FU NIH [RO1NS21328, RO1OD010944]; ARO [MURI W911NF-11-1-0024]; National Science Foundation Lifechips Integrative Graduate Education and Research Traineeship [0 549 479] FX This work was supported in part by the following grants awarded to D.C.W.: NIH RO1NS21328, RO1OD010944. P.B. acknowledges support of this work from a joint grant with D.C.W. and A.G.L. NIH IMAT R33CA183384, as well as support from the ARO (MURI W911NF-11-1-0024). Ted Pham is supported by the National Science Foundation Lifechips Integrative Graduate Education and Research Traineeship 0 549 479. We thank Jenny Lee for assistance in mitochondria isolation. NR 62 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 27 PY 2016 VL 6 AR 35907 DI 10.1038/srep35907 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EA6UB UT WOS:000386763400001 PM 27786282 ER PT J AU Kaz, AM Wong, CJ Varadan, V Willis, JE Chak, A Grady, WM AF Kaz, Andrew M. Wong, Chao-Jen Varadan, Vinay Willis, Joseph E. Chak, Amitabh Grady, William M. TI Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use SO CLINICAL EPIGENETICS LA English DT Article DE Barrett's esophagus; Esophageal adenocarcinoma; DNA methylation; Obesity; Waist-to-hip ratio; Tobacco use ID FALSE DISCOVERY RATE; BODY-MASS INDEX; HEPATOCELLULAR-CARCINOMA; NEOPLASTIC PROGRESSION; THERAPEUTIC TARGET; COLORECTAL-CANCER; GENE-EXPRESSION; GASTRIC-CANCER; HUMAN GENOME; RISK-FACTORS AB Background: The risk of developing Barrett's esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influences the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina). Results: We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups. Conclusions: Our findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation. C1 [Kaz, Andrew M.] VA Puget Sound Hlth Care Syst, Gastroenterol Sect, Seattle, WA 98108 USA. [Kaz, Andrew M.; Wong, Chao-Jen; Grady, William M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Kaz, Andrew M.; Grady, William M.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Varadan, Vinay; Chak, Amitabh] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Willis, Joseph E.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. [Chak, Amitabh] Case Western Reserve Univ, Sch Med, Div Gastroenterol, Cleveland, OH 44106 USA. RP Kaz, AM (reprint author), VA Puget Sound Hlth Care Syst, Gastroenterol Sect, Seattle, WA 98108 USA.; Kaz, AM (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. EM Andrew.Kaz@va.gov FU National Institutes of Health [U54CA163060, U01CA152756, 5P30CA015704, U01CA086402, U01CA182940, P50CA150964]; Listwin Family Foundation; Mercer Island Rotary Club; VA Puget Sound Health Care System FX This work was supported by the National Institutes of Health (U54CA163060 to AK, AC, VV, and WG, U01CA152756, 5P30CA015704, U01CA086402, and U01CA182940 to WG, and P50CA150964 to VV); the Listwin Family Foundation to WG, and the Mercer Island Rotary Club to WG. This material is the result of work supported in part by resources from the VA Puget Sound Health Care System. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 79 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1868-7083 J9 CLIN EPIGENETICS JI Clin. Epigenetics PD OCT 27 PY 2016 VL 8 AR 111 DI 10.1186/s13148-016-0273-7 PG 16 WC Oncology SC Oncology GA EA0DH UT WOS:000386255200001 PM 27795744 ER PT J AU Lesbats, P Engelman, AN Cherepanov, P AF Lesbats, Paul Engelman, Alan N. Cherepanov, Peter TI Retroviral DNA Integration SO CHEMICAL REVIEWS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; AVIAN-SARCOMA VIRUS; STRAND TRANSFER INHIBITORS; TYPE-1 PREINTEGRATION COMPLEXES; TO-AUTOINTEGRATION FACTOR; BROMODOMAIN PROTEIN BRD4; PROTOTYPE FOAMY VIRUS; LONG TERMINAL REPEAT; MAMMARY-TUMOR VIRUS AB The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3'-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications. C1 [Lesbats, Paul; Cherepanov, Peter] Francis Crick Inst, Clare Hall Labs, Blanche Lane, S Mimms EN6 3LD, Herts, England. [Engelman, Alan N.] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA. [Engelman, Alan N.] Harvard Med Sch, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. [Cherepanov, Peter] Imperial Coll London, St Marys Campus,Norfolk Pl, London W2 1PG, England. RP Cherepanov, P (reprint author), Francis Crick Inst, Clare Hall Labs, Blanche Lane, S Mimms EN6 3LD, Herts, England.; Engelman, AN (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA.; Engelman, AN (reprint author), Harvard Med Sch, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA.; Cherepanov, P (reprint author), Imperial Coll London, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM alan_engelman@dfci.harvard.edu; peter.cherepanov@crick.ac.uk RI Cherepanov, Peter/F-6859-2010 OI Cherepanov, Peter/0000-0002-0634-538X FU US National Institutes of Health [R37 AI039394, R01 AI052014, P50 GM082251]; Francis Crick Institute, Cancer Research UK; UK Medical Research Council; Wellcome Trust FX We thank H. Aihara, M. Kvaratskhelia, and M. Foster for sharing data prior to publication and V. Pie for critical reading of the manuscript. This work was in part funded by US National Institutes of Health grants R37 AI039394 and R01 AI052014 (to A.N.E) and P50 GM082251 (to P.C.). This work was additionally supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. NR 399 TC 9 Z9 9 U1 15 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 EI 1520-6890 J9 CHEM REV JI Chem. Rev. PD OCT 26 PY 2016 VL 116 IS 20 BP 12730 EP 12757 DI 10.1021/acs.chemrev.6b00125 PG 28 WC Chemistry, Multidisciplinary SC Chemistry GA EA3WX UT WOS:000386541100005 PM 27198982 ER PT J AU Zhang, JW Gao, G Begum, G Wang, JH Khanna, AR Shmukler, BE Daubner, GM de los Heros, P Davies, P Varghese, J Bhuiyan, MIH Duan, JJ Zhang, J Duran, D Alper, SL Sun, D Elledge, SJ Alessi, DR Kahle, KT AF Zhang, Jinwei Gao, Geng Begum, Gulnaz Wang, Jinhua Khanna, Arjun R. Shmukler, Boris E. Daubner, Gerrit M. de los Heros, Paola Davies, Paul Varghese, Joby Bhuiyan, Mohammad Iqbal H. Duan, Jinjing Zhang, Jin Duran, Daniel Alper, Seth L. Sun, Dandan Elledge, Stephen J. Alessi, Dario R. Kahle, Kristopher T. TI Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain SO SCIENTIFIC REPORTS LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; CELL-VOLUME; BARRIER PERMEABILITY; ACTIVATES SGK1; EAA RELEASE; NULL MICE; PHOSPHORYLATION; BLOOD; PROTEIN; KINASES AB Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr(991)/Thr(1048) phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD). In the mammalian brain, we found the Cl- -sensitive WNK3-SPAK kinase complex, required for cell shrinkage-induced regulatory volume decrease (RVI) via the stimulatory phosphorylation of NKCC1 (Thr(203)/Thr(207)/Thr(212)), is also essential for the inhibitory phosphorylation of KCC3 (Thr991/Thr1048). This is mediated in vivo by an interaction between the CCT domain in SPAK and RFXV/I domains in WNK3 and NKCC1/KCC3. Accordingly, genetic or pharmacologic WNK3-SPAK inhibition prevents cell swelling in response to osmotic stress and ameliorates post-ischemic brain swelling through a simultaneous inhibition of NKCC1-mediated Cl-uptake and stimulation of KCC3-mediated Cl-extrusion. We conclude that WNK3-SPAK is an integral component of the long-sought "Cl-/volume-sensitive kinase" of the cation-Cl- cotransporters, and functions as a molecular rheostat of cell volume in the mammalian brain. C1 [Zhang, Jinwei; Daubner, Gerrit M.; de los Heros, Paola; Davies, Paul; Varghese, Joby; Alessi, Dario R.] Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Coll Life Sci, Dundee DD1 5EH, Scotland. [Zhang, Jinwei; Duan, Jinjing; Duran, Daniel] Yale Sch Med, Dept Neurosurg, New Haven, CT 06511 USA. [Zhang, Jinwei; Duan, Jinjing; Duran, Daniel] Yale Sch Med, Dept Pediat, New Haven, CT 06511 USA. [Gao, Geng] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Begum, Gulnaz; Bhuiyan, Mohammad Iqbal H.; Sun, Dandan] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15213 USA. [Wang, Jinhua] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wang, Jinhua] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA. [Khanna, Arjun R.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Shmukler, Boris E.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA USA. [Shmukler, Boris E.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Shmukler, Boris E.; Alper, Seth L.] Harvard Med Sch, Dept Med, Boston, MA USA. [Duan, Jinjing; Zhang, Jin] Boston Childrens Hosp, Dept Cardiol, Howard Hughes Med Inst, Boston, MA 02115 USA. [Sun, Dandan] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kahle, Kristopher T.] Yale Sch Med, Dept Pediat, Interdept Neurosci Program, New Haven, CT 06511 USA. [Kahle, Kristopher T.] Yale Sch Med, Dept Cellular Mol Physiol, Interdept Neurosci Program, New Haven, CT 06511 USA. [Kahle, Kristopher T.] Yale Sch Med, Ctr Mendelian Genom, New Haven, CT 06511 USA. [de los Heros, Paola] Univ Nacl Autonoma Mexico, Fac Med, Div Invest, Mexico City, DF, Mexico. RP Zhang, JW (reprint author), Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Coll Life Sci, Dundee DD1 5EH, Scotland.; Zhang, JW (reprint author), Yale Sch Med, Dept Neurosurg, New Haven, CT 06511 USA.; Zhang, JW (reprint author), Yale Sch Med, Dept Pediat, New Haven, CT 06511 USA.; Kahle, KT (reprint author), Yale Sch Med, Dept Pediat, Interdept Neurosci Program, New Haven, CT 06511 USA.; Kahle, KT (reprint author), Yale Sch Med, Dept Cellular Mol Physiol, Interdept Neurosci Program, New Haven, CT 06511 USA.; Kahle, KT (reprint author), Yale Sch Med, Ctr Mendelian Genom, New Haven, CT 06511 USA. EM j.c.zhang@dundee.ac.uk; kristopher.kahle@yale.edu OI Duran, Daniel/0000-0001-6888-252X; Zhang, Jinwei/0000-0001-8683-509X FU Medical Research Council [MC_UU_12016/2]; AstraZeneca; Boehringer-Ingelheim; GlaxoSmithKline; Merck KGaA; Janssen Pharmaceutica; Pfizer; NIH LINCS Program [U54HL127365]; Harvard-MIT Neuroscience Grant FX We thank the excellent technical support of the MRC-Protein Phosphorylation and Ubiquitylation Unit (PPU) DNA Sequencing Service (coordinated by Nicholas Helps), the MRC-PPU tissue culture team (coordinated by Laura Fin), the Division of Signal Transduction Therapy (DSTT) antibody purification teams (coordinated by Hilary McLauchlan and James Hastie). We are grateful to the MRC PPU Proteomics facility (coordinated by David Campbell, Robert Gourlay and Joby Varghese). We thank for support the Medical Research Council (MC_UU_12016/2; DRA) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KGaA, Janssen Pharmaceutica and Pfizer; DRA). We thank Thomas J. Jentsch (Max-Delbruck-Centrum fur Molekulare Medizin) for providing the KCC1/3 double KO mice and his reading of this manuscript. We thank Nathaniel Grey (Harvard) for providing the kinase inhibitor library used in this study (NIH LINCS Program grant U54HL127365). This work was also supported by a Harvard-MIT Neuroscience Grant (to KTK/SJE). NR 76 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 26 PY 2016 VL 6 AR 35986 DI 10.1038/srep35986 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ8GP UT WOS:000386109200001 PM 27782176 ER PT J AU Wang, AL Yan, XE Wu, H Wang, WC Hu, C Chen, C Zhao, Z Zhao, P Li, XX Wang, L Wang, BL Ye, Z Wang, JH Wang, C Zhang, W Gray, NS Weisberg, EL Chen, L Liu, J Yun, CH Liu, QS AF Wang, Aoli Yan, Xiao-E Wu, Hong Wang, Wenchao Hu, Chen Chen, Cheng Zhao, Zheng Zhao, Peng Li, Xixiang Wang, Li Wang, Beilei Ye, Zi Wang, Jinhua Wang, Chu Zhang, Wei Gray, Nathanael S. Weisberg, Ellen L. Chen, Liang Liu, Jing Yun, Cai-Hong Liu, Qingsong TI Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation SO ONCOTARGET LA English DT Article DE Ibrutinib; EGFR kinase; DFG-in/c-Helix-out; inactive conformation; NSCLC ID BRUTONS TYROSINE KINASE; MANTLE-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; GROWTH-FACTOR RECEPTOR; INHIBITORS; BTK; SYSTEM; CRYSTALLOGRAPHY; ACTIVATION; RESISTANCE AB Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 mu M), Ibrutinib exhibited less efficient binding (Kd: 0.18 mu M). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix- out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC. C1 [Wang, Aoli; Wu, Hong; Wang, Wenchao; Hu, Chen; Chen, Cheng; Zhao, Zheng; Li, Xixiang; Wang, Li; Wang, Beilei; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China. [Wang, Aoli; Wu, Hong; Hu, Chen; Chen, Cheng; Wang, Li; Wang, Beilei; Liu, Qingsong] Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China. [Yan, Xiao-E; Zhao, Peng; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Beijing Key Lab Tumor Syst Biol, Inst Syst Biomed,Dept Biophys, Beijing 100191, Peoples R China. [Yan, Xiao-E; Zhao, Peng; Yun, Cai-Hong] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China. [Wang, Wenchao; Zhao, Zheng; Liu, Jing; Liu, Qingsong] Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. [Ye, Zi; Wang, Chu] Peking Univ, Peking Tsinghua Ctr Life Sci,Minist Educ, Coll Chem & Mol Engn,Key Lab Bioorgan Chem & Mol, Synthet & Funct Biomol Ctr,Beijing Natl Lab Mol S, Beijing 100871, Peoples R China. [Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Wei; Chen, Liang] Natl Inst Biol Sci, Collaborat Innovat Ctr Canc Med, Beijing 102206, Peoples R China. [Weisberg, Ellen L.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Liu, J; Liu, QS (reprint author), Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China.; Liu, QS (reprint author), Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China.; Yun, CH (reprint author), Peking Univ, Hlth Sci Ctr, Beijing Key Lab Tumor Syst Biol, Inst Syst Biomed,Dept Biophys, Beijing 100191, Peoples R China.; Yun, CH (reprint author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Mol & Translat Med, Beijing 100191, Peoples R China.; Liu, J; Liu, QS (reprint author), Chinese Acad Sci, Hefei Sci Ctr, Hefei 230031, Anhui, Peoples R China. EM jingliu@hmfl.ac.cn; yunch@hsc.pku.edu.cn; qsliu97@hmfl.ac.cn FU National Key Reasearch and Development Program of China [2016YFA0400900]; National Program for Support of Top-Notch Young Professionals; grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation" from Chinese Academy of Sciences; NIH [P01 CA154303-03]; China "Thousand Talents Program"; "Hundred Talents Program" of The Chinese Academy of Sciences; National Science Foundation of China [31270769]; National Basic Research Program of China (973 Program) [2012CB917202]; High-end User Cultivation Program of Hefei Science Center of CAS [2016HSC-IU007]; CAS/SAFEA International Partnership Program for Creative Research Teams FX J. Liu is supported by the National Key Reasearch and Development Program of China (#2016YFA0400900) and the National Program for Support of Top-Notch Young Professionals. J. Liu, Q. Liu, W. Wang and L. Cheng are supported by the grant of "Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)" from Chinese Academy of Sciences. N. Gray is supported by NIH grant P01 CA154303-03. We want to thank China "Thousand Talents Program" support for Q. Liu and C. Wang; "Hundred Talents Program" of The Chinese Academy of Sciences support for J. Liu, and W. Wang. C.-H.Y. is funded by the National Science Foundation of China (No. 31270769) and the National Basic Research Program of China (973 Program, No. 2012CB917202). Q. Liu is also supported by the High-end User Cultivation Program of Hefei Science Center of CAS (#2016HSC-IU007) and the CAS/SAFEA International Partnership Program for Creative Research Teams. NR 27 TC 1 Z9 1 U1 15 U2 15 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 69760 EP 69769 DI 10.18632/oncotarget.11951 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300051 PM 27626175 ER PT J AU Zhang, X Jia, DY Ao, JP Liu, HJ Zang, Y Azam, M Habib, SL Li, J Ruan, XS Jia, H Wang, XY Li, BJ AF Zhang, Xin Jia, Deyong Ao, Junping Liu, Huijuan Zang, Yi Azam, Mohammad Habib, Samy L. Li, Jia Ruan, Xinsen Jia, Hao Wang, Xueying Li, Baojie TI Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia SO ONCOTARGET LA English DT Article DE Bisindolylmaleimide IX; BCR-ABL; chronic myeloid leukemia (CML) ID CHRONIC MYELOID-LEUKEMIA; PROTEIN-KINASE-C; DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; CELL-DEATH; STEM/PROGENITOR CELLS; IMATINIB RESISTANCE; CDC25 PHOSPHATASES; TOPOISOMERASE-I; CANCER-THERAPY AB Chronic myeloid leukemia (CML) treatment with BCR-ABL inhibitors is often hampered by development of drug resistance. In a screen for novel chemotherapeutic drug candidates with genotoxic activity, we identified a bisindolylmaleimide derivative, IX, as a small molecule compound with therapeutic potential against CML including drug-resistant CML. We show that Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, activates the Atm-p53 and Atm-Chk2 pathways, and induces cell cycle arrest and cell death. Interestingly, Bisindolylmaleimide IX is highly effective in targeting cells positive for BCR-ABL. BCR-ABL positive cells display enhanced DNA damage and increased cell cycle arrest in response to Bisindolylmaleimide IX due to decreased expression of topoisomerases. Cells positive for BCR-ABL or drug-resistant T315I BCR-ABL also display increased cytotoxicity since Bisindolylmaleimide IX inhibits B-Raf and the downstream oncogene addiction pathway. Mouse cancer model experiments showed that Bisindolylmaleimide IX, at doses that show little side effect, was effective in treating leukemia-like disorders induced by BCR-ABL or T315I BCR-ABL, and prolonged the lifespan of these model mice. Thus, Bisindolylmaleimide IX presents a novel drug candidate to treat drug-resistant CML via activating BCR-ABL dependent genotoxic stress response and inhibiting the oncogene addiction pathway activated by BCR-ABL. C1 [Zhang, Xin; Jia, Deyong; Liu, Huijuan; Ruan, Xinsen; Jia, Hao; Li, Baojie] Shanghai Jiao Tong Univ, Minist Educ, Key Lab Genet Dev & Neuropsychiat Disorders, BioX Inst, Shanghai, Peoples R China. [Ao, Junping] Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst, Renji Hosp,Sch Med, Shanghai, Peoples R China. [Zang, Yi; Li, Jia] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Natl Ctr Drug Screening, Shanghai, Peoples R China. [Azam, Mohammad] Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Pathol, Cincinnati, OH USA. [Azam, Mohammad] Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Hematol, Cincinnati, OH USA. [Azam, Mohammad] Cincinnati Childrens Hosp & Med Ctr, Canc & Blood Dis Inst, Div Canc Biol, Cincinnati, OH USA. [Habib, Samy L.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Habib, Samy L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Wang, Xueying] Natl Univ Singapore, Dept Biochem, Singapore, Singapore. [Li, Baojie] Tongji Univ, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, Sch Med, Shanghai, Peoples R China. RP Li, BJ (reprint author), Shanghai Jiao Tong Univ, Minist Educ, Key Lab Genet Dev & Neuropsychiat Disorders, BioX Inst, Shanghai, Peoples R China.; Li, BJ (reprint author), Tongji Univ, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, Sch Med, Shanghai, Peoples R China. EM libj@sjtu.edu.cn RI Zang, Yi/C-5683-2014 OI Zang, Yi/0000-0001-9835-922X FU Natural Science Foundation of China [81130039, 81121001]; Ministry of Science and Technology of China (The National Key Scientific Program) [2012CB966901, 2014CB942900]; Shanghai Zhangjiang Stem Cell Research Project [ZJ2014-ZD-002] FX The work was supported by grants from Natural Science Foundation of China (81130039 and 81121001), the Ministry of Science and Technology of China (The National Key Scientific Program (2012CB966901 and 2014CB942900), and Shanghai Zhangjiang Stem Cell Research Project (ZJ2014-ZD-002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 0 Z9 0 U1 5 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 69945 EP 69960 DI 10.18632/oncotarget.11566 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300065 PM 27564101 ER PT J AU Koo, SJ Fernandez-Montalvan, AE Badock, V Ott, CJ Holton, SJ von Ahsen, O Toedling, J Vittori, S Bradner, JE Gorjanacz, M AF Koo, Seong Joo Fernandez-Montalvan, Amaury E. Badock, Volker Ott, Christopher J. Holton, Simon J. von Ahsen, Oliver Toedling, Joern Vittori, Sarah Bradner, James E. Gorjanacz, Matyas TI ATAD2 is an epigenetic reader of newly synthesized histone marks during DNA replication SO ONCOTARGET LA English DT Article DE cancer; ATAD2; DNA replication; bromodomain; histone acetylation ID POOR-PROGNOSIS; COREGULATOR ANCCA; CHROMATIN; ACETYLATION; BROMODOMAIN; CANCER; OVEREXPRESSION; DEACETYLATION; COACTIVATOR; RECOGNITION AB ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly. Similar to ATAD2-depletion, ectopic expression of ATAD2 mutants that are deficient in binding to these di-acetylation marks resulted in reduced DNA replication and impaired loading of PCNA onto chromatin, suggesting relevance of ATAD2 in DNA replication. Taken together, our data show a novel function of ATAD2 in cancer and for the first time identify a reader of newly synthesized histone diacetylation-marks during replication. C1 [Koo, Seong Joo; Fernandez-Montalvan, Amaury E.; Badock, Volker; Holton, Simon J.; von Ahsen, Oliver; Toedling, Joern; Gorjanacz, Matyas] Bayer Pharma AG, Drug Discovery, Berlin, Germany. [Ott, Christopher J.; Vittori, Sarah; Bradner, James E.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA USA. [Ott, Christopher J.; Vittori, Sarah; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ott, Christopher J.; Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA USA. [Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA USA. RP Koo, SJ; Gorjanacz, M (reprint author), Bayer Pharma AG, Drug Discovery, Berlin, Germany. EM seongjoo.koo@bayer.com; matyas.gorjanacz@bayer.com OI Toedling, Joern/0000-0003-1471-1295 NR 33 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 25 PY 2016 VL 7 IS 43 BP 70323 EP 70335 DI 10.18632/oncotarget.11855 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5VI UT WOS:000387448300094 PM 27612420 ER PT J AU Yousuf, MA Lee, JS Zhou, XH Ramke, M Lee, JY Chodosh, J Rajaiya, J AF Yousuf, Mohammad A. Lee, Ji Sun Zhou, Xiaohong Ramke, Mirja Lee, Jeong Yoon Chodosh, James Rajaiya, Jaya TI Protein Kinase C Signaling in Adenoviral Infection SO BIOCHEMISTRY LA English DT Article ID HUMAN CORNEAL FIBROBLASTS; BRONCHIAL EPITHELIAL-CELLS; CAVEOLIN GENE FAMILY; SRC ACTIVATION; EPIDEMIC KERATOCONJUNCTIVITIS; NOREPINEPHRINE TRANSPORTER; ALPHA(V) INTEGRINS; TYPE-19 INFECTION; LIPID RAFTS; EXPRESSION AB Activation of protein kinase C (PKC), a serine/threonine protein kinase, ubiquitously influences cellular signal transduction and has been shown to play a role in viral entry. In this study, we explored a role for PKC in human adenovirus type 37 infection of primary human corneal fibroblasts, a major target cell for infection. We sought evidence for an interaction between PKC activation and two potential downstream targets: cSrc kinase, shown previously to play a critical role in adenovirus signaling in these cells, and caveolin-1, reported earlier,to be important to entry of adenovirus type 37. Infection of fibroblasts increased PKC alpha phosphorylation and translocation of PKC alpha from the cytosol to caveolin-1 containing vesicles. Virus-induced phosphorylation of both cSrc and AKT was abolished in cell lysates pretreated with calphostin C, a chemical inhibitor of PKC. Inhibition of PKC also reduced virus associated phosphorylation of caveolin-1, while inhibition of cSrc by the chemical inhibitor PP2 reduced only caveolin-1 phosphorylation, but not PKC alpha phosphorylation, in lipid rafts. These results suggest a role for PKC alpha upstream to both cSrc and caveolin-1. Phosphorylated PKC alpha was found in the same endosomal fractions as phosphorylated cSrc, and PKC alpha was present to a greater degree in caveolin-1 pull downs from virus infected than mock infected cell lysates. Calphostin C also reduced early viral gene expression, indicating that PKC alpha activity may be required for viral entry. PKC alpha plays a central role in adenovirus infection of corneal fibroblasts and regulation of downstream molecules, including the important lipid raft component caveolin-1. C1 [Yousuf, Mohammad A.; Lee, Ji Sun; Zhou, Xiaohong; Ramke, Mirja; Lee, Jeong Yoon; Chodosh, James; Rajaiya, Jaya] Harvard Med Sch, Dept Ophthalmol, Mass Eye & Ear Infirm, Howe Lab, Boston, MA 02114 USA. RP Chodosh, J (reprint author), Harvard Med Sch, Dept Ophthalmol, Mass Eye & Ear Infirm, Howe Lab, Boston, MA 02114 USA.; Rajaiya, J (reprint author), 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu; Jaya_rajaiya@meei.harvard.edu FU NIH [EY013124, EY021558, EY014104]; Research to Prevent Blindness, Inc., New York, NY; Falk Foundation; Massachusetts Lions Eye Research Fund FX This work was supported by NIH Grants EY013124, EY021558, and EY014104, a Senior Scientific Investigator Award grant (to J.C.) from Research to Prevent Blindness, Inc., New York, NY, The Falk Foundation, and the Massachusetts Lions Eye Research Fund. NR 66 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 25 PY 2016 VL 55 IS 42 BP 5938 EP 5946 DI 10.1021/acs.biochem.6b00858 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA2KV UT WOS:000386422100006 ER PT J AU Capoulade, R Zeng, X Overbey, JR Ailawadi, G Alexander, JH Ascheim, D Bowdish, M Gelijns, AC Grayburn, P Kron, IL Levine, RA Mack, MJ Melnitchouk, S Michler, RE Mullen, JC O'Gara, P Parides, MK Smith, P Voisine, P Hung, J AF Capoulade, Romain Zeng, Xin Overbey, Jessica R. Ailawadi, Gorav Alexander, John H. Ascheim, Deborah Bowdish, Michael Gelijns, Annetine C. Grayburn, Paul Kron, Irving L. Levine, Robert A. Mack, Michael J. Melnitchouk, Serguei Michler, Robert E. Mullen, John C. O'Gara, Patrick Parides, Michael K. Smith, Peter Voisine, Pierre Hung, Judy CA Cardiothoracic Surg Trials Network TI Impact of Left Ventricular to Mitral Valve Ring Mismatch on Recurrent Ischemic Mitral Regurgitation After Ring Annuloplasty SO CIRCULATION LA English DT Article DE ischemic heart disease; mitral regurgitation; mitral valve; mitral valve annuloplasty ID MYOCARDIAL-INFARCTION; DILATED CARDIOMYOPATHY; HEART-FAILURE; REPAIR; MECHANISM; REPLACEMENT; MANAGEMENT; STRAINS; DISEASE; MOTION AB BACKGROUND: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty. METHODS: Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV enddiastolic dimension/ring size and LVESd/ring size). RESULTS: At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (P=0.02) and LVESd/ring size (P=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05-4.62; P=0.038) remained significantly associated with 1-year MR recurrence. CONCLUSIONS: LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone. C1 [Capoulade, Romain; Zeng, Xin; Levine, Robert A.; Hung, Judy] Massachusetts Gen Hosp, Div Cardiol, Blake 256,55 Fruit St, Boston, MA 02114 USA. [Melnitchouk, Serguei] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Overbey, Jessica R.; Ascheim, Deborah; Gelijns, Annetine C.; Parides, Michael K.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Cardiovasc Inst, New York, NY 10029 USA. [Ailawadi, Gorav; Kron, Irving L.] Univ Virginia Hlth Syst, Dept Surg, Heart & Vasc Ctr, Charlottesville, VA USA. [Alexander, John H.] Duke Med, Duke Clin Res Inst, Div Cardiol, Durham, NC USA. [Smith, Peter] Duke Med, Dept Surg, Durham, NC USA. [Bowdish, Michael] Univ Southern Calif, Keck Sch Med, Dept Surg, Los Angeles, CA USA. [Grayburn, Paul] Baylor Heart & Vasc Inst, Dept Cardiol, Dallas, TX USA. [Mack, Michael J.] Baylor Scott & White Hlth, Dept Cardiovasc Med, Plano, TX USA. [Michler, Robert E.] Montefiore Med Ctr, Dept Cardiovasc & Thorac Surg, 111 E 210th St, Bronx, NY 10467 USA. [Mullen, John C.] Mackenzie Hlth Sci Ctr, Dept Surg, Edmonton, AB, Canada. [O'Gara, Patrick] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Voisine, Pierre] Inst Univ Cardiol & Pneumol Quebec, Dept Surg, Quebec City, PQ, Canada. RP Hung, J (reprint author), Massachusetts Gen Hosp, Div Cardiol, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM jhung@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [U01 HL088942]; National Institute of Neurological Disorders and Stroke of the National Institutes of Health; Canadian Institutes of Health Research; National Institutes of Health/National Heart, Lung, and Blood Institute [R01 HL092101, R01 HL109506, HL129088] FX This work was supported by a cooperative agreement (U01 HL088942) funded by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the Canadian Institutes of Health Research. This work was supported in part by National Institutes of Health/National Heart, Lung, and Blood Institute R01 HL092101 (Dr Hung) and R01 HL109506 and HL129088 (Dr Levine). Dr Capoulade is supported by a postdoctoral fellowship grant from the Canadian Institutes of Health Research. NR 35 TC 2 Z9 2 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 25 PY 2016 VL 134 IS 17 BP 1247 EP + DI 10.1161/CIRCULATIONAHA.115.021014 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EA3FV UT WOS:000386487800008 PM 27777294 ER PT J AU Jones, WS Roe, MT Antman, EM Pletcher, MJ Harrington, RA Rothman, RL Oetgen, WJ Rao, SV Krucoff, MW Curtis, LH Hernandez, AF Masoudi, FA AF Jones, W. Schuyler Roe, Matthew T. Antman, Elliott M. Pletcher, Mark J. Harrington, Robert A. Rothman, Russell L. Oetgen, William J. Rao, Sunil V. Krucoff, Mitchell W. Curtis, Lesley H. Hernandez, Adrian F. Masoudi, Frederick A. TI The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aspirin; coronary artery disease; Patient-Centered Outcomes Research Institute; pragmatic clinical trial ID PERCUTANEOUS CORONARY INTERVENTION; ACUTE MYOCARDIAL-INFARCTION; ASSOCIATION TASK-FORCE; PRACTICE GUIDELINES; HEART-ASSOCIATION; FOCUSED UPDATE; ACCESS SITE; SAFE-PCI; OUTCOMES; HEALTH AB Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial. (C) 2016 by the American College of Cardiology Foundation. C1 [Jones, W. Schuyler; Roe, Matthew T.; Rao, Sunil V.; Krucoff, Mitchell W.; Curtis, Lesley H.; Hernandez, Adrian F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Jones, W. Schuyler; Roe, Matthew T.; Rao, Sunil V.; Krucoff, Mitchell W.; Curtis, Lesley H.; Hernandez, Adrian F.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Antman, Elliott M.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Antman, Elliott M.] Harvard Med Sch, Boston, MA USA. [Pletcher, Mark J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Clin Epidemiol, San Francisco, CA 94143 USA. [Harrington, Robert A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA USA. [Rothman, Russell L.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Rothman, Russell L.] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. [Oetgen, William J.] Amer Coll Cardiol, Washington, DC USA. [Masoudi, Frederick A.] Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA. RP Jones, WS (reprint author), Duke Univ, Med Ctr, POB 3330, Durham, NC 27710 USA. EM schuyler.jones@duke.edu FU National Heart, Lung, and Blood Institute (NHLBI) [1RC2HL101512-01]; Patient-Centered Outcomes Research Institute (PCORI) Award [ASP-1502-27079]; Agency for Healthcare Research and Quality; AstraZeneca; American Heart Association; Bristol-Myers Squibb; Doris Duke Charitable Foundation; PCORI; American College of Radiology; Daiichi-Sankyo; Eli Lilly; Sanofi; Janssen Pharmaceuticals; Ferring Pharmaceuticals; MyoKardia; American College of Cardiology; Familial Hypercholesterolemia Foundation; National Institutes of Health (NIH); Merck; Jansen; CSL; GlaxoSmithKline; Portola; Regado; Medicines Company; NIH; Centers for Medicare and Medicaid Services; Bellerophon; Abbott Vascular; Acist Medical Systems; AngelMed Inc.; Bellerophon Therapeutics; Boston Scientific; Epi-EP; Medtronic; Micelle Technologies Inc.; OrbusNeich; St. Jude Medical; Terumo; Volcano/Philips; Novartis; Amgen; Gilead; Bayer; Portola Pharmaceuticals; NHLBI; ACC; John. A. Hartford Foundation FX The National Heart, Lung, and Blood Institute initially funded the National Cardiovascular Research Infrastructure (NHLBI grant #1RC2HL101512-01 for SAFE-PCI for Women). The ADAPTABLE study is funded through a Patient-Centered Outcomes Research Institute (PCORI) Award (contract number ASP-1502-27079). Dr. Jones has received research grants from the Agency for Healthcare Research and Quality, AstraZeneca, American Heart Association, Bristol-Myers Squibb, Doris Duke Charitable Foundation, and PCORI; and has received honoraria/other support from the American College of Radiology and Daiichi-Sankyo. Dr. Roe has received research grants from Eli Lilly, Sanofi, Daiichi-Sankyo, Janssen Pharmaceuticals, Ferring Pharmaceuticals, MyoKardia, AstraZeneca, American College of Cardiology, American Heart Association, and Familial Hypercholesterolemia Foundation; and has served as a consultant for or received honoraria from PriMed, AstraZeneca, Boehringer Ingelheim, Merck, Amgen, MyoKardia, Eli Lilly, Daiichi-Sankyo, Quest Diagnostics, and Elsevier Publisher. Dr. Antman has received a research grant from Daiichi-Sankyo through his institution. Dr. Pletcher has received research grants from the National Institutes of Health (NIH) and PCORI. Dr. Harrington has received research grants and consultant/advisory fees from Merck; has received research grants from Jansen, CSL, GlaxoSmithKline, Portola, Regado, AstraZeneca, Sanofi, and The Medicines Company; has served as a consultant to The Medicines Company, Amgen, Gilead, and MyoKardia; has served on the science board of WebMD, Element Science, and Adverse Events; and has served on the Board of Directors of Scanadu Signal Path. Dr. Rothman has received research grants/contracts from the NIH, PCORI, and the Centers for Medicare and Medicaid Services; and has served as a consultant for EdLogics and Boehringer Ingelheim. Dr. Oetgen is the Executive Vice President of the American College of Cardiology (ACC). Dr. Rao has received a research grant from Bellerophon; and has served as a consultant for Medtronic, Boehringer Ingelheim, Merck, ZOLL, and Terumo Interventional Systems. Dr. Krucoff has received funding from Abbott Vascular, Acist Medical Systems, AngelMed Inc., Bellerophon Therapeutics, Boston Scientific, Epi-EP, Medtronic, Micelle Technologies Inc., OrbusNeich, St. Jude Medical, Terumo, and Volcano/Philips. Dr. Curtis has received research grants from GlaxoSmithKline, Novartis, Amgen, Boston Scientific, and Gilead. Dr. Hernandez has received research grants from the NIH, PCORI, Agency for Healthcare Research and Quality, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, Novartis, and Portola Pharmaceuticals; and has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis. Dr. Masoudi has received grants/research support from the NHLBI, ACC, PCORI, and the John. A. Hartford Foundation; and serves as an ACC Chief Science Officer (National Cardiovascular Data Registries) and member of the Board of Trustees. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 40 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 25 PY 2016 VL 68 IS 17 BP 1898 EP 1907 DI 10.1016/j.jacc.2016.07.781 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA7QN UT WOS:000386826700011 PM 27765193 ER PT J AU Gupta-Wright, A Fielding, KL van Oosterhout, JJ Wilson, DK Corbett, EL Flach, C Reddy, KP Walensky, RP Peters, JA Alufandika-Moyo, M Lawn, SD AF Gupta-Wright, Ankur Fielding, Katherine L. van Oosterhout, Joep J. Wilson, Douglas K. Corbett, Elizabeth L. Flach, Clare Reddy, Krishna P. Walensky, Rochelle P. Peters, Jurgens A. Alufandika-Moyo, Melanie Lawn, Stephen D. TI Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial (vol 16, 501, 2016) SO BMC INFECTIOUS DISEASES LA English DT Correction C1 [Gupta-Wright, Ankur; Corbett, Elizabeth L.; Peters, Jurgens A.; Lawn, Stephen D.] London Sch Hyg & Trop Med, Dept Clin Res, London, England. [Gupta-Wright, Ankur; Corbett, Elizabeth L.] Univ Malawi, Malawi Liverpool Wellcome Trust Clin Res Program, Coll Med, Blantyre, Malawi. [Fielding, Katherine L.; Flach, Clare] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England. [Fielding, Katherine L.] Univ Witwatersrand, Johannesburg, South Africa. [van Oosterhout, Joep J.; Alufandika-Moyo, Melanie] Dignitas Int, Zomba, Malawi. [van Oosterhout, Joep J.] Univ Malawi, Dept Med, Coll Med, Blantyre, Malawi. [Wilson, Douglas K.] Univ KwaZulu Natal, Edendale Hosp, Dept Internal Med, Pietermaritzburg, South Africa. [Reddy, Krishna P.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Reddy, Krishna P.; Walensky, Rochelle P.] Harvard Univ, Harvard Med Sch, Ctr AIDS Res, Boston, MA 02115 USA. [Lawn, Stephen D.] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, Cape Town, South Africa. RP Gupta-Wright, A (reprint author), London Sch Hyg & Trop Med, Dept Clin Res, London, England.; Gupta-Wright, A (reprint author), Univ Malawi, Malawi Liverpool Wellcome Trust Clin Res Program, Coll Med, Blantyre, Malawi. EM ankurgw@outlook.com NR 1 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD OCT 25 PY 2016 VL 16 AR 604 DI 10.1186/s12879-016-1949-5 PG 1 WC Infectious Diseases SC Infectious Diseases GA DZ7JQ UT WOS:000386041600002 PM 27782816 ER PT J AU Song, SS Zou, ZL Song, HW Wang, YM Uquillas, FD Wang, HJ Chen, H AF Song, Sensen Zou, Zhiling Song, Hongwen Wang, Yongming Uquillas, Federico d'Oleire Wang, Huijun Chen, Hong TI Romantic Love Is Associated with Enhanced Inhibitory Control in an Emotional Stop-Signal Task SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE romantic love; inhibitory control; emotional stop signal task; sadness ID MONOGAMOUS PRAIRIE VOLE; RESPONSE-INHIBITION; AUTONOMIC REACTIVITY; PREFRONTAL CORTEX; BRAIN RESPONSES; ATTENTION; DEPRESSION; ADDICTION; OXYTOCIN; AMYGDALA AB Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG), and half were single and had never been in a romantic relationship (single group, SG). Based on duration of romantic relationship (i.e., love duration), the LG were further divided into two subgroups: early stage love and longer periods of love. All participants completed an emotional Stop Signal Task, consisting of a variety of human face stimuli displaying either sad or neutral affect. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT)] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in longer periods of love or SG individuals, with no significant differences between the two latter groups. Conclusion: Compared with individuals who were single, early stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness. C1 [Song, Sensen; Zou, Zhiling; Wang, Huijun; Chen, Hong] Southwest Univ, Fac Psychol, Chongqing, Peoples R China. [Song, Hongwen] Univ Sci & Technol China, Sch Humanities & Social Sci, Hefei, Anhui, Peoples R China. [Wang, Yongming] Univ Chinese Acad Sci, Sino Danish Coll, Beijing, Peoples R China. [Uquillas, Federico d'Oleire] Harrard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. RP Zou, ZL (reprint author), Southwest Univ, Fac Psychol, Chongqing, Peoples R China. EM zouzl@swu.edu.cn FU Fundamental Research Funds organization for the Central University of China [SWU15091.34]; Chongqing Educational Funds [2015-JC-005]; Chinese National Social Science Foundation [12XSH018] FX This work was supported by grants from the Fundamental Research Funds organization for the Central University of China (SWU15091.34), Chongqing Educational Funds (2015-JC-005) and the Chinese National Social Science Foundation (12XSH018). NR 90 TC 0 Z9 0 U1 19 U2 19 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD OCT 25 PY 2016 VL 7 AR 1574 DI 10.3389/fpsyg.2016.01574 PG 10 WC Psychology, Multidisciplinary SC Psychology GA DZ8BY UT WOS:000386094800001 PM 27826260 ER PT J AU Korthauer, KD Chu, LF Newton, MA Li, Y Thomson, J Stewart, R Kendziorski, C AF Korthauer, Keegan D. Chu, Li-Fang Newton, Michael A. Li, Yuan Thomson, James Stewart, Ron Kendziorski, Christina TI A statistical approach for identifying differential distributions in single-cell RNA-seq experiments SO GENOME BIOLOGY LA English DT Article DE Single-cell RNA-seq; Differential expression; Cellular heterogeneity; Mixture modeling ID EMBRYONIC STEM-CELLS; LUNG ADENOCARCINOMA; PARTITION MODELS; GENE-EXPRESSION; HETEROGENEITY; TRANSCRIPTOME; PLURIPOTENCY; MIXTURE; NOISE; MAINTENANCE AB The ability to quantify cellular heterogeneity is a major advantage of single-cell technologies. However, statistical methods often treat cellular heterogeneity as a nuisance. We present a novel method to characterize differences in expression in the presence of distinct expression states within and among biological conditions. We demonstrate that this framework can detect differential expression patterns under a wide range of settings. Compared to existing approaches, this method has higher power to detect subtle differences in gene expression distributions that are more complex than a mean shift, and can characterize those differences. The freely available R package scDD implements the approach. C1 [Korthauer, Keegan D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Korthauer, Keegan D.] Harvard TH Chan Sch Publ Hlth, Dept Biostatist, Boston, MA 02115 USA. [Chu, Li-Fang; Thomson, James; Stewart, Ron] Univ Wisconsin, Morgridge Inst Res, Madison, WI 53706 USA. [Newton, Michael A.; Kendziorski, Christina] Univ Wisconsin, Dept Biostat, Madison, WI 53706 USA. [Newton, Michael A.; Li, Yuan; Kendziorski, Christina] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. [Thomson, James] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53706 USA. [Thomson, James] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA. RP Kendziorski, C (reprint author), Univ Wisconsin, Dept Biostat, Madison, WI 53706 USA.; Kendziorski, C (reprint author), Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. EM kendzior@biostat.wisc.edu FU National Institutes of Health (NIH) [GM102756]; NIH [U54AI117924, 4UH3TR000506-03]; [5U01HL099773-06] FX This work was supported by National Institutes of Health (NIH) grant GM102756 (CK), NIH grant U54AI117924 (CK), NIH grant 4UH3TR000506-03 (JAT), and grant 5U01HL099773-06 (JAT). NR 69 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD OCT 25 PY 2016 VL 17 AR 222 DI 10.1186/s13059-016-1077-y PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EA0VT UT WOS:000386306800001 PM 27782827 ER PT J AU Fu, XY Jeselsohn, R Pereira, R Hollingsworth, EF Creighton, CJ Li, FG Shea, M Nardone, A De Angelis, C Heiser, LM Anur, P Wang, N Grasso, CS Spellman, PT Griffith, OL Tsimelzon, A Gutierrez, C Huang, SX Edwards, DP Trivedi, MV Rimawi, MF Lopez-Terrada, D Hilsenbeck, SG Gray, JW Brown, M Osborne, CK Schiff, R AF Fu, Xiaoyong Jeselsohn, Rinath Pereira, Resel Hollingsworth, Emporia F. Creighton, Chad J. Li, Fugen Shea, Martin Nardone, Agostina De Angelis, Carmine Heiser, Laura M. Anur, Pavana Wang, Nicholas Grasso, Catherine S. Spellman, Paul T. Griffith, Obi L. Tsimelzon, Anna Gutierrez, Carolina Huang, Shixia Edwards, Dean P. Trivedi, Meghana V. Rimawi, Mothaffar F. Lopez-Terrada, Dolores Hilsenbeck, Susan G. Gray, Joe W. Brown, Myles Osborne, C. Kent Schiff, Rachel TI FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE FOXA1; estrogen receptor; breast cancer; transcriptional reprogramming; endocrine resistance ID ESTROGEN-RECEPTOR BINDING; BOX PROTEIN A1; PROSTATE-CANCER; TAMOXIFEN RESISTANCE; STEM-CELLS; SIGNALING PATHWAYS; ANDROGEN RECEPTOR; MICROARRAY DATA; IN-VITRO; GENES AB Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor alpha(ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown in-hibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors. C1 [Fu, Xiaoyong; Pereira, Resel; Shea, Martin; Nardone, Agostina; De Angelis, Carmine; Tsimelzon, Anna; Trivedi, Meghana V.; Rimawi, Mothaffar F.; Hilsenbeck, Susan G.; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Fu, Xiaoyong; Pereira, Resel; Creighton, Chad J.; Shea, Martin; Nardone, Agostina; De Angelis, Carmine; Tsimelzon, Anna; Huang, Shixia; Edwards, Dean P.; Trivedi, Meghana V.; Rimawi, Mothaffar F.; Hilsenbeck, Susan G.; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Fu, Xiaoyong; Pereira, Resel; Huang, Shixia; Edwards, Dean P.; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Jeselsohn, Rinath; Li, Fugen; Brown, Myles] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. [Hollingsworth, Emporia F.; Gutierrez, Carolina; Edwards, Dean P.; Lopez-Terrada, Dolores] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Creighton, Chad J.; Shea, Martin; Nardone, Agostina; De Angelis, Carmine; Tsimelzon, Anna; Rimawi, Mothaffar F.; Hilsenbeck, Susan G.; Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Heiser, Laura M.; Wang, Nicholas; Grasso, Catherine S.; Gray, Joe W.] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97239 USA. [Anur, Pavana; Spellman, Paul T.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Griffith, Obi L.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Trivedi, Meghana V.] Univ Houston, Dept Pharm Practice & Translat Res, Houston, TX 77204 USA. [Trivedi, Meghana V.] Univ Houston, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA. RP Schiff, R (reprint author), Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.; Schiff, R (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA.; Schiff, R (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.; Schiff, R (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA. EM rschiff@bcm.edu FU Department of Defense Breakthrough Award [W81XWH-14-1-0326]; Breast Cancer Research Foundation; Stand Up to Cancer Translational Grant [SU2C-AACR-DT0409]; NIH Breast Cancer Specialized Programs of Research Excellence [P50CA058183, P50CA186784]; NIH Cancer Center [P30CA125123]; Susan G. Komen for the Cure Foundation Promise [PG12221410, SAC110012]; Cancer Prevention Research Institute of Texas [RP120092]; NIH [P30CA125123, P30AI036211, S10RR024574]; Proteomics & Metabolomics Core Facility; Cytometry and Cell Sorting Core at Baylor College of Medicine FX We thank Drs. Robert Nicholson and Julia Gee for providing the paired MCF7RN-P and TamR cell line model; Dr. Mathieu Lupien for sharing ER ChIP-chip data; Rena Mao and Joy Guo for performing IHC; Fuli Jia, Myra Costello, and Dr. Kimberley Holloway for performing RPPA assay; Drs. Kimal Rajapakshe, Cristian Coarfa, and Qianxing Mo for RPPA data processing; and Dr. Gary Chamness for reading and reviewing this manuscript. This work was supported by Department of Defense Breakthrough Award W81XWH-14-1-0326 (to X.F.), the Breast Cancer Research Foundation (R.S. and C.K.O.), Stand Up to Cancer Translational Grant SU2C-AACR-DT0409 (to R.S., C.K.O., and J.W.G.), NIH Breast Cancer Specialized Programs of Research Excellence Grants P50CA058183 and P50CA186784 (to C.K.O. and R.S.), NIH Cancer Center Grant P30CA125123 (to C.K.O.), and Susan G. Komen for the Cure Foundation Promise Grants PG12221410 (to C.K.O. and R.S.) and SAC110012 (to J.W. G.). This work was supported by Proteomics & Metabolomics Core Facility with funding from Cancer Prevention Research Institute of Texas Grant RP120092 (to S.H. and D.P.E.) and Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from NIH Grants P30AI036211, P30CA125123, and S10RR024574 and the expert assistance of Joel M.Sederstrom. NR 73 TC 1 Z9 1 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6600 EP E6609 DI 10.1073/pnas.1612835113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100010 PM 27791031 ER PT J AU Lewis, LD Setsompop, K Rosen, BR Polimeni, JR AF Lewis, Laura D. Setsompop, Kawin Rosen, Bruce R. Polimeni, Jonathan R. TI Fast fMRI can detect oscillatory neural activity in humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oscillations; hemodynamics; imaging; BOLD ID PRIMARY VISUAL-CORTEX; EVENT-RELATED FMRI; BOLD FMRI; BALLOON MODEL; NEURONAL OSCILLATIONS; HEMODYNAMIC-RESPONSES; TEMPORAL DYNAMICS; BRAIN ACTIVATION; IMPULSE-RESPONSE; SLOW WAVES AB Oscillatory neural dynamics play an important role in the coordination of large-scale brain networks. High-level cognitive processes depend on dynamics evolving over hundreds of milliseconds, so measuring neural activity in this frequency range is important for cognitive neuroscience. However, current noninvasive neuroimaging methods are not able to precisely localize oscillatory neural activity above 0.2 Hz. Electroencephalography and magnetoencephalography have limited spatial resolution, whereas fMRI has limited temporal resolution because it measures vascular responses rather than directly recording neural activity. We hypothesized that the recent development of fast fMRI techniques, combined with the extra sensitivity afforded by ultra-high-field systems, could enable precise localization of neural oscillations. We tested whether fMRI can detect neural oscillations using human visual cortex as a model system. We detected small oscillatory fMRI signals in response to stimuli oscillating at up to 0.75 Hz within single scan sessions, and these responses were an order of magnitude larger than predicted by canonical linear models. Simultaneous EEG-fMRI and simulations based on a biophysical model of the hemodynamic response to neuronal activity suggested that the blood oxygen level-dependent response becomes faster for rapidly varying stimuli, enabling the detection of higher frequencies than expected. Accounting for phase delays across voxels further improved detection, demonstrating that identifying vascular delays will be of increasing importance with higher-frequency activity. These results challenge the assumption that the hemodynamic response is slow, and demonstrate that fMRI has the potential to map neural oscillations directly throughout the brain. C1 [Lewis, Laura D.] Harvard Univ, Soc Fellows, Cambridge, MA 02138 USA. [Lewis, Laura D.; Setsompop, Kawin; Rosen, Bruce R.; Polimeni, Jonathan R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Setsompop, Kawin; Rosen, Bruce R.; Polimeni, Jonathan R.] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. RP Lewis, LD (reprint author), Harvard Univ, Soc Fellows, Cambridge, MA 02138 USA.; Lewis, LD (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. EM lauralewis@fas.harvard.edu FU Athinoula A. Martinos Center for Biomedical Imaging; NIH [K01-EB011498, R01-EB019437]; Harvard Society; NIH National Institute of Biomedical Imaging and Bioengineering Grant [P41-EB015896]; National Center for Research Resources Shared Resource Instrumentation Grants [S10-RR023401, S10-RR023403, S10-OD010759, S10-RR020948] FX This work was funded by the Athinoula A. Martinos Center for Biomedical Imaging; NIH Grants K01-EB011498 and R01-EB019437 (to J.R.P.); a Fellowship from the Harvard Society of Fellows (L.D.L.); NIH National Institute of Biomedical Imaging and Bioengineering Grant P41-EB015896; and National Center for Research Resources Shared Resource Instrumentation Grants S10-RR023401, S10-RR023403, S10-OD010759, and S10-RR020948. NR 69 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6679 EP E6685 DI 10.1073/pnas.1608117113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100018 PM 27729529 ER PT J AU Liu, CF Brandt, GS Hoang, QYQ Naumova, N Lazarevic, V Hwang, ES Dekker, J Glimcher, LH Ringe, D Petsko, GA AF Liu, Ce Feng Brandt, Gabriel S. Hoang, Quyen Q. Naumova, Natalia Lazarevic, Vanja Hwang, Eun Sook Dekker, Job Glimcher, Laurie H. Ringe, Dagmar Petsko, Gregory A. TI Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T-bet; transcriptional regulation; DNA looping; crystal structure; master regulator ID IFNG GENE-EXPRESSION; INTERFERON-GAMMA; CELL-DIFFERENTIATION; LINEAGE COMMITMENT; DENDRITIC CELLS; BOX DOMAIN; ENHANCER; LOCUS; CTCF; ELEMENTS AB The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the T(H)1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. The data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes. C1 [Liu, Ce Feng; Petsko, Gregory A.] Weill Cornell Med Coll, Appel Alzheimers Dis Res Inst, Brain & Mind Res Inst, New York, NY 10021 USA. [Liu, Ce Feng; Brandt, Gabriel S.; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Brandt, Gabriel S.] Franklin & Marshall Coll, Dept Chem, Lancaster, PA 17604 USA. [Hoang, Quyen Q.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Naumova, Natalia; Dekker, Job] Univ Massachusetts, Sch Med, Program Syst Biol, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. [Lazarevic, Vanja; Hwang, Eun Sook; Glimcher, Laurie H.] Harvard Med Sch, Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Hwang, Eun Sook] Ewha Womans Univ, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Glimcher, Laurie H.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Glimcher, Laurie H.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Glimcher, Laurie H.] Harvard Univ, Charlestown, MA 02129 USA. [Naumova, Natalia] Epinomics, Menlo Pk, CA 94030 USA. [Lazarevic, Vanja] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Glimcher, Laurie H.] Dana Farber Canc Inst, Off President, Boston, MA 02215 USA. RP Liu, CF; Petsko, GA (reprint author), Weill Cornell Med Coll, Appel Alzheimers Dis Res Inst, Brain & Mind Res Inst, New York, NY 10021 USA.; Liu, CF; Petsko, GA (reprint author), Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. EM cel2010@med.cornell.edu; gpetsko@med.cornell.edu FU NIH [P01-AI056296]; National Research Service Award Individual Training Grant Fellowship [5F32GM069057]; National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]; Argonne National Laboratory [DE-AC02-06CH11357] FX This work was supported by NIH Grant P01-AI056296 (to L.H.G. and G.A.P.). G.S.B. was supported in part by National Research Service Award Individual Training Grant Fellowship 5F32GM069057. This work is based on research conducted at the GM/CA CAT (GM/CA@APS) and the Structural Biology Center of the Advanced Photon Source. GM/CA@APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. NR 63 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6572 EP E6581 DI 10.1073/pnas.1613914113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100007 PM 27791029 ER PT J AU Tam, HH Melo, MB Kang, M Pelet, JM Ruda, VM Foley, MH Hu, JK Kumari, S Crampton, J Baldeon, AD Sanders, RW Moore, JP Crotty, S Langer, R Anderson, DG Chakraborty, AK Irvine, DJ AF Tam, Hok Hei Melo, Mariane B. Kang, Myungsun Pelet, Jeisa M. Ruda, Vera M. Foley, Maria H. Hu, Joyce K. Kumari, Sudha Crampton, Jordan Baldeon, Alexis D. Sanders, Rogier W. Moore, John P. Crotty, Shane Langer, Robert Anderson, Daniel G. Chakraborty, Arup K. Irvine, Darrell J. TI Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vaccination kinetics; antigen retention; humoral response; computational immunology; germinal center formation ID FOLLICULAR HELPER-CELL; HIV-1 ENVELOPE TRIMER; CENTER B-CELLS; IMMUNE-RESPONSES; AFFINITY MATURATION; MALARIA ANTIGEN; RELEASE; INFECTION; ADJUVANT; VACCINES AB Natural infections expose the immune system to escalating antigen and inflammation over days to weeks, whereas nonlive vaccines are single bolus events. We explored whether the immune system responds optimally to antigen kinetics most similar to replicating infections, rather than a bolus dose. Using HIV antigens, we found that administering a given total dose of antigen and adjuvant over 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting > 10-fold increases in antibody production relative to bolus vaccination post prime. Computational modeling of the germinal center response suggested that antigen availability as higher-affinity antibodies evolve enhances antigen capture in lymph nodes. Consistent with these predictions, we found that exp-inc dosing led to prolonged antigen retention in lymph nodes and increased Tfh cell and germinal center B-cell numbers. Thus, regulating the antigen and adjuvant kinetics may enable increased vaccine potency. C1 [Tam, Hok Hei; Kang, Myungsun; Langer, Robert; Anderson, Daniel G.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Tam, Hok Hei; Melo, Mariane B.; Pelet, Jeisa M.; Ruda, Vera M.; Foley, Maria H.; Kumari, Sudha; Baldeon, Alexis D.; Langer, Robert; Anderson, Daniel G.; Irvine, Darrell J.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Melo, Mariane B.; Kumari, Sudha; Chakraborty, Arup K.; Irvine, Darrell J.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Kang, Myungsun; Langer, Robert; Anderson, Daniel G.; Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Hu, Joyce K.; Crampton, Jordan; Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Sanders, Rogier W.; Moore, John P.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Crotty, Shane; Irvine, Darrell J.] Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Crotty, Shane] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92037 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.; Irvine, Darrell J.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Anderson, DG; Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Anderson, DG; Irvine, DJ (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK; Irvine, DJ (reprint author), Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.; Anderson, DG; Chakraborty, AK (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK; Irvine, DJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA.; Irvine, DJ (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM dgander@mit.edu; arupc@mit.edu; djirvine@mit.edu OI Melo, Mariane/0000-0002-0409-2454 FU Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology (MIT), and Harvard; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI100663, AI110657]; Skolkovo-MIT program FX We thank the International AIDS Vaccine Initiative and CSL Ltd. for provision of ISCOMATRIX. We thank Sal Butera, The Scripps Research Institute/Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), for logistical support; the La Jolla Institute animal facility staff for expert assistance with surgeries; and Al Cupo for assistance with HIV Env trimer production. The authors thank the Koch Institute Swanson Biotechnology Center Flow Cytometry and Microscopy core facilities for technical support. This work was supported in part by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology (MIT), and Harvard and the Skolkovo-MIT program. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Awards UM1AI100663 and AI110657. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 68 TC 1 Z9 1 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 25 PY 2016 VL 113 IS 43 BP E6639 EP E6648 DI 10.1073/pnas.1606050113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ7ZI UT WOS:000386087100014 PM 27702895 ER PT J AU Berger, MF Van Allen, EM AF Berger, Michael F. Van Allen, Eliezer M. TI Delivering on the promise of precision cancer medicine SO GENOME MEDICINE LA English DT Editorial Material ID BRAF V600 MUTATIONS; LUNG-CANCER; CHEMOTHERAPY; IMPACT C1 [Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Berger, Michael F.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Van Allen, Eliezer M.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. RP Berger, MF (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA.; Berger, MF (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA.; Van Allen, EM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Van Allen, EM (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. EM bergerm1@mskcc.org; evanallen@partners.org NR 15 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD OCT 25 PY 2016 VL 8 AR 110 DI 10.1186/s13073-016-0373-1 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DZ6QK UT WOS:000385986800002 PM 27782852 ER PT J AU Bernini, F Malferrari, D Pignataro, M Bortolotti, CA Di Rocco, G Lancellotti, L Brigatti, MF Kayed, R Borsari, M del Monte, F Castellini, E AF Bernini, Fabrizio Malferrari, Daniele Pignataro, Marcello Bortolotti, Carlo Augusto Di Rocco, Giulia Lancellotti, Lidia Brigatti, Maria Franca Kayed, Rakez Borsari, Marco del Monte, Federica Castellini, Elena TI Pre-amyloid oligomers budding: a metastatic mechanism of proteotoxicity SO SCIENTIFIC REPORTS LA English DT Article ID NUCLEATION-DEPENDENT POLYMERIZATION; ATOMIC-FORCE MICROSCOPY; ALZHEIMERS-DISEASE; BETA-PROTEIN; PEPTIDE AGGREGATION; A-BETA-42 OLIGOMERS; BILAYER-MEMBRANES; MEMORY LOSS; MODEL; PATHOLOGY AB The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology. C1 [Bernini, Fabrizio; Malferrari, Daniele; Pignataro, Marcello; Bortolotti, Carlo Augusto; Di Rocco, Giulia; Lancellotti, Lidia; Brigatti, Maria Franca; Borsari, Marco; Castellini, Elena] Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Modena, Italy. [Pignataro, Marcello; del Monte, Federica] BIDMC, Cardiovasc Inst, Boston, MA 02215 USA. [Kayed, Rakez] UTMD Sch Med, Dept Neurol, Galveston, TX USA. RP Castellini, E (reprint author), Univ Modena & Reggio Emilia, Dept Chem & Geol Sci, Modena, Italy.; del Monte, F (reprint author), BIDMC, Cardiovasc Inst, Boston, MA 02215 USA. EM fdelmont@bidmc.harvard.edu; elena.castellini@unimore.it RI Pignataro, Marcello/J-6107-2016; OI Pignataro, Marcello/0000-0003-0058-3659; malferrari, daniele/0000-0002-0879-1703 FU National Institute of Health [R21HL102716, R01 HL098468]; American Heart Association [14IRG18980028]; BIDMC; University of Modena Reggio Emilia FX We would like to thank Prof. Colin Combs, Prof. Dennis Selkoe for critical review of the manuscript and Dr. Maria Ericsson from the Harvard Electron Microscopy Core for help with electron microscopy, Dr. Massimo Tonelli and Centro Interdipartimentale Grandi Strumenti of the University of Modena and Reggio Emilia for providing the facilities of the VEECO nanoscope III AFM instrument. This work was supported by the National Institute of Health (R21HL102716 and R01 HL098468), American Heart Association (14IRG18980028) and departmental funds from BIDMC to F.d.M.; Departmental funds from University of Modena & Reggio Emilia to MFB, E.C, GDR and M.B.; PhD program of University of Modena & Reggio Emilia, to F.B, MP and LL. NR 43 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 24 PY 2016 VL 6 AR 35865 DI 10.1038/srep35865 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ6PF UT WOS:000385983700001 PM 27775057 ER PT J AU Bonaca, MP Creager, MA Olin, J Scirica, BM Gilchrist, IC Murphy, SA Goodrich, EL Braunwald, E Morrow, DA AF Bonaca, Marc P. Creager, Mark A. Olin, Jeffrey Scirica, Benjamin M. Gilchrist, Ian C., Jr. Murphy, Sabina A. Goodrich, Erica L. Braunwald, Eugene Morrow, David A. TI Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar Insights From the TRA 2 degrees P-TIMI 50 Trial SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE major adverse limb event(s); MALE; PAD; peripheral artery disease; peripheral intervention ID PROTEASE-ACTIVATED RECEPTORS; TASK-FORCE; ATHEROSCLEROTIC DISEASE; PRACTICE GUIDELINES; LOWER-EXTREMITY; MANAGEMENT; THERAPY; SOCIETY; BIOLOGY; RATES AB OBJECTIVES The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both. BACKGROUND The protease-activated receptor-1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD. METHODS The TRA 2 degrees P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of vorapaxar was consistent across indication and type of procedure. RESULTS Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication. CONCLUSIONS Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of vorapaxar is directionally consistent across type of procedure and indication. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2 degrees P - TIMI 50] [P04737]; NCT00526474) (C) 2016 by the American College of Cardiology Foundation. C1 [Bonaca, Marc P.; Scirica, Benjamin M.; Gilchrist, Ian C., Jr.; Murphy, Sabina A.; Goodrich, Erica L.; Braunwald, Eugene; Morrow, David A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Bonaca, Marc P.; Scirica, Benjamin M.; Gilchrist, Ian C., Jr.; Murphy, Sabina A.; Goodrich, Erica L.; Braunwald, Eugene; Morrow, David A.] Harvard Med Sch, Boston, MA USA. [Creager, Mark A.] Geisel Sch Med Dartmouth, Dartmouth Hitchcock Heart & Vasc Ctr, Lebanon, NH USA. [Olin, Jeffrey] Mt Sinai Sch Med, Wiener Cardiovasc Inst, New York, NY USA. [Olin, Jeffrey] Mt Sinai Sch Med, Marie Jose & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM mbonaca@partners.org FU Merck; Research Career Development Award from the National Heart, Lung, and Blood Institute [K12 HL083786]; Accumetrics; Amgen; AstraZeneca; Beckman Coulter; Bristol-Myers Squibb; CV Therapeutics; Daiichi-Sankyo; Eli Lilly; GlaxoSmithKline; Integrated Therapeutics; Nanosphere; Novartis Pharmaceuticals; Nuvelo; Ortho-Clinical Diagnostics; Pfizer; Roche Diagnostics; Sanofi; Sanofi-Synthelabo; Siemens Medical Solutions; Singulex; Bayer; Gilead; Eisai; Poxel; Biogen Idec; Boehringer Ingelheim; Dr. Reddy's Laboratory; Forest Pharmaceuticals; Lexicon; St. Jude Medical; Amarin Pharmaceuticals; Beckman-Coulter; Critical Diagnostics; Genentech; Instrumentation Laboratory; Servier FX The TRA 2 degrees P-TIMI 50 trial was supported by a grant from Merck to Brigham and Women's Hospital. Dr. Bonaca was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. The TIMI Study Group has received significant research grant support from Accumetrics, Amgen, AstraZeneca, Beckman Coulter, Bristol-Myers Squibb, CV Therapeutics, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Integrated Therapeutics, Merck, Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi, Sanofi-Synthelabo, Siemens Medical Solutions, and Singulex. Dr. Bonaca has received consulting fees from Merck, AstraZeneca, and Bayer. Dr. Olin is on the medical advisory board and Steering Committee TRA-2P for Merck and is also on the medical advisory board and the International Steering Committee EUCLID Trial for AstraZeneca. Dr. Scirica received research grants from Merck, AstraZeneca, Daiichi-Sankyo, Gilead, Eisai, Poxel, Biogen Idec, Boehringer Ingelheim, Dr. Reddy's Laboratory, Forest Pharmaceuticals, GlaxoSmithKline, Lexicon, and St. Jude Medical; and received consulting fees from AstraZeneca and Merck. Ms. Murphy has received consulting fees from Eli Lilly and Amarin Pharmaceuticals and has received speaking fees from Merck. Dr. Braunwald received research grant support from Merck. Dr. Morrow has received consulting fees from Beckman-Coulter, Boehringer Ingelheim, Critical Diagnostics, Genentech, Gilead, Instrumentation Laboratory, Merck, Roche Diagnostics, AstraZeneca, GlaxoSmithKline, Novartis, and Servier; and has also received research grant support from Merck, Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 17 TC 2 Z9 2 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD OCT 24 PY 2016 VL 9 IS 20 BP 2157 EP 2164 DI 10.1016/j.jcin.2016.07.034 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ3AR UT WOS:000385716000017 PM 27765312 ER PT J AU Iyer, AS Bouhenia, M Rumunu, J Abubakar, A Gruninger, RJ Pita, J Lino, RL Deng, LL Wamala, JF Ryan, ET Martin, S Legros, D Lessler, J Sack, DA Luquero, FJ Leung, DT Azman, AS AF Iyer, Anita S. Bouhenia, Malika Rumunu, John Abubakar, Abdinasir Gruninger, Randon J. Pita, Jane Lino, Richard Lako Deng, Lul L. Wamala, Joseph F. Ryan, Edward T. Martin, Stephen Legros, Dominique Lessler, Justin Sack, David A. Luquero, Francisco J. Leung, Daniel T. Azman, Andrew S. TI Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan SO SCIENTIFIC REPORTS LA English DT Article ID O-SPECIFIC POLYSACCHARIDE; PLACEBO-CONTROLLED TRIAL; VIBRIO-CHOLERAE; CELL RESPONSES; DOUBLE-BLIND; CVD 103-HGR; BANGLADESH; BIVALENT; IMMUNOGENICITY; INFECTION AB Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 pre-emptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1-5 years old), 67 older children (6-17 years old) and 101 adults (>= 18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers <= 80, 90% young children, 73% older children and 72% adults seroconverted (>= 4 fold titer rise) after the 1st OCV dose; with no additional seroconversion after the 2nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed. C1 [Iyer, Anita S.; Gruninger, Randon J.; Leung, Daniel T.] Univ Utah, Sch Med, Dept Internal Med, Div Infect Dis, Salt Lake City, UT USA. [Bouhenia, Malika; Abubakar, Abdinasir; Pita, Jane; Wamala, Joseph F.] World Hlth Org, Juba, South Sudan, Sudan. [Rumunu, John; Lino, Richard Lako; Deng, Lul L.] Republ South Sudan Minist Hlth, Juba, South Sudan, Sudan. [Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Martin, Stephen; Legros, Dominique] World Hlth Org, Geneva, Switzerland. [Lessler, Justin; Azman, Andrew S.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Sack, David A.; Luquero, Francisco J.] Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD USA. [Luquero, Francisco J.] Epicentre, Paris, France. [Leung, Daniel T.] Univ Utah, Sch Med, Dept Pathol, Div Microbiol & Immunol, Salt Lake City, UT USA. RP Azman, AS (reprint author), Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. EM azman@jhu.edu OI Azman, Andrew/0000-0001-8662-9077; leung, daniel/0000-0001-8401-0801 FU National Institute of Health [K08 AI100923, R01 AI106878]; Bill and Melinda Gates Foundation [OPP1089243]; Delivering Oral Vaccine Effectively (DOVE) Project [OPP153556, OPP 1089248]; Margaret A Cargill Foundation FX The authors would like to thank the study staff, participants, community leaders in the UN House PoC, staff at the WHO Juba Country Office, IMC Staff (Dr Meroni Abraham, Alejandro Guzman, Kourtney Rusow, Emebet Dlasso), MSF-Switzerland for help with logistics, Paul Kovac and Peng Xu at NIDDK for the gift of OSP:BSA. This work was sponsored by The National Institute of Health (K08 AI100923 grants to D.T.L, R01 AI106878 to E.T.R.), The Bill and Melinda Gates Foundation (OPP1089243 to J.L., A.S.A, Delivering Oral Vaccine Effectively (DOVE) Project, OPP153556 to D.A.S., F.J.L., A.S.A., and OPP 1089248 to WHO) and Margaret A Cargill Foundation grants to the WHO. NR 34 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 24 PY 2016 VL 6 AR 35742 DI 10.1038/srep35742 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ5SF UT WOS:000385921100001 PM 27775046 ER PT J AU Voss, JE Macauley, MS Rogers, KA Villinger, F Duan, LJ Shang, L Fink, EA Andrabi, R Colantonio, AD Robinson, JE Johnson, RP Burton, DR Haase, AT AF Voss, James E. Macauley, Matthew S. Rogers, Kenneth A. Villinger, Francois Duan, Lijie Shang, Liang Fink, Elizabeth A. Andrabi, Raiees Colantonio, Arnaud D. Robinson, James E. Johnson, R. Paul Burton, Dennis R. Haase, Ashley T. TI Reproducing SIVnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines SO AIDS LA English DT Article DE mucosal concentration; SIV VACCINE; trimeric gp41 antibodies ID SIMIAN IMMUNODEFICIENCY VIRUS; ATTENUATED SIV; TRANSMEMBRANE PROTEIN; CONTROL REPLICATION; IMMUNE-RESPONSES; MACAQUES; LIVE; INFECTION; TYPE-1; SIVMAC239-DELTA-NEF AB Vaccination with SIV(mac239)nef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (SIV), but safety issues have precluded designing an HIV-1 vaccine based on a live-attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIV(mac239)nef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-monophosphoryl lipid A adjuvant liposomal nanoparticle for intramuscular (i.m.) immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIV(mac239)nef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIV(mac239)nef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization. C1 [Voss, James E.; Andrabi, Raiees; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Voss, James E.; Andrabi, Raiees; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Macauley, Matthew S.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Rogers, Kenneth A.; Villinger, Francois] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Rogers, Kenneth A.; Villinger, Francois] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Duan, Lijie; Shang, Liang; Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol & Immunol, Minneapolis, MN 55455 USA. [Fink, Elizabeth A.] Univ Calif San Diego, Prot Express & Prote Core, Ctr AIDS Res, La Jolla, CA 92093 USA. [Colantonio, Arnaud D.] Harvard Med Sch, New England Primate Res Ctr, Southborough, MA USA. [Robinson, James E.] Tulane Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, Boston, MA 02114 USA. [Johnson, R. Paul] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Cambridge, MA USA. [Rogers, Kenneth A.] Univ Louisiana Lafayette, New Iberia Res Ctr, New Iberia, LA USA. RP Haase, AT (reprint author), Univ Minnesota, Sch Med, Dept Microbiol & Immunol, Minneapolis, MN 55455 USA.; Haase, AT (reprint author), Univ Minnesota, Dept Microbiol & Immunol, 689-23rd Ave SE,Campus Delivery Code 2821A, Minneapolis, MN 55455 USA. EM haase001@umn.edu FU National Institutes of Health [R01 AI102625, P30 AI036214]; NIH [OD010976]; NIAID [HHSN272200130031C] FX We thank Jon Warren and Akiko Iwasaki for helpful discussion. J.E.V., M.S.M., R.P.J., D.R.B., and A.T.H. designed the experiments. J.E.V. designed and produced protein immunogens, carried out mouse and rabbit immunization experiments, evaluated serum and CVF Ig by ELISA and western blot, prepared figures and helped to write the manuscript. M.S.M. incorporated protein into liposomes for immunizations, prepared figures and helped to write the manuscript. K.A.R. and F.V. performed the rhesus macaque experiments. L.D. evaluated serum and CVF levels of antibodies by quantitative western blotting. L.S. performed the neutralization assays. J.E.R. generated the rhesus version of monoclonal antibody 4.9C for the passive immunization experiments. E.A.F. helped with protein production and purification. R.A. helped prepare figures. All the authors analyzed the data and helped write the manuscript. This work was supported by National Institutes of Health Grants R01 AI102625 and P30 AI036214. The 4.9C antibody used in the passive immunization studies was produced by the NIH Nonhuman Primate Reagent Resource funded by NIH grant OD010976 and NIAID contract HHSN272200130031C. Portions of this work were facilitated by the Protein Expression and Proteomics Core of the University of California, San Diego, Center for AIDS Research (CFAR). NR 32 TC 2 Z9 2 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD OCT 23 PY 2016 VL 30 IS 16 BP 2427 EP 2438 DI 10.1097/QAD.0000000000001199 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DZ0KV UT WOS:000385528600004 PM 27428745 ER PT J AU Charidimou, A AF Charidimou, Andreas TI The ABC risk score for patients with atrial fibrillation SO LANCET LA English DT Letter ID MICROBLEEDS C1 [Charidimou, Andreas] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. RP Charidimou, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. EM andreas.charidimou.09@ucl.ac.uk NR 6 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 22 PY 2016 VL 388 IS 10055 BP 1979 EP 1979 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6EQ UT WOS:000385954800017 PM 27789013 ER PT J AU Kesselheim, AS Eddings, W Raj, T Campbell, EG Franklin, JM Ross, KM Fulchino, LA Avorn, J Gagne, JJ AF Kesselheim, Aaron S. Eddings, Wesley Raj, Tara Campbell, Eric G. Franklin, Jessica M. Ross, Kathryn M. Fulchino, Lisa A. Avorn, Jerry Gagne, Joshua J. TI Physicians' Trust in the FDA's Use of Product-Specific Pathways for Generic Drug Approval SO PLOS ONE LA English DT Article ID BRAND-NAME DRUGS; SCIENTIFIC CONSIDERATIONS; CARDIOVASCULAR-DISEASE; PERCEPTIONS; TACROLIMUS; MEDICINES AB Background Generic drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process. Methods and Findings A survey was administered to a national sample of primary care internists and specialists between August 2014 and January 2015. In total, 1,152 physicians comprising of internists with no reported specialty certification and those with specialty certification in hematology, infectious diseases, and endocrinology were surveyed. The survey assessed physicians' perceptions of the FDA's generic drug approval process, as well as their experiences prescribing six generic drugs approved between 2008 and 2012 using product-specific approval pathways and selected comparator drugs. Among 718 respondents (62% response rate), a majority were comfortable with the FDA's process in ensuring the safety and effectiveness of generic drugs overall (91%) and with letting the FDA determine which tests were necessary to determine bioequivalence in a particular drug (92%). A minority (13-26%) still reported being uncomfortable prescribing generic drugs approved using product-specific pathways. Overall, few physicians heard reports of concerns about generic versions of the study drugs or their comparators, with no differences between the two groups. Physicians tended to hear about concerns about the safety or effectiveness of generic drugs from patients, pharmacists, and physician colleagues. Conclusions Physicians hold largely positive views of the FDA's generic drug approval process even when some questioned the performance of certain generic drugs in comparison to brand-name drugs. Better education about the generic drug approval process and standards may alleviate concerns among the physician community and support the delivery of cost-effective health care. C1 [Kesselheim, Aaron S.; Eddings, Wesley; Raj, Tara; Franklin, Jessica M.; Fulchino, Lisa A.; Avorn, Jerry; Gagne, Joshua J.] Brigham & Womens Hosp, Dept Med, PORTAL, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Kesselheim, Aaron S.; Eddings, Wesley; Raj, Tara; Franklin, Jessica M.; Fulchino, Lisa A.; Avorn, Jerry; Gagne, Joshua J.] Harvard Med Sch, Boston, MA 02115 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Ross, Kathryn M.] Amer Board Internal Med, Philadelphia, PA USA. RP Kesselheim, AS (reprint author), Brigham & Womens Hosp, Dept Med, PORTAL, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA.; Kesselheim, AS (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM akesselheim@partners.org FU FDA Office of Generic Drugs FX This study was funded by a grant from the FDA Office of Generic Drugs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 21 PY 2016 VL 11 IS 10 AR e0163339 DI 10.1371/journal.pone.0163339 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9OE UT WOS:000386205400003 PM 27768700 ER PT J AU Sundaram, AYM Hughes, T Biondi, S Bolduc, N Bowman, SK Camilli, A Chew, YC Couture, C Farmer, A Jerome, JP Lazinski, DW McUsic, A Peng, X Shazand, K Xu, F Lyle, R Gilfillan, GD AF Sundaram, Arvind Y. M. Hughes, Timothy Biondi, Shea Bolduc, Nathalie Bowman, Sarah K. Camilli, Andrew Chew, Yap C. Couture, Catherine Farmer, Andrew Jerome, John P. Lazinski, David W. McUsic, Andrew Peng, Xu Shazand, Kamran Xu, Feng Lyle, Robert Gilfillan, Gregor D. TI A comparative study of ChIP-seq sequencing library preparation methods SO BMC GENOMICS LA English DT Article DE HTS; NGS; Low-input; Micro-ChIP; Chromatin immunoprecipitation ID CHROMATIN IMMUNOPRECIPITATION ASSAY; PROTEIN-DNA INTERACTIONS; MU-CHIP; EPIGENETIC CHARACTERIZATION; LIMITED NUMBERS; GENOME; CELLS; AMPLIFICATION; STATE; CONSTRUCTION AB Background: ChIP-seq is the primary technique used to investigate genome-wide protein-DNA interactions. As part of this procedure, immunoprecipitated DNA must undergo "library preparation" to enable subsequent high-throughput sequencing. To facilitate the analysis of biopsy samples and rare cell populations, there has been a recent proliferation of methods allowing sequencing library preparation from low-input DNA amounts. However, little information exists on the relative merits, performance, comparability and biases inherent to these procedures. Notably, recently developed single-cell ChIP procedures employing microfluidics must also employ library preparation reagents to allow downstream sequencing. Results: In this study, seven methods designed for low-input DNA/ChIP-seq sample preparation (Accel-NGS (R) 2S, Bowman-method, HTML-PCR, SeqPlex (TM) , DNA SMART (TM), TELP and ThruPLEX (R)) were performed on five replicates of 1 ng and 0.1 ng input H3K4me3 ChIP material, and compared to a "gold standard" reference PCR-free dataset. The performance of each method was examined for the prevalence of unmappable reads, amplification-derived duplicate reads, reproducibility, and for the sensitivity and specificity of peak calling. Conclusions: We identified consistent high performance in a subset of the tested reagents, which should aid researchers in choosing the most appropriate reagents for their studies. Furthermore, we expect this work to drive future advances by identifying and encouraging use of the most promising methods and reagents. The results may also aid judgements on how comparable are existing datasets that have been prepared with different sample library preparation reagents. C1 [Sundaram, Arvind Y. M.; Hughes, Timothy; Lyle, Robert; Gilfillan, Gregor D.] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Sundaram, Arvind Y. M.; Hughes, Timothy; Lyle, Robert; Gilfillan, Gregor D.] Univ Oslo, Oslo, Norway. [Biondi, Shea; Chew, Yap C.] Zymo Res Corp, 7062 Murphy Ave, Irvine, CA 92614 USA. [Bolduc, Nathalie; Farmer, Andrew] Takara Bio USA Inc, 1290 Terra Bella Ave, Mountain View, CA 94043 USA. [Bowman, Sarah K.] Harvard Med Sch, Mass Gen Hosp, Mol Biol, 185 Cambridge St,CPZN 7250, Boston, MA 02114 USA. [Camilli, Andrew; Lazinski, David W.] Tufts Univ, Dept Mol Biol & Microbiol, 136 Harrison Ave, Boston, MA 02111 USA. [Camilli, Andrew; Lazinski, David W.] Tufts Univ, Howard Hughes Med Inst, 136 Harrison Ave, Boston, MA 02111 USA. [Couture, Catherine; McUsic, Andrew] Swift Biosci Inc, Suite 100,58 Parkland Plaza, Ann Arbor, MI 48103 USA. [Jerome, John P.; Shazand, Kamran] Rubicon Genom Inc, 4743 Venture Dr, Ann Arbor, MI 48108 USA. [Peng, Xu; Xu, Feng] ASTAR, Singapore Inst Clin Sci, Singapore 117609, Singapore. [Bowman, Sarah K.] Directed Genom, 240 Cty Rd, Ipswich, MA 01938 USA. RP Lyle, R; Gilfillan, GD (reprint author), Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.; Lyle, R; Gilfillan, GD (reprint author), Univ Oslo, Oslo, Norway. EM robert.lyle@medisin.uio.no; gregor.gilfillan@medisin.uio.no FU Research Council of Norway FX The study was funded by the Research Council of Norway. NR 42 TC 0 Z9 0 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 21 PY 2016 VL 17 AR 816 DI 10.1186/s12864-016-3135-y PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DZ5AG UT WOS:000385873500001 PM 27769162 ER PT J AU Park, KW Batule, BS Kang, KS Park, KS Park, HG AF Park, Kwan Woo Batule, Bhagwan S. Kang, Kyoung Suk Park, Ki Soo Park, Hyun Gyu TI Rapid and ultrasensitive detection of microRNA by target-assisted isothermal exponential amplification coupled with poly (thymine)-templated fluorescent copper nanoparticles SO NANOTECHNOLOGY LA English DT Article DE isothermal amplification; TAIEA; miRNA detection; fluorescent biosensor; CuNPs ID ROLLING CIRCLE AMPLIFICATION; LABEL-FREE DETECTION; CANCER-CELLS; ELECTROCHEMICAL DETECTION; SIGNAL AMPLIFICATION; SENSITIVE DETECTION; BREAST-CANCER; PROTEIN; NANOCLUSTERS; BIOGENESIS AB We devised a novel method for rapid and ultrasensitive detection of target microRNA (miRNA) by employing target-assisted isothermal exponential amplification (TAIEA) combined with poly (thymine)-templated fluorescent copper nanoparticles (CuNPs) as signaling probes. The target miRNA hybridizes to the unimolecular template DNA and works as a primer for the extension reaction to form double-stranded product, which consequently generates two nicking endonuclease recognition sites. By simultaneous nicking and displacement reactions, exponential amplification generates many poly (thymine) strands as final products, which are employed for the synthesis of fluorescent CuNPs. Based on the fluorescent signal from CuNPs, target miRNA is detected as low as 0.27 fM around 1 h of total analysis time. The diagnostic capability of this system has been successfully demonstrated by reliably detecting target miRNA from different cell lysates, showing its great potential towards real clinical applications. C1 [Park, Kwan Woo; Batule, Bhagwan S.; Kang, Kyoung Suk; Park, Hyun Gyu] Korea Adv Inst Sci & Technol, Dept Chem & Biomol Engn, 291 Daehak Ro, Daejeon 34141, South Korea. [Park, Ki Soo] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Park, Ki Soo] Harvard Med Sch, Boston, MA 02114 USA. RP Park, HG (reprint author), Korea Adv Inst Sci & Technol, Dept Chem & Biomol Engn, 291 Daehak Ro, Daejeon 34141, South Korea. EM hgpark@kaist.ac.kr RI PARK, HYUN GYU/C-1597-2011 FU Mid-career Researcher Support Program through the National Research Foundation (NRF) - Ministry of Science, ICT and Future Planning (MSIP) of Korea [2015R1A2A1A01005393]; Bio-Synergy Research Project through the NRF - MISP of Korea [NRF-2015M3A9C4070484]; Industrial Source Technology Development Program of the Ministry of Trade, Industry and Energy (MOTIE) [2010-10038662] FX This work was supported by the Mid-career Researcher Support Program through the National Research Foundation (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP) of Korea (No. 2015R1A2A1A01005393) and Bio-Synergy Research Project through the NRF funded by the MISP of Korea (NRF-2015M3A9C4070484). This work was also supported by the grant from the Industrial Source Technology Development Program (No. 2010-10038662) of the Ministry of Trade, Industry and Energy (MOTIE). NR 38 TC 0 Z9 0 U1 39 U2 39 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD OCT 21 PY 2016 VL 27 IS 42 AR 425502 DI 10.1088/0957-4484/27/42/425502 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA DY9VQ UT WOS:000385483600002 ER PT J AU Qin, N Botas, P Giantsoudi, D Schuemann, J Tian, Z Jiang, SB Paganetti, H Jia, X AF Qin, Nan Botas, Pablo Giantsoudi, Drosoula Schuemann, Jan Tian, Zhen Jiang, Steve B. Paganetti, Harald Jia, Xun TI Recent developments and comprehensive evaluations of a GPU-based Monte Carlo package for proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE GPU; proton therapy; Monte Carlo ID LINEAR-ENERGY-TRANSFER; DOSE CALCULATION; RADIATION-THERAPY; SIMULATION; OPTIMIZATION; ALGORITHM; PLATFORM; TOPAS AB Monte Carlo (MC) simulation is commonly considered as the most accurate dose calculation method for proton therapy. Aiming at achieving fast MC dose calculations for clinical applications, we have previously developed a graphics-processing unit (GPU)-based MC tool, gPMC. In this paper, we report our recent updates on gPMC in terms of its accuracy, portability, and functionality, as well as comprehensive tests on this tool. The new version, gPMC v2.0, was developed under the OpenCL environment to enable portability across different computational platforms. Physics models of nuclear interactions were refined to improve calculation accuracy. Scoring functions of gPMC were expanded to enable tallying particle fluence, dose deposited by different particle types, and dose-averaged linear energy transfer (LETd). A multiple counter approach was employed to improve efficiency by reducing the frequency of memory writing conflict at scoring. For dose calculation, accuracy improvements over gPMC v1.0 were observed in both water phantom cases and a patient case. For a prostate cancer case planned using high-energy proton beams, dose discrepancies in beam entrance and target region seen in gPMC v1.0 with respect to the gold standard tool for proton Monte Carlo simulations (TOPAS) results were substantially reduced and gamma test passing rate (1%/ 1 mm) was improved from 82.7%-93.1%. The average relative difference in LETd between gPMC and TOPAS was 1.7%. The average relative differences in the dose deposited by primary, secondary, and other heavier particles were within 2.3%, 0.4%, and 0.2%. Depending on source proton energy and phantom complexity, it took 8-17 s on an AMD Radeon R9 290x GPU to simulate 10(7) source protons, achieving less than 1% average statistical uncertainty. As the beam size was reduced from 10 x 10 cm(2) to 1 x 1 cm(2), the time on scoring was only increased by 4.8% with eight counters, in contrast to a 40% increase using only one counter. With the OpenCL environment, the portability of gPMC v2.0 was enhanced. It was successfully executed on different CPUs and GPUs and its performance on different devices varied depending on processing power and hardware structure. C1 [Qin, Nan; Tian, Zhen; Jiang, Steve B.; Jia, Xun] Univ Texas Southwestern Med Ctr, Dept Radiat Oncol, Dallas, TX 75390 USA. [Botas, Pablo; Giantsoudi, Drosoula; Schuemann, Jan; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Botas, Pablo; Giantsoudi, Drosoula; Schuemann, Jan; Paganetti, Harald] Harvard Med Sch, Boston, MA 02114 USA. [Botas, Pablo] Heidelberg Univ, Dept Phys & Astron, Heidelberg, Germany. RP Jiang, SB (reprint author), Univ Texas Southwestern Med Ctr, Dept Radiat Oncol, Dallas, TX 75390 USA. EM steve.jiang@utsouthwestern.edu; hpaganetti@mgh.harvard.edu; xun.jia@utsouthwestern.edu FU NIH [P20CA183639-01A1]; Federal Share of program [C06 CA059267] FX This work is supported in part by an NIH grant (P20CA183639-01A1) and the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267. NR 30 TC 0 Z9 0 U1 3 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2016 VL 61 IS 20 BP 7347 EP 7362 DI 10.1088/0031-9155/61/20/7347 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DZ2BM UT WOS:000385647100002 PM 27694712 ER PT J AU Zhu, JG Song, JK Liu, ZZ Han, J Luo, H Liu, YL Jia, ZY Dong, YB Zhang, W Jiang, FN Wu, CL Sun, ZL Zhong, WD AF Zhu, Jianguo Song, Jukun Liu, Zezhen Han, Jin Luo, Heng Liu, Yunlin Jia, Zhenyu Dong, Yuanbo Zhang, Wei Jiang, Funeng Wu, Chinlee Sun, Zaolin Zhong, Weide TI Association between allergic conditions and risk of prostate cancer: A Prisma-Compliant Systematic Review and Meta-Analysis SO SCIENTIFIC REPORTS LA English DT Article ID NEWCASTLE-OTTAWA SCALE; IMMUNOGLOBULIN-E; ASTHMA PATIENTS; HAY-FEVER; MORTALITY; POPULATION; INFLAMMATION; COHORT; ATOPY; STATISTICS AB Association between allergic conditions and prostate cancer risk has been investigated for many years. However, the results from available evidence for the association are inconsistent. We conducted a meta-analysis to evaluate the relationship between allergic conditions (asthma, atopy, hay fever and "any allergy") and risk of prostate cancer. The PubMed and Embase databases were searched to screen observational studies meeting our meta-analysis criteria. Study selection and data extraction from included studies were independently performed by two authors. Twenty studies were considered eligible involving 5 case-control studies and 15 cohort studies. The summary relative risk (RR) for developing prostate cancer risk was 1.04 (95% CI: 0.92-1.17) for asthma, and 1.25 (95% CI: 0.74-2.10) for atopy, 1.04 (95% CI: 0.99-1.09) for hay fever, 0.96 (95% CI: 0.86-1.06) for any allergy. In the Subgroup and sensitivity analysis, similar results were produced. Little evidence of publication bias was observed. The present meta-analysis of observational studies indicates that no indication of an association between allergic conditions and risk of prostate cancer was found, and the meta-analysis does not support neither the original hypothesis of an overall cancer protective effect of allergic conditions, nor that of an opposite effect in the development of prostate cancer. C1 [Zhu, Jianguo; Liu, Zezhen; Luo, Heng; Jia, Zhenyu; Jiang, Funeng; Wu, Chinlee; Zhong, Weide] Guangzhou Med Univ, Guangzhou Peoples Hosp 1, Guangdong Key Lab Clin Mol Med & Diagnost, Dept Urol, Guangzhou 510180, Guangdong, Peoples R China. [Zhu, Jianguo; Liu, Zezhen; Luo, Heng; Jia, Zhenyu; Jiang, Funeng; Zhong, Weide] Guangzhou Med Univ, Affiliated Hosp 1, Urol Key Lab Guangdong Prov, Guangzhou 510230, Guangdong, Peoples R China. [Zhu, Jianguo; Dong, Yuanbo; Sun, Zaolin] Guizhou Prov Peoples Hosp, Dept Urol, Guiyang 550002, Guizhou, Peoples R China. [Song, Jukun; Zhang, Wei] Guizhou Prov Peoples Hosp, Dept Oral & Maxillofacial Surg, Guiyang 550002, Guizhou, Peoples R China. [Han, Jin] Guizhou Prov Peoples Hosp, Dept Resp & Crit Care Med, Guiyang 550002, Guizhou, Peoples R China. [Liu, Yunlin] Univ Calif Davis, Coll Agr & Environm Sci, Davis, CA 95616 USA. [Wu, Chinlee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Wu, Chinlee] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wu, Chinlee] Harvard Med Sch, Boston, MA 02114 USA. RP Zhong, WD (reprint author), Guangzhou Med Univ, Guangzhou Peoples Hosp 1, Guangdong Key Lab Clin Mol Med & Diagnost, Dept Urol, Guangzhou 510180, Guangdong, Peoples R China.; Zhong, WD (reprint author), Guangzhou Med Univ, Affiliated Hosp 1, Urol Key Lab Guangdong Prov, Guangzhou 510230, Guangdong, Peoples R China.; Sun, ZL (reprint author), Guizhou Prov Peoples Hosp, Dept Urol, Guiyang 550002, Guizhou, Peoples R China. EM doctorsunzaolin@126.cm; zhongwd2009@live.cn FU National Natural Science Foundation of China [81170699, 81360119]; Projects of Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics; Guangzhou Municipal Science and Technology Key Project [2014J4100072]; Outstanding Youth Science and Technology Talent Cultivating Object of Guizhou Province [2013-18]; International Scientific and Technological Cooperation Projects of Guizhou Province [20137031]; China Postdoctoral Science Foundation [2014M562157]; Zhejiang provincial medical and health science and technology project [2016KYB265]; Guizhou Province Science and Technology Agency - Guizhou Provincial People's Hospital Joint Fund [SY[2010]3124] FX This work was supported by grants from National Natural Science Foundation of China (81170699, 81360119), Projects of Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou Municipal Science and Technology Key Project (2014J4100072), Outstanding Youth Science and Technology Talent Cultivating Object of Guizhou Province in 2013 (2013-18), International Scientific and Technological Cooperation Projects of Guizhou Province (20137031), China Postdoctoral Science Foundation (2014M562157), Zhejiang provincial medical and health science and technology project (2016KYB265), Guizhou Province Science and Technology Agency - Guizhou Provincial People's Hospital Joint Fund SY[2010]3124. NR 54 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 21 PY 2016 VL 6 AR 35682 DI 10.1038/srep35682 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ4LP UT WOS:000385830500001 PM 27767045 ER PT J AU Wang, ZW Qi, H Shen, QR Lu, GD Li, MY Bao, K Wu, YL Zhang, WG AF Wang, Zhiwei Qi, Huan Shen, Qirong Lu, Guodong Li, Mingyang Bao, Kai Wu, Yingliang Zhang, Weige TI 4,5-Diaryl-3H-1,2-dithiole-3-thiones and related compounds as combretastatin A-4/oltipraz hybrids: Synthesis, molecular modelling and evaluation as antiproliferative agents and inhibitors of tubulin SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Combretastatin A-4/oltipraz hybrids; Antiproliferative activity; Tubulin polymerization; Cell cycle arrest; Molecular modelling studies ID VASCULAR DISRUPTING AGENTS; BIOLOGICAL-ACTIVITY; ANTIMITOTIC AGENTS; CYTOTOXIC AGENTS; CELL-DEATH; IN-VITRO; CANCER; BINDING; COLCHICINE; DERIVATIVES AB A new series of 4,5-diaryl-3H-1,2-dithiole-3-thiones and related compounds were designed and synthesised as combretastatin A-4/oltipraz hybrids. We evaluated the antiproliferative activities, inhibition of tubulin polymerization, and cell-cycle effects of these compounds. Several compounds in this series, such as 4d and 5c, displayed significant activity against SGC-7901, KB and HT-1080 cell lines, as determined using MTT assays. The most active compound, 4d, markedly inhibited tubulin polymerization, with an IC50 value of 4.44 mu M being observed. In mechanistic studies, 4d caused cell arrest in G2/M phase, induced apoptotic cell death, and disrupted microtubule formation. Molecular docking studies revealed that 4d interacts and binds efficiently with the tubulin protein. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Wang, Zhiwei; Shen, Qirong; Lu, Guodong; Li, Mingyang; Bao, Kai; Zhang, Weige] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China. [Wang, Zhiwei] Jinzhou Med Univ, Dept Pharmaceut Chem, 40,Sect 3,Songpo Rd, Jinzhou 121001, Peoples R China. [Qi, Huan; Wu, Yingliang] Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China. [Bao, Kai] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Gordon Ctr Med Imaging, Boston, MA 02214 USA. [Bao, Kai] Harvard Med Sch, Boston, MA 02214 USA. RP Zhang, WG (reprint author), Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China.; Wu, YL (reprint author), Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China. EM yingliang_1016@163.com; zhangweige2000@sina.com FU National Natural Science Foundation of China [81502932]; State Key Laboratory of Natural Medicines and Active Substance [GTZK201603]; Program for Innovative Research Team of the Ministry of Education; Program for Liaoning Innovative Research Team in University FX We gratefully acknowledge the National Natural Science Foundation of China (81502932) and State Key Laboratory of Natural Medicines and Active Substance (No. GTZK201603) for their generous financial support. This work was also supported by Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University. NR 42 TC 2 Z9 2 U1 15 U2 15 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD OCT 21 PY 2016 VL 122 BP 520 EP 529 DI 10.1016/j.ejmech.2016.06.055 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DV5XL UT WOS:000383003900045 PM 27428395 ER PT J AU Fu, TM Li, Y Lu, A Li, ZL Vajjhala, PR Cruz, AC Srivastava, DB DiMaio, F Penczek, PA Siegel, RM Stacey, KJ Egelman, EH Wu, H AF Fu, Tian-Min Li, Yang Lu, Alvin Li, Zongli Vajjhala, Parimala R. Cruz, Anthony C. Srivastava, Devendra B. DiMaio, Frank Penczek, Pawel A. Siegel, Richard M. Stacey, Katryn J. Egelman, Edward H. Wu, Hao TI Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex SO MOLECULAR CELL LA English DT Article ID CRYSTAL-STRUCTURE; EFFECTOR DOMAIN; IMMUNE-SYSTEM; UNIFIED MODEL; CELL-DEATH; RECEPTOR; DISC; ACTIVATION; INHIBITION; APOPTOSIS AB Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively. C1 [Fu, Tian-Min; Li, Yang; Lu, Alvin; Li, Zongli; Srivastava, Devendra B.; Wu, Hao] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Fu, Tian-Min; Li, Yang; Lu, Alvin; Srivastava, Devendra B.; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Zongli] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Vajjhala, Parimala R.; Stacey, Katryn J.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia. [Cruz, Anthony C.; Siegel, Richard M.] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [DiMaio, Frank] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Penczek, Pawel A.] Univ Texas Houston, Sch Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Stacey, Katryn J.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Egelman, Edward H.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Wu, H (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Wu, H (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM wu@crystal.harvard.edu FU NIH [DP1-HD087988, R37-AI050872, R01-AI045937, R01-EB001567, R01-GM60635]; National Health and Medical Research Council of Australia [1050651, 1109738, 1059729] FX We thank Drs. Narayanasami Sukumar, Kay Perry, Ryan Ferrao, Gunes Bozkurt, and Li Wang for their assistance in X-ray diffraction data collection at the Advanced Photon Source. The work was supported by funding from the NIH (DP1-HD087988, R37-AI050872, and R01-AI045937 to H.W.; R01-EB001567 to E.H.E.; and R01-GM60635 to P.A.P.) and the National Health and Medical Research Council of Australia (1050651, 1109738, and 1059729 to K.J.S.). NR 47 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 20 PY 2016 VL 64 IS 2 BP 236 EP 250 DI 10.1016/j.molcel.2016.09.009 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RP UT WOS:000389515000005 ER PT J AU MacDonald, SM Rapalino, O Sherry, NA Cohen, AB Ebb, DH Tarbell, NJ Oakley, DH AF MacDonald, Shannon M. Rapalino, Otto Sherry, Nicole A. Cohen, Adam B. Ebb, David H. Tarbell, Nancy J. Oakley, Derek H. TI Case 32-2016: A 20-Year-Old Man with Gynecomastia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GERM-CELL TUMORS; CENTRAL-NERVOUS-SYSTEM; STEROID-INDUCED HYPOGONADISM; ADIPSIC DIABETES-INSIPIDUS; SYNCHRONOUS LESIONS; SUPRASELLAR REGION; DELAYED DIAGNOSIS; PINEAL; GERMINOMA; CHILDREN C1 [MacDonald, Shannon M.; Tarbell, Nancy J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sherry, Nicole A.] Massachusetts Gen Hosp, Dept Pediat Endocrinol, Boston, MA 02114 USA. [Cohen, Adam B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ebb, David H.] Massachusetts Gen Hosp, Dept Pediat Hematol Oncol, Boston, MA 02114 USA. [Oakley, Derek H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [MacDonald, Shannon M.; Tarbell, Nancy J.] Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02115 USA. [Rapalino, Otto] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Sherry, Nicole A.] Harvard Med Sch, Dept Pediat Endocrincol, Boston, MA USA. [Cohen, Adam B.] Harvard Med Sch, Dept Neurol, Boston, MA USA. [Ebb, David H.] Harvard Med Sch, Dept Pediat Hematologyoncol, Boston, MA USA. [Oakley, Derek H.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP MacDonald, SM (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; MacDonald, SM (reprint author), Harvard Med Sch, Dept Radiat Oncol, Boston, MA 02115 USA. NR 44 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 20 PY 2016 VL 375 IS 16 BP 1567 EP 1579 DI 10.1056/NEJMcpc1610098 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3HF UT WOS:000393102500011 PM 27797319 ER PT J AU Harrington, D Parmigiani, G AF Harrington, David Parmigiani, Giovanni TI Adaptive Randomization of Neratinib in Early Breast Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Harrington, David; Parmigiani, Giovanni] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Harrington, D (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 20 PY 2016 VL 375 IS 16 BP 1593 EP 1594 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EJ3HF UT WOS:000393102500021 PM 28103002 ER PT J AU Gilbert, GE AF Gilbert, Gary E. TI Inhibitory antibodies against factor VIII C1 domain SO BLOOD LA English DT Editorial Material C1 [Gilbert, Gary E.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Gilbert, Gary E.] Harvard Med Sch, Boston, MA 02115 USA. RP Gilbert, GE (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Gilbert, GE (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 2001 EP 2002 DI 10.1182/blood-2016-08-727818 PG 4 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900003 PM 28157676 ER PT J AU Boyraz, B Bellomo, CM Fleming, MD Cutler, CS Agarwal, S AF Boyraz, Baris Bellomo, Courtney M. Fleming, Mark D. Cutler, Corey S. Agarwal, Suneet TI A novel TERC CR4/CR5 domain mutation causes telomere disease via decreased TERT binding SO BLOOD LA English DT Letter ID BONE-MARROW FAILURE; DYSKERATOSIS-CONGENITA; FUNCTIONAL-CHARACTERIZATION; REVERSE-TRANSCRIPTASE; PULMONARY-FIBROSIS; CATALYTIC SUBUNIT; APLASTIC-ANEMIA; RNA COMPONENT; DISORDERS; CELLS C1 [Boyraz, Baris; Agarwal, Suneet] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Boyraz, Baris; Agarwal, Suneet] Boston Childrens Hosp, Stem Cell Program, Boston, MA USA. [Boyraz, Baris; Agarwal, Suneet] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Boyraz, Baris; Agarwal, Suneet] Harvard Stem Cell Inst, Boston, MA USA. [Boyraz, Baris; Agarwal, Suneet] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Boyraz, Baris] Hacettepe Univ, Inst Canc, Dept Basic Oncol, Ankara, Turkey. [Bellomo, Courtney M.] Albany Med Ctr, New York Oncol Hematol, Albany, NY USA. [Fleming, Mark D.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Cutler, Corey S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Agarwal, S (reprint author), Boston Childrens Hosp, CLS 3002,3 Blackfan Circle, Boston, MA 02115 USA. EM suneet.agarwal@childrens.harvard.edu NR 28 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 2089 EP 2092 DI 10.1182/blood-2016-04-710160 PG 4 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900014 PM 27587879 ER PT J AU Abdulhay, N Fiorini, C Kumanovics, A Sun, AA Hansen-Rejali, J Voelkerding, KV Rosenzweig, SD Hill, HR Sankaran, VG AF Abdulhay, Nour Fiorini, Claudia Kumanovics, Attila Sun, Ashleigh A. Hansen-Rejali, Jeannette Voelkerding, Karl V. Rosenzweig, Sergio D. Hill, Harry R. Sankaran, Vijay G. TI Normal hematologic parameters and fetal hemoglobin silencing with heterozygous IKZF1 mutations SO BLOOD LA English DT Letter ID IKAROS; BCL11A; EXPRESSION; DIFFERENTIATION; ANEMIA C1 [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Boston Childrens Hosp, Div Hematol Oncol, 3 Blackfan Cir,CLS 03001, Boston, MA 02115 USA. [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Abdulhay, Nour; Fiorini, Claudia; Sankaran, Vijay G.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Kumanovics, Attila; Hansen-Rejali, Jeannette; Voelkerding, Karl V.; Hill, Harry R.] ARUP Inst Clin & Expt Pathol, ARUP Labs, Salt Lake City, UT USA. [Kumanovics, Attila; Hansen-Rejali, Jeannette; Voelkerding, Karl V.; Hill, Harry R.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Sun, Ashleigh A.; Rosenzweig, Sergio D.] NIAID, Serv Immunol, Dept Lab Med, Ctr Clin,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sun, Ashleigh A.; Rosenzweig, Sergio D.] NIAID, Primary Immune Deficiency Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hansen-Rejali, Jeannette; Hill, Harry R.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Hansen-Rejali, Jeannette; Hill, Harry R.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 3 Blackfan Cir,CLS 03001, Boston, MA 02115 USA. EM sankaran@broadinstitute.org NR 25 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 20 PY 2016 VL 128 IS 16 BP 2100 EP 2103 DI 10.1182/blood-2016-08-731943 PG 4 WC Hematology SC Hematology GA DZ3IL UT WOS:000385739900018 PM 27581358 ER PT J AU Luttrell, LM AF Luttrell, Louis M. TI GPCR Signaling Rides a Wave of Conformational Changes SO CELL LA English DT Editorial Material ID RECEPTOR AB The ability of structurally distinct ligands to "bias" G protein-coupled receptor signaling affords the opportunity to tailor efficacy to suit specific therapeutic needs. Furness et al. demonstrate that ligand structure controls not only which effectors are activated, but also the way they are activated and the kinetics of downstream signaling. C1 [Luttrell, Louis M.] Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA. [Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Luttrell, LM (reprint author), Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA.; Luttrell, LM (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. EM luttrell@musc.edu FU NIDDK NIH HHS [R01 DK055524]; NIGMS NIH HHS [R01 GM095497] NR 6 TC 0 Z9 0 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 20 PY 2016 VL 167 IS 3 BP 602 EP 603 DI 10.1016/j.cell.2016.10.006 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HW UT WOS:000386344100007 PM 27768883 ER PT J AU Lemmela, S Solovieva, S Shiri, R Benner, C Heliovaara, M Kettunen, J Anttila, V Ripatti, S Perola, M Seppala, I Juonala, M Kahonen, M Salomaa, V Viikari, J Raitakari, OT Lehtimaki, T Palotie, A Viikari-Juntura, E Husgafvel-Pursiainen, K AF Lemmela, Susanna Solovieva, Svetlana Shiri, Rahman Benner, Christian Heliovaara, Markku Kettunen, Johannes Anttila, Verneri Ripatti, Samuli Perola, Markus Seppala, Ilkka Juonala, Markus Kahonen, Mika Salomaa, Veikko Viikari, Jorma Raitakari, Olli T. Lehtimaki, Terho Palotie, Aarno Viikari-Juntura, Eira Husgafvel-Pursiainen, Kirsti TI Genome-Wide Meta-Analysis of Sciatica in Finnish Population SO PLOS ONE LA English DT Article ID LOW-BACK-PAIN; LUMBAR DISC DEGENERATION; NUCLEAR FACTOR-I; CLASS II/III REGION; MYOSIN-V FUNCTION; KNEE OSTEOARTHRITIS; ASSOCIATION; GENE; DISEASE; TRANSCRIPTION AB Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10(-6)) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:1 (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10(-8), MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10(-8), MAF = 0.06; p = 2.32x10(-8), MAF = 0.07; p = 3.85x10(-8), MAF = 0.06; p = 4.78x10(-8), MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:1, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate. C1 [Lemmela, Susanna; Solovieva, Svetlana; Shiri, Rahman; Husgafvel-Pursiainen, Kirsti] Finnish Inst Occupat Hlth, Hlth & Work Abil, Helsinki 00250, Finland. [Benner, Christian; Ripatti, Samuli; Perola, Markus; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland, FIN-00014 Helsinki, Finland. [Benner, Christian; Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Heliovaara, Markku] Natl Inst Hlth & Welf, Populat Hlth Unit, Helsinki 00251, Finland. [Kettunen, Johannes] Univ Oulu, Inst Hlth Sci, Fac Med, SF-90220 Oulu, Finland. [Kettunen, Johannes] Univ Eastern Finland, NMR Metab Lab, Kuopio, Finland. [Kettunen, Johannes] Natl Inst Hlth & Welf, Helsinki, Finland. [Anttila, Verneri; Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Anttila, Verneri; Palotie, Aarno] Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Ripatti, Samuli] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. [Perola, Markus] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki 00271, Finland. [Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Seppala, Ilkka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Fimlab Labs, Tampere 33520, Finland. [Juonala, Markus; Viikari, Jorma] Turku Univ Hosp, Div Med, Turku 20521, Finland. [Juonala, Markus; Viikari, Jorma] Univ Turku, Dept Med, Turku 20521, Finland. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Hlth, Helsinki 00251, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Viikari-Juntura, Eira] Finnish Inst Occupat Hlth, Disabil Prevent Ctr, Helsinki 00250, Finland. RP Husgafvel-Pursiainen, K (reprint author), Finnish Inst Occupat Hlth, Hlth & Work Abil, Helsinki 00250, Finland. EM kirsti.husgafvel-pursiainen@ttl.fi FU Academy of Finland, Responding to Public Health Challenges Research Programme [129364]; Finnish Work Environment Fund [113077]; Academy of Finland [283045, 126925, 124282, 129378, 117797, 141071, 121584, 134309, 139635, 251217, 285380, 251704]; Orion Farmos Research Foundation; Sigrid Juselius Foundation; Finnish Foundation for Cardiovascular Research; Biocentrum Helsinki; NordForsk e-Science NIASC [62721]; EU-7th FP [EU FP7-242167]; Wellcome Trust [098051]; Social Insurance Institution of Finland, Kuopio, Tampere; Tampere and Turku University Hospital Medical Funds; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Finnish Cultural Foundation FX The study was supported by the Academy of Finland, Responding to Public Health Challenges Research Programme (129364 to EVJ) and the Finnish Work Environment Fund (113077 to KHP). Financial support from the Academy of Finland was also received through grants 283045 to JK; 126925, 124282, 129378, 117797, and 141071 to OTR; 121584 to JV; 134309 to MK; 139635 to VS; 251217 and 285380 to SR; 251704 to A.P. In addition, the study was supported by the Orion Farmos Research Foundation to VA; Sigrid Juselius Foundation (to SR and AP), Finnish Foundation for Cardiovascular Research (to SR); Biocentrum Helsinki (to SR); NordForsk e-Science NIASC (62721 to SR); EU-7th FP (The SynSys Project and EU FP7-242167 to AP), the Wellcome Trust (098051 to AP). The Young Finns Study has also received financial support from the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 0 Z9 0 U1 11 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2016 VL 11 IS 10 AR e0163877 DI 10.1371/journal.pone.0163877 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9NZ UT WOS:000386204500010 PM 27764105 ER PT J AU Yang, J Yang, J Liang, SH Xu, YG Moore, A Ran, CZ AF Yang, Jian Yang, Jing Liang, Steven H. Xu, Yungen Moore, Anna Ran, Chongzhao TI Imaging hydrogen peroxide in Alzheimer's disease via cascade signal amplification SO SCIENTIFIC REPORTS LA English DT Article ID OXIDATIVE STRESS HYPOTHESIS; NECROSIS-FACTOR-ALPHA; IN-VIVO; LIVING CELLS; A-BETA; PROBE; MICE; ACTIVATION; PYRUVATE; PLAQUES AB In brains of Alzheimer's disease (AD), reactive oxygen species (ROS) levels are significantly higher than that of healthy brains. Evidence suggests that, during AD onset and progression, a vicious cycle revolves around amyloid beta (A beta) production, aggregation, plaque formation, microglia/immunological responses, inflammation, and ROS production. In this cycle, ROS species play a central role, and H2O2 is one of the most important ROS species. In this report, we have designed a fluorescent imaging probe CRANAD-88, which is capable of cascade amplifying near infrared fluorescence (NIRF) signals at three levels upon interacting with H2O2 in AD brains. We demonstrated that the amplification was feasible in vitro and in vivo. Remarkably, we showed that, for the first time, it was feasible to monitor the changes of H2O2 concentrations in AD brains before and after treatment with an H2O2 scavenger. Our method opens new revenues to investigate H2O2 in AD brains and can be very instructive for drug development. C1 [Yang, Jian; Yang, Jing; Moore, Anna; Ran, Chongzhao] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Mol Imaging Lab, Boston, MA 01890 USA. [Yang, Jian; Yang, Jing; Moore, Anna; Ran, Chongzhao] Harvard Med Sch, Boston, MA 01890 USA. [Yang, Jian; Xu, Yungen] China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Peoples R China. [Yang, Jing] Soochow Univ, Coll Pharmaceut Sci, Suzhou 215006, Peoples R China. [Liang, Steven H.] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Liang, Steven H.] Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. [Liang, Steven H.] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. RP Ran, CZ (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Mol Imaging Lab, Boston, MA 01890 USA.; Ran, CZ (reprint author), Harvard Med Sch, Boston, MA 01890 USA.; Xu, YG (reprint author), China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Peoples R China. EM xyg64@126.com; cran@nmr.mgh.harvard.edu FU NIH [K25AG036760, R21AG050158]; China Scholarship Council of Ministry of Education of China FX This work was supported by NIH K25AG036760 and R21AG050158 awards (C.R.). We thank Pamela Pantazopoulos, B.S. for proofreading this manuscript. We also thank China Scholarship Council of Ministry of Education of China for supporting (J.Y. and J.Y.). NR 35 TC 0 Z9 0 U1 27 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 20 PY 2016 VL 6 AR 35613 DI 10.1038/srep35613 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ9LX UT WOS:000386197800001 PM 27762326 ER PT J AU Shanmugasundaram, K Block, K AF Shanmugasundaram, Karthigayan Block, Karen TI Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review DE tumor heterogeneity; oxidative stress; NOX oxidases; mitochondrial electron transfer chain; renal cancer; high-throughput analysis ID HYPOXIA-INDUCIBLE FACTOR; MITOCHONDRIAL OXIDATIVE-METABOLISM; EPITHELIAL-MESENCHYMAL TRANSITION; MICRORNA EXPRESSION SIGNATURES; MESSENGER-RNA TRANSLATION; OXIDASE SUBUNIT NOX4; HUMAN KIDNEY CANCER; CELL CARCINOMA; NADPH OXIDASE; TGF-BETA AB Significance: The number of kidney cancers is growing 3-5% each year due to unknown etiologies. Intra-and inter-tumor mediators increase oxidative stress and drive tumor heterogeneity. Recent Advances: Technology advancement in state-of-the-art instrumentation and methodologies allows researchers to detect and characterize global landscaping modifications in genes, proteins, and pathophysiology patterns at the single-cell level. Critical Issues: We postulate that the sources of reactive oxygen species (ROS) and their activation within subcellular compartments will change over a timeline of tumor evolvement and contribute to tumor heterogeneity. Therefore, the complexity of intracellular changes within a tumor and ROS-induced tumor heterogeneity coupled to the advancement of detecting these events globally are limited at the level of data collection, organization, and interpretation using software algorithms and bioinformatics. Future Directions: Integrative and collaborative research, combining the power of numbers with careful experimental design, protocol development, and data interpretation, will translate cancer biology and therapeutics to a heightened level or leave the abundant raw data as stagnant and underutilized. C1 [Shanmugasundaram, Karthigayan; Block, Karen] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, MC 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Block, Karen] Audie L Murphy Mem Hosp Div, South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Block, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, MC 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM block@uthscsa.edu FU Veterans Administration Merit Award; NIH [P30 CA054174] FX The authors would like to thank Dr. Yves Gorin for the creative drawing of figures presented in this article. Grant support was provided by Veterans Administration Merit Award (K.B.) and NIH P30 CA054174 (K.B.). NR 167 TC 0 Z9 0 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT 20 PY 2016 VL 25 IS 12 BP 685 EP 701 DI 10.1089/ars.2015.6569 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DY8MH UT WOS:000385383800004 PM 27287984 ER PT J AU Gupta, S Alladina, J Heaton, K Miloslavsky, E AF Gupta, Shruti Alladina, Jehan Heaton, Kevin Miloslavsky, Eli TI A randomized trial of an intervention to improve resident-fellow teaching interactions on the wards SO BMC MEDICAL EDUCATION LA English DT Article DE Inpatient subspecialty consultation; Internal medicine; Fellows; Residents; Teaching interaction; Communication ID POSTGRADUATE MEDICAL-EDUCATION; INPATIENT CONSULTATION; EMERGENCY-DEPARTMENT; CURRICULUM; TEACHERS; SKILLS AB Background: Subspecialty fellows can serve as a tremendous educational resource to residents; however, there are multiple barriers to an effective resident-fellow teaching interaction in the setting of inpatient consultation. We designed and evaluated a resident-directed intervention to enhance communication and teaching during consultation on the general medicine wards. Methods: Five medical teams were randomized to receive the intervention over a 3 month period (3 control, 2 intervention teams). The intervention was evaluated with pre and post-intervention surveys. Results: Fifty-nine of 112 interns completed the pre-intervention survey, and 58 completed the post-intervention survey (53 % response rate). At baseline, 83 % of the interns noted that they had in-person interactions with fellows less than 50 % of the time. 81 % responded that they received teaching from fellows in less than 50 % of consultations. Following the intervention, the percentage of interns who had an in-person interaction with fellows greater than 50 % of the time increased in the intervention group (9 % control versus 30 % intervention, p = 0.05). Additionally, interns in the intervention group reported receiving teaching in more than 50 % of their interactions more frequently (19 % control versus 42 % intervention, p = 0.05). There were no differences in other measures of teaching and communication. Conclusions: We demonstrate that a time-efficient intervention increased perceptions of in-person communication and the number of teaching interactions between interns and fellows. Further studies are warranted to determine whether such an approach can impact resident learning and improve patient care. C1 [Gupta, Shruti] Massachusetts Gen Hosp, Dept Med, Div Nephrol, 55 Fruit St, Boston, MA 02114 USA. [Alladina, Jehan] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Heaton, Kevin] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Miloslavsky, Eli] Harvard Med Sch, Div Rheumatol, Dept Med, Massachusetts Gen Hosp,Yawkey Ctr Outpatient Care, 55 Fruit St,Suite 2C, Boston, MA 02114 USA. RP Miloslavsky, E (reprint author), Harvard Med Sch, Div Rheumatol, Dept Med, Massachusetts Gen Hosp,Yawkey Ctr Outpatient Care, 55 Fruit St,Suite 2C, Boston, MA 02114 USA. EM Emiloslavksy@partners.org NR 24 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD OCT 20 PY 2016 VL 16 AR 276 DI 10.1186/s12909-016-0796-9 PG 8 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA DZ7GS UT WOS:000386033500001 PM 27765029 ER PT J AU Dykstra, AR Halgren, E Gutschalk, A Eskandars, EN Cash, SS AF Dykstra, Andrew R. Halgren, Eric Gutschalk, Alexander Eskandars, Emad N. Cash, Sydney S. TI Neural Correlates of Auditory Perceptual Awareness and Release from Informational Masking Recorded Directly from Human Cortex: A Case Study SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE auditory cortex; conscious perception; electrocorticography; high-gamma activity; informational masking ID SELECTIVE ATTENTION; MULTICOMPONENT MASKERS; CONSCIOUS PERCEPTION; SIGNAL-DETECTION; COCKTAIL PARTY; VISUAL-CORTEX; POTENTIALS; RESPONSES; BRAIN; EEG AB In complex acoustic environments, even salient supra-threshold sounds sometimes go unperceived, a phenomenon known as informational masking. The neural basis of informational masking (and its release) has not been well-characterized, particularly outside auditory cortex. We combined electrocorticography in a neurosurgical patient undergoing invasive epilepsy monitoring with trial-by-trial perceptual reports of isochronous target tone streams embedded in random multi tone maskers. Awareness of such masker-embedded target streams was associated with a focal negativity between 100 and 200 ms and high-gamma activity (HGA) between 50 and 250 ms (both in auditory cortex on the posterolateral superior temporal gyrus) as well as a broad P3b-like potential (between similar to 300 and 600 ms) with generators in ventrolateral frontal and lateral temporal cortex. Unperceived target tones elicited drastically reduced versions of such responses, if at all. While it remains unclear whether these responses reflect conscious perception, itself, as opposed to pre- or post-perceptual processing, the results suggest that conscious perception of target sounds in complex listening environments may engage diverse neural mechanisms in distributed brain areas. C1 [Dykstra, Andrew R.] Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Dykstra, Andrew R.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dykstra, Andrew R.; Eskandars, Emad N.; Cash, Sydney S.] Harvard Med Sch, Boston, MA USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Dykstra, Andrew R.; Gutschalk, Alexander] Heidelberg Univ, Dept Neurol, Heidelberg, Germany. [Eskandars, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Dykstra, AR (reprint author), Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA.; Dykstra, AR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Dykstra, AR (reprint author), Harvard Med Sch, Boston, MA USA.; Dykstra, AR (reprint author), Heidelberg Univ, Dept Neurol, Heidelberg, Germany. EM andrew.dykstra@med.uni-heidelberg.de NR 69 TC 1 Z9 1 U1 3 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD OCT 20 PY 2016 VL 10 AR 472 DI 10.3389/fnins.7016.00472 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DZ2PN UT WOS:000385683800001 PM 27812318 ER PT J AU Nguyen, PL AF Nguyen, Paul L. TI Value of Extra-Early Initiation of Salvage Radiation for Increasing Prostate-Specific Antigen After Prostatectomy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; RADIOTHERAPY; CANCER; THERAPY; RISK; ADJUVANT; DEFINITION; BENEFIT; TRIAL C1 [Nguyen, Paul L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nguyen, Paul L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Nguyen, PL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 19 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3597 EP + DI 10.1200/JCO.2016.69.0396 PG 4 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600004 ER PT J AU Temel, JS Shaw, AT Greer, JA AF Temel, Jennifer S. Shaw, Alice T. Greer, Joseph A. TI Challenge of Prognostic Uncertainty in the Modern Era of Cancer Therapeutics SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CELL LUNG-CANCER; EARLY PALLIATIVE CARE; TERMINALLY-ILL PATIENTS; OF-LIFE DISCUSSIONS; UNTREATED MELANOMA; EGFR MUTATIONS; END; NIVOLUMAB; CHEMOTHERAPY; ASSOCIATIONS C1 [Temel, Jennifer S.; Shaw, Alice T.; Greer, Joseph A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jtemel@partners.org NR 43 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3605 EP + DI 10.1200/JCO.2016.67.8573 PG 5 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600006 ER PT J AU Tendulkar, RD Agrawal, S Gao, T Efstathiou, JA Pisansky, TM Michalski, JM Koontz, BF Hamstra, DA Feng, FY Liauw, SL Abramowitz, MC Pollack, A Anscher, MS Moghanaki, D Den, RB Stephans, KL Zietman, AL Lee, WR Kattan, MW Stephenson, AJ AF Tendulkar, Rahul D. Agrawal, Shree Gao, Tianming Efstathiou, Jason A. Pisansky, Thomas M. Michalski, Jeff M. Koontz, Bridget F. Hamstra, Daniel A. Feng, Felix Y. Liauw, Stanley L. Abramowitz, Matthew C. Pollack, Alan Anscher, Mitchell S. Moghanaki, Drew Den, Robert B. Stephans, Kevin L. Zietman, Anthony L. Lee, W. Robert Kattan, Michael W. Stephenson, Andrew J. TI Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; CANCER; ADJUVANT; RISK; TRIAL; MEN AB Purpose We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Methods Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Results Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) <= 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Conclusion Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era. (C) 2016 by American Society of Clinical Oncology C1 [Tendulkar, Rahul D.; Gao, Tianming; Stephans, Kevin L.; Kattan, Michael W.; Stephenson, Andrew J.] Cleveland Clin, Cleveland, OH 44106 USA. [Agrawal, Shree] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Efstathiou, Jason A.; Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pisansky, Thomas M.] Mayo Clin, Rochester, MN USA. [Michalski, Jeff M.] Washington Univ, St Louis, MO USA. [Koontz, Bridget F.; Lee, W. Robert] Duke Univ, Durham, NC USA. [Hamstra, Daniel A.] Texas Ctr Proton Therapy, Irving, TX USA. [Feng, Felix Y.] Univ Michigan, Ann Arbor, MI 48109 USA. [Liauw, Stanley L.] Univ Chicago, Chicago, IL 60637 USA. [Abramowitz, Matthew C.; Pollack, Alan] Univ Miami, Miami, FL USA. [Anscher, Mitchell S.; Moghanaki, Drew] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Moghanaki, Drew] Hunter Holmes McGuire Vet Affairs Med Ctr, Richmond, VA USA. [Den, Robert B.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Tendulkar, RD (reprint author), Cleveland Clin, Dept Radiat Oncol, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM tendulr@ccf.org FU Janssen Pharmaceuticals; Novartis; Varian Medical Systems; Celgene; Elekta; Medivation; Medivation/Astellas Pharma FX Janssen Pharmaceuticals; Novartis; Varian Medical Systems, Celgene; Elekta; Medivation; Medivation/Astellas Pharma (Inst) NR 24 TC 3 Z9 3 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3648 EP + DI 10.1200/JCO.2016.67.9647 PG 9 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600011 ER PT J AU Albiges, L Hakimi, AA Xie, WL McKay, RR Simantov, R Lin, X Lee, JL Rini, BI Srinivas, S Bjarnason, GA Ernst, S Wood, LA Vaishamayan, UN Rha, SY Agarwal, N Yuasa, T Pal, SK Bamias, A Zabor, EC Skanderup, AJ Furberg, H Fay, AP de Velasco, G Preston, MA Wilson, KM Cho, E McDermott, DF Signoretti, S Heng, DYC Choueiri, TK AF Albiges, Laurence Hakimi, A. Ari Xie, Wanling McKay, Rana R. Simantov, Ronit Lin, Xun Lee, Jae-Lyun Rini, Brian I. Srinivas, Sandy Bjarnason, Georg A. Ernst, Scott Wood, Lori A. Vaishamayan, Ulka N. Rha, Sun-Young Agarwal, Neeraj Yuasa, Takeshi Pal, Sumanta K. Bamias, Aristotelis Zabor, Emily C. Skanderup, Anders J. Furberg, Helena Fay, Andre P. de Velasco, Guillermo Preston, Mark A. Wilson, Kathryn M. Cho, Eunyoung McDermott, David F. Signoretti, Sabina Heng, Daniel Y. C. Choueiri, Toni K. TI Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FATTY-ACID SYNTHASE; TARGETED THERAPY; PROSTATE-CANCER; OBESITY PARADOX; KIDNEY CANCER; SURVIVAL; RISK; EPIDEMIOLOGY; METAANALYSIS; MECHANISMS AB Purpose Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. Methods The impact of BMI (high BMI: >= 25 kg/m(2) v low BMI: < 25 kg/m(2)) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. Results In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). Conclusion High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway. (C) 2016 by American Society of Clinical Oncology C1 [Albiges, Laurence; Xie, Wanling; McKay, Rana R.; Fay, Andre P.; de Velasco, Guillermo; Signoretti, Sabina; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Xie, Wanling; McKay, Rana R.; Preston, Mark A.; Cho, Eunyoung; Signoretti, Sabina; Choueiri, Toni K.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Albiges, Laurence; Xie, Wanling; McKay, Rana R.; Fay, Andre P.; de Velasco, Guillermo; Cho, Eunyoung; McDermott, David F.; Signoretti, Sabina; Choueiri, Toni K.] Harvard Med Sch, Boston, MA USA. [Preston, Mark A.; Wilson, Kathryn M.] Harvard Sch Publ Hlth, Boston, MA USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Albiges, Laurence] Univ Paris Saclay, Gustave Roussy, Villejuif, France. [Hakimi, A. Ari; Zabor, Emily C.; Skanderup, Anders J.; Furberg, Helena] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Simantov, Ronit; Lin, Xun] Pfizer Oncol, New York, NY USA. [Lee, Jae-Lyun] Univ Ulsan, Coll Med, Asan, South Korea. [Rha, Sun-Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Srinivas, Sandy] Stanford Canc Inst, Stanford, CA USA. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Bjarnason, Georg A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Ernst, Scott] London Hlth Sci Ctr, London, ON, Canada. [Wood, Lori A.] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Vaishamayan, Ulka N.] Karmanos Canc Ctr, Detroit, MI USA. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Yuasa, Takeshi] Japanese Fdn Canc Res, Canc Inst Hosp, Tokyo, Japan. [Bamias, Aristotelis] Univ Athens, Sch Med, Alexandra Hosp, Athens, Greece. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Cho, Eunyoung] Brown Univ, Sch Publ Hlth, Providence, RI 02912 USA. RP Choueiri, TK (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, 450 Brookline Ave,DANA 1230, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu FU Dana-Farber Harvard Cancer Center Kidney Cancer SPORE Grant [P50 CA101942-01]; Kidney Cancer Association; Unicancer - Fondation de France; Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute FX Supported by the Dana-Farber Harvard Cancer Center Kidney Cancer SPORE Grant No. P50 CA101942-01 (T.K.C., S. Signoretti, D.F.M.); the Kidney Cancer Association (T.K.C., S. Signoretti, D.Y.H.) for the International Metastatic Renal Cell Carcinoma Database Consortium Biospecimen Repository; and in part by the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute (T.K.C.); and by Unicancer - Fondation de France (L.A.). NR 33 TC 3 Z9 3 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3655 EP + DI 10.1200/JCO.2016.66.7311 PG 15 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600012 ER PT J AU Cespedes Feliciano, EM Kroenke, CH Meyerhardt, JA Prado, CM Bradshaw, PT Dannenberg, AJ Kwan, ML Xiao, J Quesenberry, C Weltzien, EK Castillo, AL Caan, BJ AF Cespedes Feliciano, Elizabeth M. Kroenke, Candyce H. Meyerhardt, Jeffrey A. Prado, Carla M. Bradshaw, Patrick T. Dannenberg, Andrew J. Kwan, Marilyn L. Xiao, Jingjie Quesenberry, Charles Weltzien, Erin K. Castillo, Adrienne L. Caan, Bette J. TI Metabolic Dysfunction, Obesity, and Survival Among Patients With Early-Stage Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; BREAST-CANCER; COLON-CANCER; MOLECULAR-MECHANISMS; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; COMPETING RISK; STATIN USE; MORTALITY; METAANALYSIS AB Purpose The effects of obesity and metabolic dysregulation on cancer survival are inconsistent. To identify high-risk subgroups of obese patients and to examine the joint association of metabolic syndrome (MetSyn) in combination with obesity, we categorized patients with early-stage (I to III) colorectal cancer (CRC) into four metabolic categories defined by the presence of MetSyn and/or obesity and examined associations with survival. Methods We studied 2,446 patients diagnosed from 2006 to 2011 at Kaiser Permanente. We assumed MetSyn if patients had three or more of five components present at diagnosis: fasting glucose > 100 mg/dL or diabetes; elevated blood pressure (systolic >= 130 mm Hg, diastolic >= 85 mm Hg, or antihypertensives); HDL cholesterol < 40 mg/dL (men) or < 50 mg/dL (women); triglycerides 150 mg/dL or antilipids; and/or highest sex-specific quartile of visceral fat by computed tomography scan (in lieu of waist circumference). We then classified participants according to the presence (or absence) of MetSyn and obesity (BMI < 30 or >= 30 kg/m(2)) and assessed associations with overall and CRC-related survival using Cox proportional hazards models adjusted for demographic, tumor, and treatment factors and muscle mass at diagnosis. Results Over a median follow-up of 6 years, 601 patients died, 325 as a result of CRC. Mean (SD) age was 64 (11) years. Compared with the reference of nonobese patients without MetSyn (n = 1,225), for overall survival the hazard ratios (HR) and 95% CIs were 1.45 (1.12 to 1.82) for obese patients with MetSyn (n = 480); 1.09 (0.83 to 1.44) for the nonobese with MetSyn (n = 417), and 1.00 (0.80 to 1.26) for obese patients without MetSyn (n = 324). Obesity with MetSyn also predicted CRC-related survival: 1.49 (1.09 to 2.02). The hazard of death increased with the number of MetSyn components present, independent of obesity. Conclusion Patients with early-stage CRC with obesity and MetSyn have worse survival, overall and CRC related. (C) 2016 by American Society of Clinical Oncology C1 [Cespedes Feliciano, Elizabeth M.; Kroenke, Candyce H.; Kwan, Marilyn L.; Quesenberry, Charles; Weltzien, Erin K.; Castillo, Adrienne L.; Caan, Bette J.] Kaiser Permanente Northern Calif, Oakland, CA USA. [Bradshaw, Patrick T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Meyerhardt, Jeffrey A.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Prado, Carla M.; Xiao, Jingjie] Univ Alberta, Edmonton, AB, Canada. [Dannenberg, Andrew J.] Weill Cornell Med Coll, New York, NY USA. RP Cespedes Feliciano, EM (reprint author), 2000 Broadway,5th Floor, Oakland, CA 94612 USA. EM elizabeth.m.cespedes@kp.org OI Cespedes Feliciano, Elizabeth/0000-0003-1192-4017 FU National Cancer Institute [R01 CA175011-01] FX Supported by National Cancer Institute Grant No. R01 CA175011-01. NR 54 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2016 VL 34 IS 30 BP 3664 EP + DI 10.1200/JCO.2016.67.4473 PG 11 WC Oncology SC Oncology GA DZ6KZ UT WOS:000385972600013 ER PT J AU Kwon, YM Khormaee, S Lincoln, MH Tsai, TY Freiberg, AA Rubash, HE AF Kwon, Young-Min Khormaee, Sariah Lincoln, Ming Han Tsai, Tsung-Yuan Freiberg, Andrew A. Rubash, Harry E. TI Asymptomatic Pseudotumors in Patients with Taper Corrosion of a Dual-Taper Modular Femoral Stem MARS-MRI and Metal Ion Study SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TOTAL HIP-ARTHROPLASTY; LOCAL TISSUE-REACTIONS; IMAGING FINDINGS; NECK REJUVENATE; JUNCTION; COBALT; THA; PROSTHESIS; COMPONENT; IMPLANTS AB Background: Modularity in total hip arthroplasty facilitates intraoperative restoration of patient anatomy. Although dual-taper modular total hip arthroplasty offers potential advantages for optimizing the hip center of rotation, it has been associated with modular taper corrosion. This corrosion has led to adverse local tissue reactions (pseudotumors) at the neck-stem junction and elevated metal-ion levels. However, the occurrence of taper-corrosion-related pseudotumors in patients who remain asymptomatic following total hip arthroplasty with a dual-tapermodular femoral stem remains largely unknown. The aims of this study were (1) to determine the prevalence of asymptomatic pseudotumors by utilizing metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) and (2) compare serum metal-ion levels between symptomatic and asymptomatic patients with a dual-taper modular stem total hip replacement. Methods: We performed a retrospective cross-sectional study of 97 consecutive patients who had been treated with a dual-taper modular femoral stem total hip arthroplasty. Eighty-three patients were stratified into symptomatic and asymptomatic groups and evaluated with MARS-MRI, measurement of serum metal-ion levels, and the University of California at Los Angeles (UCLA) functional hip score. Results: The prevalence of pseudotumors as determined with MARS-MRI was 15% in our asymptomatic patients and 36% in the overall cohort. The median serum cobalt level and cobalt/chromium ratio were significantly higher in patients with a pseudotumor than in those without a pseudotumor (8.0 versus 2.0 mg/L [p = 0.004] and 10.3 versus 2.4 mu g/L [p = 0.012], respectively). However, there was no significant difference in the serum cobalt level or cobalt/chromium ratio between symptomatic patients with a pseudotumor and asymptomatic patients with a pseudotumor (7.6 versus 6.2 mu g/L [p = 0.37] and 8.3 versus 10.6 mu g/L [p = 0.46], respectively). The UCLA scores of asymptomatic patients with a pseudotumor were similar to those of patients without a pseudotumor (6.7 versus 6.6). Conclusions: The prevalence of asymptomatic taper-corrosion-related pseudotumors on MARS-MRI in this study demonstrated that the absence of symptoms does not exclude the presence of adverse local tissue reactions. Elevated cobalt levels and cobalt/chromium ratios were associated with the presence of pseudotumors in asymptomatic and symptomatic patients. Cross-sectional imaging such as MARS-MRI is indicated for patients with elevated metal-ion levels. A longitudinal study is required to determine whether asymptomatic patients with taper- corrosion-related pseudotumors will develop symptoms with time. C1 [Kwon, Young-Min; Khormaee, Sariah; Lincoln, Ming Han; Tsai, Tsung-Yuan; Freiberg, Andrew A.; Rubash, Harry E.] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Metal Met Hip Replacement Evaluat & Treatm, Boston, MA 02114 USA. [Kwon, Young-Min; Khormaee, Sariah; Lincoln, Ming Han; Tsai, Tsung-Yuan; Freiberg, Andrew A.; Rubash, Harry E.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Ctr Metal Met Hip Replacement Evaluat & Treatm, Boston, MA 02114 USA.; Kwon, YM (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02114 USA. EM ymkwon@mgh.harvard.edu NR 42 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02492 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 19 PY 2016 VL 98 IS 20 DI 10.2106/JBJS.15.01325 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AI UT WOS:000395949100015 PM 27869625 ER PT J AU Park, J Wysocki, RW Amoozgar, Z Maiorino, L Fein, MR Jorns, J Schott, AF Kinugasa-Katayama, Y Lee, Y Won, NH Nakasone, ES Hearn, SA Kuttner, V Qiu, J Almeida, AS Perurena, N Kessenbrock, K Goldberg, MS Egeblad, M AF Park, Juwon Wysocki, Robert W. Amoozgar, Zohreh Maiorino, Laura Fein, Miriam R. Jorns, Julie Schott, Anne F. Kinugasa-Katayama, Yumi Lee, Youngseok Nam Hee Won Nakasone, Elizabeth S. Hearn, Stephen A. Kuettner, Victoria Qiu, Jing Almeida, Ana S. Perurena, Naiara Kessenbrock, Kai Goldberg, Michael S. Egeblad, Mikala TI Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID BREAST-CANCER; MOLECULAR-MECHANISMS; MAMMARY-TUMOR; NET FORMATION; MICE; LUNG; INFLAMMATION; PROMOTE; DISEASE; DEOXYRIBONUCLEASE AB Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasispromoting tumor-host interaction and a potential therapeutic target. C1 [Park, Juwon; Wysocki, Robert W.; Maiorino, Laura; Fein, Miriam R.; Kinugasa-Katayama, Yumi; Nakasone, Elizabeth S.; Kuettner, Victoria; Qiu, Jing; Almeida, Ana S.; Perurena, Naiara; Egeblad, Mikala] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Wysocki, Robert W.] SUNY Stony Brook, Sch Med, Med Scientist Training Program, Stony Brook, NY 11794 USA. [Wysocki, Robert W.; Fein, Miriam R.] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY 11794 USA. [Amoozgar, Zohreh; Goldberg, Michael S.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Maiorino, Laura; Nakasone, Elizabeth S.] Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Jorns, Julie; Schott, Anne F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Lee, Youngseok; Nam Hee Won] Korea Univ, Anam Hosp, Dept Pathol, Seoul, South Korea. [Hearn, Stephen A.] NCI, Shared Resources & St Giles Fdn Adv Microscopy Ct, Cold Spring Harbor Lab Canc Ctr, Cold Spring Harbor, NY 11724 USA. [Kessenbrock, Kai] Univ Calif Irvine, Irvine, CA 92697 USA. [Goldberg, Michael S.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Park, Juwon] Univ Hawaii, John Burns Sch Med, Ctr Cardiovasc Res, Honolulu, HI 96813 USA. [Amoozgar, Zohreh] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. [Amoozgar, Zohreh; Perurena, Naiara] Harvard Med Sch, Boston, MA 02115 USA. [Perurena, Naiara] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. RP Egeblad, M (reprint author), Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. EM egeblad@cshl.edu FU CSHL Cancer Center Support Grant [5P30CA045508]; U.S. Department of Defense [W81XWH-14-1-0078]; Long Island 2-Day Walk to Fight Breast Cancer; Joni Gladowsky Breast Cancer Foundation; NIH [5U01CA180944-02]; Hope Foundation; Cancer Research Institute CLIP (Clinic and Laboratory Integration Program) Grant; National Institute of General Medical Sciences Medical Scientist Training Program Training Award [T32-GM008444]; Aid for Cancer Research; Boehringer Ingelheim Fonds; Formacion de Profesorado Universitario fellowship [AP2010-2197]; National Cancer Institute [K99 CA181490]; Deutsche Forschungsgemeinschaft research fellowship [KU 3264/1-1] FX This work was supported by the CSHL Cancer Center Support Grant 5P30CA045508, funds to M.E. from the U.S. Department of Defense (W81XWH-14-1-0078), the Long Island 2-Day Walk to Fight Breast Cancer, and the Joni Gladowsky Breast Cancer Foundation. M.E., J.J., and A.F.S. were supported by funds from NIH (5U01CA180944-02) and the Hope Foundation. M.S.G. was supported by the Cancer Research Institute CLIP (Clinic and Laboratory Integration Program) Grant; R.W.W. was supported by the National Institute of General Medical Sciences Medical Scientist Training Program Training Award (T32-GM008444); Z.A. was supported by Aid for Cancer Research; L.M. is a George A. and Marjorie H. Anderson fellow and is supported by a fellowship from the Boehringer Ingelheim Fonds; N.P. was supported by a Formacion de Profesorado Universitario fellowship (AP2010-2197); K.K. was supported by the National Cancer Institute (K99 CA181490); and V.K. was supported by the Deutsche Forschungsgemeinschaft research fellowship (KU 3264/1-1). NR 48 TC 1 Z9 1 U1 9 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 19 PY 2016 VL 8 IS 361 AR 361ra138 DI 10.1126/scitranslmed.aag1711 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2VE UT WOS:000389442300003 PM 27798263 ER PT J AU Hong, S Pirovich, D Kilcoyne, A Huang, CH Lee, H Weissleder, R AF Hong, Seonki Pirovich, David Kilcoyne, Aoife Huang, Chen-Han Lee, Hakho Weissleder, Ralph TI Supramolecular Metallo-Bioadhesive for Minimally Invasive Use SO ADVANCED MATERIALS LA English DT Article ID ENDOSCOPIC MANAGEMENT; FIBRIN GLUE; FISTULAS; HYDROGELS; SURGERY; MECHANICS; ADHESIVE; GELATIN; TRIAL; IONS AB A novel metallo-bioadhesive to be used as tissue sealant in minimally invasive procedures is reported. Metal complexation can be used to render gelatin derivatives adhesive, which occurs in minutes, is efficient, and fully biodegradable within weeks. C1 [Hong, Seonki; Pirovich, David; Kilcoyne, Aoife; Huang, Chen-Han; Lee, Hakho; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. [Kilcoyne, Aoife; Weissleder, Ralph] Massachusetts Gen Hosp, Div Intervent Radiol, 55 Fruit St, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA.; Weissleder, R (reprint author), Massachusetts Gen Hosp, Div Intervent Radiol, 55 Fruit St, Boston, MA 02114 USA.; Weissleder, R (reprint author), Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. EM rweissleder@mgh.harvard.edu FU Mac Erlaine Research Scholarship from the Academic Radiology Research Trust, St. Vincent's Radiology Group, Dublin, Ireland; [R01EB010011] FX The authors are grateful to the following individuals: Yoshiko Iwamoto, for assistance in performing histology, Dr. Jun Seok Park for discussions on use of animal models and video editing, and Dr. Jonathan Carlson for performing initial kinetic experiments. Part of this work was funded by R01EB010011 (R.W.). A.K. was supported by the Mac Erlaine Research Scholarship from the Academic Radiology Research Trust, St. Vincent's Radiology Group, Dublin, Ireland. NR 30 TC 0 Z9 0 U1 30 U2 30 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD OCT 19 PY 2016 VL 28 IS 39 BP 8675 EP 8680 DI 10.1002/adma.201602606 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EB1WO UT WOS:000387147200013 PM 27515068 ER PT J AU Minikel, EV MacArthur, DG AF Minikel, Eric Vallabh MacArthur, Daniel G. TI Publicly Available Data Provide Evidence against NR1H3 R415Q Causing Multiple Sclerosis SO NEURON LA English DT Article ID SEQUENCE VARIANTS; DISEASE; GUIDELINES; MUTATION AB It has recently been reported that an NR1H3 missense variant, R415Q, causes a novel familial formofmultiple sclerosis (Wang et al., 2016a). This claim is at odds with publicly available data from the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). The allele frequency of R415Q is not significantly higher in cases (0.024%-0.049%) than in ExAC population controls (0.031%), whereas if R415Q conferred even 50% lifetime risk of developing MS, it would be hundreds of timesmore common in cases than in controls. The upper bound of the 95% confidence interval of penetrance for R415Q can be estimated at 2.2% for women and 1.2% for men, indicating that even if this variant is disease associated, individuals harboring the variant would have a lifetime risk of developing MS no higher than a few percent. ExAC data should be considered when evaluating claimsof variant pathogenicity. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by The International Multiple Sclerosis Genetics Consortium (2016) and the response by Wang et al. (2016b), published in this issue. C1 [Minikel, Eric Vallabh; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Minikel, Eric Vallabh; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Minikel, Eric Vallabh] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA 02115 USA. RP Minikel, EV (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Minikel, EV (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Minikel, EV (reprint author), Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA 02115 USA. EM eminikel@broadinstitute.org FU NIAID NIH HHS [F31 AI122592]; NIDDK NIH HHS [U54 DK105566]; NIGMS NIH HHS [R01 GM104371] NR 19 TC 3 Z9 3 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 19 PY 2016 VL 92 IS 2 BP 336 EP 338 DI 10.1016/j.neuron.2016.09.054 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EA6TN UT WOS:000386762000016 PM 27764668 ER PT J AU Wang, ME Patel, AB Hansen, NI Arlington, L Prakash, A Hibberd, PL AF Wang, Marie E. Patel, Archana B. Hansen, Nellie I. Arlington, Lauren Prakash, Amber Hibberd, Patricia L. TI Risk factors for possible serious bacterial infection in a rural cohort of young infants in central India SO BMC PUBLIC HEALTH LA English DT Article DE Cohort; Possible serious bacterial infection; Young infant; India ID NEONATAL-MORTALITY; PRETERM BIRTH; SEPSIS; COUNTRIES; TRIAL; POPULATION; AFRICA; DEATHS; CARE AB Background: Possible serious bacterial infection (PBSI) is a major cause of neonatal mortality worldwide. We studied risk factors for PSBI in a large rural population in central India where facility deliveries have increased as a result of a government financial assistance program. Methods: We studied 37,379 pregnant women and their singleton live born infants with birth weight >= 1.5 kg from 20 rural primary health centers around Nagpur, India, using data from the 2010-13 population-based Maternal and Newborn Health Registry supported by NICHD's Global Network for Women's and Children's Health Research. Factors associated with PSBI were identified using multivariable Poisson regression. Results: Two thousand one hundred twenty-three infants (6 %) had PSBI. Risk factors for PSBI included nulliparity (RR 1.13, 95 % CI 1.03-1.23), parity > 2 (RR 1.30, 95 % CI 1.07-1.57) compared to parity 1-2, first antenatal care visit in the 2nd/3rd trimester (RR 1.46, 95 % CI 1.08-1.98) compared to 1st trimester, administration of antenatal corticosteroids (RR 2.04, 95 % CI 1.60-2.61), low birth weight (RR 3.10, 95 % CI 2.17-4.42), male sex (RR 1.20, 95 % CI 1.10-1.31) and lack of early initiation of breastfeeding (RR 3.87, 95 % CI 2.69-5.58). Conclusion: Infants who are low birth weight, born to mothers who present late to antenatal care or receive antenatal corticosteroids, or born to nulliparous women or those with a parity > 2, could be targeted for interventions before and after delivery to improve early recognition of signs and symptoms of PSBI and prompt referral. There also appears to be a need for a renewed focus on promoting early initiation of breastfeeding following delivery in facilities. C1 [Wang, Marie E.] Boston Childrens Hosp, Div Infect Dis, Dept Med, Boston, MA 02115 USA. [Wang, Marie E.] Massachusetts Gen Hosp, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. [Patel, Archana B.; Prakash, Amber] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Hansen, Nellie I.] RTI Int, Res Triangle Pk, NC USA. [Arlington, Lauren; Hibberd, Patricia L.] Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA USA. RP Wang, ME (reprint author), Boston Childrens Hosp, Div Infect Dis, Dept Med, Boston, MA 02115 USA.; Wang, ME (reprint author), Massachusetts Gen Hosp, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. EM marie.wang@childrens.harvard.edu FU US National Institutes of Health [U01HD058332, U10HD078439, 5K24AT003683, 5T32HD055148] FX This research was supported by the US National Institutes of Health (Grants U01HD058332, U10HD078439, 5K24AT003683, and 5T32HD055148). The funding body had no role in the study design, data collection, analysis, interpretation, or manuscript writing. NR 31 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD OCT 19 PY 2016 VL 16 AR 1097 DI 10.1186/s12889-016-3688-3 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DZ6IB UT WOS:000385964500004 PM 27760543 ER PT J AU Wein, MN Liang, YK Goransson, O Sundberg, TB Wang, JH Williams, EA O'Meara, MJ Govea, N Beqo, B Nishimori, S Nagano, K Brooks, DJ Martins, JS Corbin, B Anselmo, A Sadreyev, R Wu, JY Sakamoto, K Foretz, M Xavier, RJ Baron, R Bouxsein, ML Gardella, TJ Divieti-Pajevic, P Gray, NS Kronenberg, HM AF Wein, Marc N. Liang, Yanke Goransson, Olga Sundberg, Thomas B. Wang, Jinhua Williams, Elizabeth A. O'Meara, Maureen J. Govea, Nicolas Beqo, Belinda Nishimori, Shigeki Nagano, Kenichi Brooks, Daniel J. Martins, Janaina S. Corbin, Braden Anselmo, Anthony Sadreyev, Ruslan Wu, Joy Y. Sakamoto, Kei Foretz, Marc Xavier, Ramnik J. Baron, Roland Bouxsein, Mary L. Gardella, Thomas J. Divieti-Pajevic, Paola Gray, Nathanael S. Kronenberg, Henry M. TI SIKs control osteocyte responses to parathyroid hormone SO NATURE COMMUNICATIONS LA English DT Article ID KAPPA-B LIGAND; DISTANT TRANSCRIPTIONAL ENHANCER; SALT-INDUCIBLE KINASES; HISTONE DEACETYLASE 4; RECEPTOR ACTIVATOR; GENE-EXPRESSION; CHONDROCYTE HYPERTROPHY; MUSCLE DIFFERENTIATION; TARGETED DISRUPTION; BONE HOMEOSTASIS AB Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH. C1 [Wein, Marc N.; Williams, Elizabeth A.; O'Meara, Maureen J.; Govea, Nicolas; Beqo, Belinda; Nishimori, Shigeki; Brooks, Daniel J.; Martins, Janaina S.; Corbin, Braden; Baron, Roland; Bouxsein, Mary L.; Gardella, Thomas J.; Kronenberg, Henry M.] Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, Dept Med, 50 Blossom St, Boston, MA 02114 USA. [Liang, Yanke; Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, 450 Brookline Ave, Boston, MA 02215 USA. [Goransson, Olga] Lund Univ, Dept Expt Med Sci, Box 188, SE-22100 Lund, Sweden. [Sundberg, Thomas B.] Broad Inst, Ctr Dev Therapeut, 415 Main St, Cambridge, MA 02142 USA. [Nagano, Kenichi; Baron, Roland] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Brooks, Daniel J.; Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Dept Orthoped Surg, 330 Brookline Ave, Boston, MA 02215 USA. [Anselmo, Anthony; Sadreyev, Ruslan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. [Wu, Joy Y.] Stanford Univ, Div Endocrinol, Dept Med, Sch Med, 300 Pasteur Dr R175, Stanford, CA 94305 USA. [Sakamoto, Kei] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Foretz, Marc] Univ Paris 05, Sorbonne Pairs Cite, INSERM U1016, Inst Cochin,CNRS,UMR8104, F-75013 Paris, France. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Med Sch, Ctr Computat & Integrat Biol, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst, Program Med & Populat Genet, 415 Main St, Cambridge, MA 02142 USA. [Divieti-Pajevic, Paola] Boston Univ, Henry M Goldman Sch Dent Med, 100 E Newton St, Boston, MA 02118 USA. [Sakamoto, Kei] Nestle Inst Hlth Sci SA, Campus EPFL,Batiment G, CH-1015 Lausanne, Switzerland. RP Kronenberg, HM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, Dept Med, 50 Blossom St, Boston, MA 02114 USA. EM kronenberg@helix.mgh.harvard.edu FU Ellison Foundation; NIH [K08AR067285, R03AR059942, P01DK011794, P30AR066261] FX We thank Drs David Fisher, Michael Ominsky, Kelly Lauter, Chris Cowan, Eric Olson, Jerry Feng, Alykhan Shamji and John Doench for providing reagents and suggestions, Dr Sean Wu for performing blastocyst injections, and Drs Michael Mannstadt, Joseph Avruch and Tatsuya Kobayashi for comments on this manuscript. Sclerostin antibody was generously provided by Amgen Inc. and UCB Pharma. We thank for MGH Endocrine Unit Center for Skeletal Research P30 core (P30AR066261) for assistance. This work is supported by grants from the Ellison Foundation (HMK) and the NIH: K08AR067285 (MNW), R03AR059942 (JYW), P01DK011794 (HMK) and P30AR066261 (HMK). NR 70 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 19 PY 2016 VL 7 AR 13176 DI 10.1038/ncomms13176 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1RT UT WOS:000385617700001 PM 27759007 ER PT J AU Im, M Fried, SI AF Im, Maesoon Fried, Shelley I. TI Directionally selective retinal ganglion cells suppress luminance responses during natural viewing SO SCIENTIFIC REPORTS LA English DT Article ID STARBURST AMACRINE CELLS; RABBIT RETINA; RECEPTIVE-FIELD; VISUAL-SYSTEM; INHIBITION; IMAGES; STATISTICS; CIRCUIT; NEURONS; SCENES AB The ON-OFF directionally selective cells of the retina respond preferentially to movement in a preferred direction, but under laboratory conditions they are also sensitive to changes in the luminance of the stationary stimulus. If the response of these neurons contains information about both direction and luminance downstream neurons are faced with the challenge of extracting the motion component, a computation that may be difficult under certain viewing conditions. Here, we show that during natural viewing the response to luminance is suppressed, leaving a relatively pure motion signal that gets transmitted to the brain. C1 [Im, Maesoon; Fried, Shelley I.] Boston VA Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. [Im, Maesoon; Fried, Shelley I.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 50 Blossom St, Boston, MA 02114 USA. [Im, Maesoon] Henry Ford Hlth Syst, Dept Ophthalmol, 1 Ford Pl, Detroit, MI 48202 USA. [Im, Maesoon] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, 540 East Canfield St, Detroit, MI 48201 USA. RP Im, M; Fried, SI (reprint author), Boston VA Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA.; Im, M; Fried, SI (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, 50 Blossom St, Boston, MA 02114 USA.; Im, M (reprint author), Henry Ford Hlth Syst, Dept Ophthalmol, 1 Ford Pl, Detroit, MI 48202 USA.; Im, M (reprint author), Wayne State Univ, Sch Med, Dept Anat & Cell Biol, 540 East Canfield St, Detroit, MI 48201 USA. EM mim1@hfhs.org; fried.shelly@mgh.harvard.edu FU VA Healthcare System [1I01RX000350]; NIH [1R01 EY019967, 1R01 EY023651] FX We thank Richard Masland and Thomas Munch for helpful discussion and reviews of earlier versions of the manuscript, Seungwoo Lee and Perry Twyford for technical assistance with experiments. This work was supported in part by the VA Healthcare System (1I01RX000350) and the NIH (1R01 EY019967 & 1R01 EY023651). NR 44 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 19 PY 2016 VL 6 AR 35708 DI 10.1038/srep35708 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UA UT WOS:000385695900002 PM 27759086 ER PT J AU Alvarez, V Lee, JW Westover, MB Drislane, FW Novy, J Faouzi, M Marchi, NA Dworetzky, BA Rossetti, AO AF Alvarez, Vincent Lee, Jong Woo Westover, M. Brandon Drislane, Frank W. Novy, Jan Faouzi, Mohamed Marchi, Nicola A. Dworetzky, Barbara A. Rossetti, Andrea O. TI Therapeutic coma for status epilepticus Differing practices in a prospective multicenter study SO NEUROLOGY LA English DT Article ID REFRACTORY STATUS EPILEPTICUS; CONVULSIVE STATUS EPILEPTICUS; NONCONVULSIVE STATUS EPILEPTICUS; INTENSIVE-CARE-UNIT; SEIZURES DAMAGE; MANAGEMENT; MORTALITY; ADULTS; LEVETIRACETAM; PREDICTORS AB Objective: Our aim was to analyze and compare the use of therapeutic coma (TC) for refractory status epilepticus (SE) across different centers and its effect on outcome. Methods: Clinical data for all consecutive adults (>16 years) with SE of all etiologies (except postanoxic) admitted to 4 tertiary care centers belonging to Harvard Affiliated Hospitals (HAH) and the Centre Hospitalier Universitaire Vaudois (CHUV) were prospectively collected and analyzed for TC details, mortality, and duration of hospitalization. Results: Two hundred thirty-six SE episodes in the CHUV and 126 in the HAH were identified. Both groups were homogeneous in demographics, comorbidities, SE characteristics, and Status Epilepticus Severity Score (STESS); TC was used in 25.4% of cases in HAH vs 9.75% in CHUV. After adjustment, TC use was associated with younger age, lower Charlson Comorbidity Index, increasing SE severity, refractory SE, and center (odds ratio 11.3 for HAH vs CHUV, 95% confidence interval 2.47-51.7). Mortality was associated with increasing Charlson Comorbidity Index and STESS, etiology, and refractory SE. Length of stay correlated with STESS, etiology, refractory SE, and use of TC (incidence rate ratio 1.6, 95% confidence interval 1.22-2.11). Conclusions: Use of TC for SE treatment seems markedly different between centers from the United States and Europe, and did not affect mortality considering the whole cohort. However, TC may increase length of hospital stay and related costs. Classification of evidence: This study provides Class III evidence that for patients with SE, TC does not significantly affect mortality. The study lacked the precision to exclude an important effect of TC on mortality. C1 [Alvarez, Vincent] Hop Valais, Dept Neurol, Sion, Switzerland. [Alvarez, Vincent; Novy, Jan; Marchi, Nicola A.; Rossetti, Andrea O.] CHU Vaudois, Dept Clin Neurosci, Lausanne, Switzerland. [Faouzi, Mohamed] CHU Vaudois, Inst Social & Prevent Med, Lausanne, Switzerland. [Faouzi, Mohamed] Univ Lausanne, CH-1015 Lausanne, Switzerland. [Alvarez, Vincent; Lee, Jong Woo; Dworetzky, Barbara A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Westover, M. Brandon] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Drislane, Frank W.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. [Marchi, Nicola A.] Univ Hosp Geneva, Dept Clin Neurosci, Geneva, Switzerland. RP Alvarez, V (reprint author), Hop Valais, Dept Neurol, Sion, Switzerland.; Alvarez, V (reprint author), CHU Vaudois, Dept Clin Neurosci, Lausanne, Switzerland.; Alvarez, V (reprint author), Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. EM vincent.alvarez@hopitalvs.ch NR 40 TC 3 Z9 3 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 18 PY 2016 VL 87 IS 16 BP 1650 EP 1659 DI 10.1212/WNL.0000000000003224 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EI1II UT WOS:000392230000010 PM 27664985 ER PT J AU Martinez, BR Staboli, IM Kamonseki, DH Budiman-Mak, E Yi, LC AF Martinez, Bruna Reclusa Staboli, Isabela Maschk Kamonseki, Danilo Harudy Budiman-Mak, Elly Yi, Liu Chiao TI Validity and reliability of the Foot Function Index (FFI) questionnaire Brazilian-Portuguese version SO SPRINGERPLUS LA English DT Article DE Foot diseases; Questionnaires; Outcome assessment; Validation studies ID CROSS-CULTURAL ADAPTATION; CHRONIC ANKLE INSTABILITY; HEALTH-STATUS; VALIDATION; INSTRUMENTS; DISABILITY; TRANSLATION; CRITERIA; PAIN; TOOLS AB Purpose: To evaluate the validity and reliability of the Foot Function Index (FFI) in its Brazilian Portuguese version. Methods: The validity and reliability of the FFI were tested in 50 volunteers, with plantar fasciitis, metatarsalgia and chronic ankle sprain. The FFI validity process used the Short Form-36 (SF-36) and Foot and Ankle Outcome Score (FAOS) questionnaires. The correlation between FFI, SF-36 and FAOS was done using the Pearson's linear coefficient. The inter and intra-evaluator reliability was ascertained by means of the intraclass correlation coefficient (ICC) and the internal consistency by means of Cronbach's alpha coefficient. The scores were used to assess the standard error measurement (SEM), minimal detectable change (MDC) and ceiling floor and effects. Results: The validity process showed that there were correlations between FFI and the "pain" and "social aspects" subscales of SF-36 and all subscales of FAOS, except for "other symptoms". The Brazilian-Portuguese version of FFI showed excellent intra and interevaluator correlations, with an ICC range of 0.99-0.97 and score reliability that was considered highly satisfactory, with Cronbach's alpha range of 0.80-0.61. The SEMs for inter and intra-evaluator reliability were 1.32 and 1.08, respectively. The MDC was 2.42 (90 % confidence interval). No ceiling and floor effect were detected. Conclusions: The Brazilian-Portuguese version of the FFI questionnaire was found to be a valid and reliable instrument for foot function evaluation, and can be used both in scientific settings and in clinical practice. C1 [Martinez, Bruna Reclusa; Staboli, Isabela Maschk; Kamonseki, Danilo Harudy; Yi, Liu Chiao] Univ Fed Sao Paulo, Dept Human Movement Sci, Rua Silva Jardim,136, BR-11015020 Santos, SP, Brazil. [Budiman-Mak, Elly] US Dept Vet Affairs, Washington, DC USA. RP Yi, LC (reprint author), Univ Fed Sao Paulo, Dept Human Movement Sci, Rua Silva Jardim,136, BR-11015020 Santos, SP, Brazil. EM liu.unifesp@gmail.com NR 32 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 2193-1801 J9 SPRINGERPLUS JI SpringerPlus PD OCT 18 PY 2016 VL 5 AR 1810 DI 10.1186/s40064-016-3507-4 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH5JD UT WOS:000391808300015 PM 27812449 ER PT J AU Germine, L Robinson, EB Smoller, JW Calkins, ME Moore, TM Hakonarson, H Daly, MJ Lee, PH Holmes, AJ Buckner, RL Gur, RC Gur, RE AF Germine, L. Robinson, E. B. Smoller, J. W. Calkins, M. E. Moore, T. M. Hakonarson, H. Daly, M. J. Lee, P. H. Holmes, A. J. Buckner, R. L. Gur, R. C. Gur, R. E. TI Association between polygenic risk for schizophrenia, neurocognition and social cognition across development SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID EMOTION RECOGNITION; INDIVIDUAL-DIFFERENCES; PSYCHIATRIC-DISORDERS; CHILDHOOD TRAUMA; PSYCHOSIS; ENDOPHENOTYPES; BATTERY; ABNORMALITIES; PERFORMANCE; DEFICITS AB Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8-21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18-35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development. C1 [Germine, L.; Smoller, J. W.; Lee, P. H.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Germine, L.; Smoller, J. W.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Germine, L.; Buckner, R. L.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Germine, L.; Robinson, E. B.; Smoller, J. W.; Daly, M. J.; Lee, P. H.] Broad Inst MIT & Harvard, Boston, MA USA. [Robinson, E. B.; Daly, M. J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Smoller, J. W.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Calkins, M. E.; Moore, T. M.; Gur, R. C.; Gur, R. E.] Univ Penn, Dept Psychiat, Perelman Sch Med, Neuropsychiat Sect, Philadelphia, PA 19104 USA. [Hakonarson, H.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Holmes, A. J.] Yale Univ, Dept Psychol, New Heaven, CT USA. [Buckner, R. L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, R. L.] Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Germine, L (reprint author), McLean Hosp, Div Depress & Anxiety Disorders, Belmont, MA 02478 USA. EM lgermine@mclean.harvard.edu OI Germine, Laura/0000-0001-8690-8412 FU National Institutes of Health [F32MH102971, MH089983, MH096891, MH089924, K08MH079364, K99MH101367, U01MH094432, K01MH099286, K24MH094614] FX This study was supported by National Institutes of Health grants F32MH102971 (Dr Germine), MH089983 and MH096891 (Dr Gur) and MH089924 (Dr Hakonarson), K08MH079364 (Dr Calkins), K99MH101367 (Dr Lee), U01MH094432 (Dr Daly), K01MH099286 (Dr Robinson) and K24MH094614 (Dr Smoller). NR 57 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT 18 PY 2016 VL 6 AR e924 DI 10.1038/tp.2016.147 PG 7 WC Psychiatry SC Psychiatry GA EH9ZU UT WOS:000392131700007 PM 27754483 ER PT J AU Rumshisky, A Ghassemi, M Naumann, T Szolovits, P Castro, VM Mccoy, TH Perlis, RH AF Rumshisky, A. Ghassemi, M. Naumann, T. Szolovits, P. Castro, V. M. Mccoy, T. H. Perlis, R. H. TI Predicting early psychiatric readmission with natural language processing of narrative discharge summaries SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; IDENTIFICATION; DEPRESSION; VALIDATION; MODEL AB The ability to predict psychiatric readmission would facilitate the development of interventions to reduce this risk, a major driver of psychiatric health-care costs. The symptoms or characteristics of illness course necessary to develop reliable predictors are not available in coded billing data, but may be present in narrative electronic health record (EHR) discharge summaries. We identified a cohort of individuals admitted to a psychiatric inpatient unit between 1994 and 2012 with a principal diagnosis of major depressive disorder, and extracted inpatient psychiatric discharge narrative notes. Using these data, we trained a 75-topic Latent Dirichlet Allocation (LDA) model, a form of natural language processing, which identifies groups of words associated with topics discussed in a document collection. The cohort was randomly split to derive a training (70%) and testing (30%) data set, and we trained separate support vector machine models for baseline clinical features alone, baseline features plus common individual words and the above plus topics identified from the 75-topic LDA model. Of 4687 patients with inpatient discharge summaries, 470 were readmitted within 30 days. The 75-topic LDA model included topics linked to psychiatric symptoms (suicide, severe depression, anxiety, trauma, eating/weight and panic) and major depressive disorder comorbidities (infection, postpartum, brain tumor, diarrhea and pulmonary disease). By including LDA topics, prediction of readmission, as measured by area under receiver-operating characteristic curves in the testing data set, was improved from baseline (area under the curve 0.618) to baseline + 1000 words (0.682) to baseline+75 topics (0.784). Inclusion of topics derived from narrative notes allows more accurate discrimination of individuals at high risk for psychiatric readmission in this cohort. Topic modeling and related approaches offer the potential to improve prediction using EHRs, if generalizability can be established in other clinical cohorts. C1 [Rumshisky, A.; Ghassemi, M.; Naumann, T.; Szolovits, P.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Rumshisky, A.] Univ Massachusetts Lowell, Dept Comp Sci, Lowell, MA USA. [Castro, V. M.; Mccoy, T. H.; Perlis, R. H.] Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Castro, V. M.; Mccoy, T. H.; Perlis, R. H.] Massachusetts Gen Hosp, Dept Psychiat, Simches Res Bldg,185 Cambridge St,6th Floor, Boston, MA 02114 USA. [Castro, V. M.; Mccoy, T. H.; Perlis, R. H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Castro, V. M.] Partners HealthCare Syst, Partners Res Informat Syst & Comp, Boston, MA USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Simches Res Bldg,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI McCoy, Thomas/0000-0002-5624-0439; Naumann, Tristan/0000-0003-2150-1747 NR 24 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT 18 PY 2016 VL 6 AR e921 DI 10.1038/tp.2015.182 PG 5 WC Psychiatry SC Psychiatry GA EH9ZU UT WOS:000392131700004 PM 27754482 ER PT J AU Darb-Esfahani, S Denkert, C Stenzinger, A Salat, C Sinn, B Schem, C Endris, V Klare, P Schmitt, W Blohmera, JU Weichert', W Mobs, M Teschl, H Kummeln, S Sinn, P Jackisch, C Dietel, M Reimer', T Loi, S Untch, M von Minckwitz, G Nekljudoval, V Loibl, S AF Darb-Esfahani, Silvia Denkert, Carsten Stenzinger, Albrecht Salat, Christoph Sinn, Bruno Schem, Christian Endris, Volker Klare, Peter Schmitt, Wolfgang Blohmera, Jens-Uwe Weichert', Wilko Moebs, Markus Teschl, Hans Kuemmeln, Sherko Sinn, Peter Jackisch, Christian Dietel, Manfred Reimer', Toralf Loi, Sherene Untch, Michael von Minckwitz, Gunter Nekljudoval, Valentina Loibl, Sibylle TI Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy SO ONCOTARGET LA English DT Article DE TP53; mutation; triple negative breast cancer; HER2; pathological complete response ID P53; TRIAL; CARBOPLATIN; RESISTANCE; PATTERNS AB Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. Methods: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/ taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Results: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). Conclusions: Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes. C1 [Darb-Esfahani, Silvia; Denkert, Carsten; Sinn, Bruno; Schmitt, Wolfgang; Moebs, Markus; Dietel, Manfred] Charite, Inst Pathol, Charitepl 1, Berlin, Germany. [Denkert, Carsten; Weichert', Wilko] German Canc Consortium, DKTK, Berlin, Germany. [Stenzinger, Albrecht; Endris, Volker; Sinn, Peter] Univ Heidelberg Hosp, Inst Pathol, Neuenheimer Feld 220-224, Heidelberg, Germany. [Stenzinger, Albrecht] Massachusetts Gen Hosp, Dept Pathol, Ctr Integrated Diagnost CID, Boston, MA 02114 USA. [Salat, Christoph] Hamatoonkol Schwerpunktpraxis, Winthirstr 7, Munich, Germany. [Schem, Christian] Univ Hosp Schleswig Hostein, Dept Gynecol & Obstet, Arnold Heller Str 3, Kiel, Germany. [Klare, Peter] Praxisklin Krebsheilkunde Frauen Brustzentrum, Mollendorffstr 52, Berlin, Germany. [Blohmera, Jens-Uwe] Charite, Dept Gynecol & Obstet, Charitepl 1, Berlin, Germany. [Weichert', Wilko] Tech Univ Munich, Inst Pathol, Trogerstr 18, Munich, Germany. [Teschl, Hans] Ctr Hematol & Oncol Bethanien, Prufling 17-19, Frankfurt, Germany. [Kuemmeln, Sherko] Kliniken Essen Mitte, Breast Unit, Henricistr 92, Essen, Germany. [Jackisch, Christian] Sana Klinikum Offenbach, Dept Gynecol & Obstet, Starkenburgring 66, Offenbach, Germany. [Reimer', Toralf] Klinikum Sudstadt Rostock, Dept Gynecol, Sudring 81, Rostock, Germany. [Loi, Sherene] Peter MacCallum Canc Ctr, St Andrews Pl, East Melbourne, Vic, Australia. [Untch, Michael] Helios Klinikum Berlin Buch, Dept Gynecol & Obstet, Schwanebecker Chaussee 50, Berlin, Germany. [von Minckwitz, Gunter; Nekljudoval, Valentina; Loibl, Sibylle] GBG Forsch GmbH, German Breast Grp, Neu Isenburg, Germany. RP Darb-Esfahani, S (reprint author), Charite, Inst Pathol, Charitepl 1, Berlin, Germany. EM silvia.darb-esfahani@charite.de FU EU-FP7 RESPONSIFY project; Teva Pharmaceutical Industries Ltd.; Glaxo-Smith-Kline; Roche FX This translational study was performed within the EU-funded FP7 RESPONSIFY project. The GeparSixto clinical trial was funded by Teva Pharmaceutical Industries Ltd., Glaxo-Smith-Kline, and Roche. NR 25 TC 0 Z9 0 U1 6 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 18 PY 2016 VL 7 IS 42 BP 67686 EP 67698 DI 10.18632/oncotarget.11891 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UT UT WOS:000387446800001 PM 27611952 ER PT J AU Mechanick, JI Zhao, S Garvey, WT AF Mechanick, Jeffrey I. Zhao, Shan Garvey, W. Timothy TI The Adipokine-Cardiovascular-Lifestyle Network Translation to Clinical Practice SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiovascular disease; diabetes; hypertension; lifestyle medicine; network; obesity; systems biology ID CORONARY-ARTERY-DISEASE; RETINOL-BINDING-PROTEIN; GELATINASE-ASSOCIATED LIPOCALIN; CARDIOMETABOLIC RISK-FACTORS; HUMAN NEUTROPHIL GELATINASE; TYPE-2 DIABETES-MELLITUS; NECROSIS-FACTOR-ALPHA; NORMAL-WEIGHT OBESITY; ALL-CAUSE MORTALITY; METABOLIC SYNDROME AB Adipokines are peptides, secreted by adipocytes and other cell types with targets in other tissues, participating in a complex network of humoral factors involved in obesity, insulin resistance, and cardiovascular (CV) disease. This review describes recent information about adipokine effects on the CV system. Rather than simply providing a listing of adipokines and their respective effects, network analysis is used to enhance understanding. Various relationships and emergent processes in the adipokine-CV system network are discussed, with the most significant interactors being responses to hypoxia, regulation of cell migration, effects on blood coagulation, and platelet activation. Clinical translation is provided through network representations of the "obesity paradox," "metabolically healthy obese," "metabolic syndrome," and beneficial role of lifestyle medicine. As more translatable information about the larger adipokine-CV-lifestyle network is acquired from laboratory and clinical research, the strategic and precise role of lifestyle intervention can be fashioned to improve CV outcomes. (C) 2016 by the American College of Cardiology Foundation. C1 [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, 1192 Pk Ave, New York, NY 10128 USA. [Zhao, Shan] Telequire, New York, NY USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Diabet Res Ctr, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. RP Mechanick, JI (reprint author), Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, 1192 Pk Ave, New York, NY 10128 USA. EM jeffreymechanick@gmail.com FU Novo Nordisk; Eisai; Janssen; Vivus; Takeda; AstraZeneca; Alexion; Merck FX From the aDivision of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York; bTelequire, New York, New York; cDepartment of Nutrition Sciences and Diabetes Research Center, University of Alabama at Birmingham, Birmingham, Alabama; and the dGeriatric Research Education and Clinical Center, Birmingham VA Medical Center, Birmingham, Alabama. Dr. Mechanick has received honoraria for lectures and program development from Abbott Nutrition International. Dr. Garvey has received consulting fees from Novo Nordisk, Eisai, Janssen, Vivus, Takeda, AstraZeneca, Alexion, and Merck. Dr. Zhao has reported that he has no relationships relevant to the contents of this paper to disclose. Carl "Chip" Lavie, MD, served as Guest Editor for this paper. NR 169 TC 3 Z9 3 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 18 PY 2016 VL 68 IS 16 BP 1785 EP 1803 DI 10.1016/j.jacc.2016.06.072 PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA7OP UT WOS:000386821200011 PM 27737746 ER PT J AU Macias-Konstantopoulos, W AF Macias-Konstantopoulos, Wendy TI Human Trafficking: The Role of Medicine in Interrupting the Cycle of Abuse and Violence SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CHILDHOOD SEXUAL-ABUSE; HIV PREVALENCE; UNITED-STATES; HEALTH; WOMEN; YOUTH; GIRLS; CARE; VICTIMIZATION; PREDICTORS AB Human trafficking, a form of modern slavery, is an egregious violation of human rights with profound personal and public health implications. It includes forced labor and sexual exploitation of both U.S. and non-U.S. citizens and has been reported in all 50 states. Victims of human trafficking are currently among the most abused and disenfranchised persons in society, and they face a wide range of negative health outcomes resulting from their subjugation and exploitation. Medicine has an important role to play in mitigating the devastating effects of human trafficking on individuals and society. Victims are cared for in emergency departments, primary care offices, urgent care centers, community health clinics, and reproductive health clinics. In addition, they are unknowingly being treated in hospital inpatient units. Injuries and illnesses requiring medical attention thus represent unique windows of opportunity for trafficked persons to receive assistance from trusted health care professionals. With education and training, health care providers can recognize signs and symptoms of trafficking, provide trauma-informed care to this vulnerable population, and respond to exploited persons who are interested and ready to receive assistance. Multidisciplinary response protocols, research, and policy advocacy can enhance the impact of antitrafficking health care efforts to interrupt the cycle of abuse and violence for these victims. C1 [Macias-Konstantopoulos, Wendy] Massachusetts Gen Hosp, Freedom Clin, Boston, MA 02114 USA. RP Macias-Konstantopoulos, W (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. EM wmacias@mgh.harvard.edu FU Freedom Reimagine Opportunity Innovations Challenge Award FX By the Partnership for Freedom 2014 Reimagine Opportunity Innovations Challenge Award (for Dr. Macias-Konstantopoulos' work with the MGH Freedom Clinic and the MGH Human Trafficking Initiative [Boston, Massachusetts]). Led by Humanity United (San Francisco, California) and the U.S. Departments of Justice, Health and Human Services, Housing and Urban Development, State, and Labor (Washington, DC), the Partnership for Freedom is a public-private partnership dedicated to promoting innovative solutions to end modern-day slavery. NR 48 TC 0 Z9 0 U1 11 U2 11 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 18 PY 2016 VL 165 IS 8 BP 582 EP + DI 10.7326/M16-0094 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6BM UT WOS:000385946600019 PM 27537695 ER PT J AU LaRocque, RL Ryan, ET AF LaRocque, Regina L. Ryan, Edward T. TI Personal Actions to Minimize Mosquito-Borne Illnesses, Including Zika Virus SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [LaRocque, Regina L.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Jackson 504,55 Fruit St, Boston, MA 02114 USA. Harvard Univ, Boston, MA 02115 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM etryan@mgh.harvard.edu FU NCEZID CDC HHS [U01 CK000175] NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 18 PY 2016 VL 165 IS 8 BP 589 EP + DI 10.7326/M16-1397 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DZ6BM UT WOS:000385946600020 PM 27399646 ER PT J AU Kim, HI Weon, S Kang, H Hagstrom, AL Kwon, OS Lee, YS Choi, W Kim, JH AF Kim, Hyoung-il Weon, Seunghyun Kang, Homan Hagstrom, Anna L. Kwon, Oh Seok Lee, Yoon-Sik Choi, Wonyong Kim, Jae-Hong TI Plasmon-Enhanced Sub-Bandgap Photocatalysis via Triplet-Triplet Annihilation Upconversion for Volatile Organic Compound Degradation SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID SENSITIZED SOLAR-CELLS; LOW-POWER; SEMICONDUCTOR PHOTOCATALYSIS; VISIBLE-LIGHT; NANOPARTICLES; TIO2; ENERGY; WATER; NANOCAPSULES; EFFICIENCY AB This study demonstrates the first reported photocatalytic decomposition of an indoor air pollutant, acetaldehyde, using low-energy, sub-bandgap photons harnessed through sensitized triplet triplet annihilation (TTA) upconversion (UC). To utilize low-intensity noncoherent indoor light and maximize photocatalytic activity, we designed a plasmon-enhanced sub-bandgap photocatalyst device consisting of two main components: (1) TTA-UC rubbery polymer films containing broad-band plasmonic particles (Ag-SiO2) to upconvert sub-bandgap photons, and (2) nanodiamond (ND)-loaded WO3 as a visible-light photocatalyst composite. Effective decomposition of acetaldehyde was achieved using ND/WO3 (E-g = 2.8 eV) coupled with TTA-UC polymer films that emit blue photons (lambda(Ex) = 425 nm, 2.92 eV) upconverted from green photons (lambda(Ex) = 532 nm, 2.33 eV), which are wasted in most environmental photocatalysis. The overall photocatalytic efficiency was amplified by the broad-band surface plasmon resonance of AgNP-SiO2 particles incorporated into the TTA-UC films. C1 [Kim, Hyoung-il; Hagstrom, Anna L.; Kwon, Oh Seok; Kim, Jae-Hong] Yale Univ, Sch Engn & Appl Sci, Dept Chem & Environm Engn, New Haven, CT 06511 USA. [Weon, Seunghyun; Choi, Wonyong] Pohang Univ Sci & Technol POSTECH, Sch Environm Sci & Engn, Pohang 790784, South Korea. [Kang, Homan; Lee, Yoon-Sik] Seoul Natl Univ, Interdisciplinary Program Nanosci & Technol, Seoul 08826, South Korea. [Lee, Yoon-Sik] Seoul Natl Univ, Sch Chem & Biol Engn, Seoul 08826, South Korea. [Kang, Homan] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Dept Radiol, Boston, MA 02114 USA. [Kang, Homan] Harvard Med Sch, Boston, MA 02114 USA. [Kwon, Oh Seok] Korea Res Inst Biosci & Biotechnol, BioNanotechnol Res Ctr, Yuseong 305600, Daejeon, South Korea. RP Kim, JH (reprint author), Yale Univ, Sch Engn & Appl Sci, Dept Chem & Environm Engn, New Haven, CT 06511 USA.; Choi, W (reprint author), Pohang Univ Sci & Technol POSTECH, Sch Environm Sci & Engn, Pohang 790784, South Korea. EM wchoi@postech.edu; jaehong.kim@yale.edu RI Choi, Wonyong/F-8206-2010 OI Choi, Wonyong/0000-0003-1801-9386 FU National Science Foundation [CBET-1335934]; Global Research Laboratory (GRL) Program - Korean government (MSIP) through NRF [NRF-2014K1A1A2041044] FX This work was supported by the National Science Foundation (Grant CBET-1335934) and by the Global Research Laboratory (GRL) Program (Grant NRF-2014K1A1A2041044) funded by the Korean government (MSIP) through NRF. NR 54 TC 1 Z9 1 U1 44 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD OCT 18 PY 2016 VL 50 IS 20 BP 11184 EP 11192 DI 10.1021/acs.est.6b02729 PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DZ5MW UT WOS:000385907200047 PM 27684445 ER PT J AU Ozieh, MN Bishu, KG Walker, RJ Campbell, JA Egede, LE AF Ozieh, Mukoso N. Bishu, Kinfe G. Walker, Rebekah J. Campbell, Jennifer A. Egede, Leonard E. TI Geographic variation in access among adults with kidney disease: evidence from medical expenditure panel survey, 2002-2011 SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Geographic variation; Kidney disease; Access to care; MEPS ID SOCIOECONOMIC-STATUS; UNITED-STATES; CARE; TRANSPLANTATION; IMPACT; CKD; COSTS; MODEL AB Background: To understand geographic variation in access to care over time in patients with kidney disease. Methods: We analyzed 4404 (weighted sample of 4,251,129) adults with kidney disease from the United States using the Medical Expenditure Panel Survey over 10 years. Three dependent variables were created to investigate variation in access: usual source of care, overall medical access to care, which took into account usual source of care, ability to get care, and delay in care, and prescription access, which took into account ability to get prescriptions and delay in getting prescriptions. Multiple logistic regression was used with geographic region as the main independent variable, adjusting for relevant covariates. Results: Compared to the Northeast region, adults living in the Midwest (OR = 0.56; 95 % CI 0.35-0.89), South (OR = 0. 48; 95 % CI 0.32-0.72) and West (OR = 0.53; 95 % CI 0.34-0.84) had significantly lower odds of reporting usual source of care. For the combined access measure, compared to Northeast, adults in Midwest (OR = 0.60; 95 % CI 0.40-0.88), South (OR = 0.62; 95 % CI 0.44-0.88) and West (OR = 0.50; 95 % CI 0.34-0.72) had significantly lower odds of medical access to care. Region was not significantly associated with the odds of having prescription access, though a significant increase in prescription access was observed over time. Conclusions: Geographic variation in access to care among adults with kidney disease exists independent of income, education, insurance and comorbid conditions, with those in the South least likely to have a usual source of care and those in the West least likely to have overall access to care when compared to the Northeast United States. C1 [Ozieh, Mukoso N.; Bishu, Kinfe G.; Walker, Rebekah J.; Campbell, Jennifer A.; Egede, Leonard E.] Med Univ South Carolina, Ctr Hlth Dispar Res, Dept Med, Charleston, SC 29425 USA. [Ozieh, Mukoso N.; Bishu, Kinfe G.; Walker, Rebekah J.; Campbell, Jennifer A.; Egede, Leonard E.] Med Univ South Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Walker, Rebekah J.; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ South Carolina, Ctr Hlth Dispar Res, Dept Med, Charleston, SC 29425 USA.; Egede, LE (reprint author), Med Univ South Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA.; Egede, LE (reprint author), Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K24DK093699] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant K24DK093699, Principal Investigator: Leonard Egede, MD). NR 31 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD OCT 18 PY 2016 VL 16 AR 585 DI 10.1186/s12913-016-1844-1 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DZ2OR UT WOS:000385681600006 PM 27756393 ER PT J AU Brenan, L Andreev, A Cohen, O Pantel, S Kamburov, A Cacchiarelli, D Persky, NS Zhu, C Bagul, M Goetz, EM Burgin, AB Garraway, LA Getz, G Mikkelsen, TS Piccioni, F Root, DE Johannessen, CM AF Brenan, Lisa Andreev, Aleksandr Cohen, Ofir Pantel, Sasha Kamburov, Atanas Cacchiarelli, Davide Persky, Nicole S. Zhu, Cong Bagul, Mukta Goetz, Eva M. Burgin, Alex B. Garraway, Levi A. Getz, Gad Mikkelsen, Tarjei S. Piccioni, Federica Root, David E. Johannessen, Cory M. TI Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants SO CELL REPORTS LA English DT Article ID MUTATIONS CONFER RESISTANCE; MAP KINASES; SOMATIC MUTATIONS; CANCER GENES; IN-VIVO; ERK2; ACTIVATION; DISCOVERY; VARIANTS; MEK AB Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain-and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK-, and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology. C1 [Brenan, Lisa; Andreev, Aleksandr; Cohen, Ofir; Pantel, Sasha; Kamburov, Atanas; Cacchiarelli, Davide; Persky, Nicole S.; Zhu, Cong; Bagul, Mukta; Goetz, Eva M.; Burgin, Alex B.; Garraway, Levi A.; Getz, Gad; Mikkelsen, Tarjei S.; Piccioni, Federica; Root, David E.; Johannessen, Cory M.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Cohen, Ofir; Goetz, Eva M.; Garraway, Levi A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Cacchiarelli, Davide] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Andreev, Aleksandr] Univ Pittsburgh, Montefiore Hosp, Med Ctr, Dept Med, Pittsburgh, PA 15213 USA. [Mikkelsen, Tarjei S.] 10X Genom, 7068 Koll Ctr Pkwy 401, Pleasanton, CA 94566 USA. RP Johannessen, CM (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM johannes@broadinstitute.org FU Carlos Slim Foundation in Mexico; Melanoma Research Foundation; William Guy Forbeck Research Foundation; Broad Institute; Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital; NIH TCGA Genome Data Analysis Center [U24CA143845]; Novartis; Astellas; BMS; Merck FX We thank Xiaolan Zhang and Robert Lintner for technical assistance. We thank Amit Majithia, Amanda Walker, Brett Tomson, William G. Kaelin, Jr., Nicole Persky, and the Broad Institute Research Associate/Associate Computational Biologist Journal Club for manuscript review. We thank Adam Tracy for assistance in data management. This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico. This work was supported by a Career Development Award from the Melanoma Research Foundation (C.M.J.), a Collaborative Research Award from the William Guy Forbeck Research Foundation (C.M.J.), a Broad Institute Scientific Projects to Accelerate Research and Collaboration (T.S.M.), by the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital (G.G.), and by the NIH TCGA Genome Data Analysis Center (U24CA143845, G. G.). L.A.G. is a consultant for Foundation Medicine, Novartis, Boehringer-Ingelheim, Third Rock; an equity holder in Foundation Medicine; and a member of the Scientific Advisory Board at Warp Drive. L.A.G. receives sponsored research support from Novartis, Astellas, BMS, and Merck. NR 41 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 18 PY 2016 VL 17 IS 4 BP 1171 EP 1183 DI 10.1016/j.celrep.2016.09.061 PG 13 WC Cell Biology SC Cell Biology GA DZ4TV UT WOS:000385853600020 PM 27760319 ER PT J AU Long, XY Huang, WJ Napadow, V Liang, FR Pleger, B Villringer, A Witt, CM Nierhaus, T Pach, D AF Long, Xiangyu Huang, Wenjing Napadow, Vitaly Liang, Fanrong Pleger, Burkhard Villringer, Arno Witt, Claudia M. Nierhaus, Till Pach, Daniel TI Sustained Effects of Acupuncture Stimulation Investigated with Centrality Mapping Analysis SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE resting-state fMRI; acupuncture; functional connectivity; centrality; pain ID DEFAULT MODE NETWORK; RANDOMIZED CONTROLLED-TRIAL; RESTING-STATE NETWORKS; FUNCTIONAL CONNECTIVITY; BRAIN NETWORKS; CHRONIC PAIN; ALZHEIMERS-DISEASE; CEREBRAL RESPONSE; SHAM ACUPUNCTURE; MATTER VOLUME AB Acupuncture can have instant and sustained effects, however, its mechanisms of action are still unclear. Here, we investigated the sustained effect of acupuncture by evaluating centrality changes in resting-state functional magnetic resonance imaging after manually stimulating the acupuncture point ST36 at the lower leg or two control point locations (CP1 same dermatome, CP2 different dermatome). Data from a previously published experiment evaluating instant BOLD effects and S2-seed-based resting state connectivity was re-analyzed using eigenvector centrality mapping and degree centrality mapping. These data driven methods might add new insights into sustained acupuncture effects on both global and local inter-region connectivity (centrality) by evaluating the summary of connections of every voxel. We found higher centrality in parahippocampal gyrus and middle temporal gyrus after ST36 stimulation in comparison to the two control points. These regions are positively correlated to major hubs of the default mode network, which might be the primary network affected by chronic pain. The stronger integration of both regions within the whole-brain connectome after stimulation of ST36 might be a potential contributor to pain modulation by acupuncture. These findings highlight centrality mapping as a valuable analysis for future imaging studies investigating clinically relevant outcomes associated with physiological response to acupuncture stimulation. Clinical trial registration: NCT01079689, ClinicalTrials.gov. C1 [Long, Xiangyu; Pleger, Burkhard; Villringer, Arno; Nierhaus, Till] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany. [Huang, Wenjing; Witt, Claudia M.; Pach, Daniel] Charite, Inst Social Med Epidemiol & Hlth Econ, Berlin, Germany. [Huang, Wenjing; Liang, Fanrong] Chengdu Univ Tradit Chinese Med, Acupuncture & Tuina Sch, Teaching Hosp 3, Chengdu, Peoples R China. [Napadow, Vitaly] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Napadow, Vitaly] Logan Univ, Dept Radiol, Chesterfield, MO USA. [Villringer, Arno; Nierhaus, Till] Charite & Humboldt Univ, Mind Brain Inst, Berlin Sch Mind & Brain, Berlin, Germany. [Witt, Claudia M.] Univ Zurich, Inst Complementary & Integrat Med, Zurich, Switzerland. [Witt, Claudia M.] Univ Zurich Hosp, Zurich, Switzerland. [Nierhaus, Till] Free Univ Berlin, Neurocomputat & Neuroimaging Unit, Dept Educ & Psychol, Berlin, Germany. RP Nierhaus, T (reprint author), Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany.; Pach, D (reprint author), Charite, Inst Social Med Epidemiol & Hlth Econ, Berlin, Germany.; Nierhaus, T (reprint author), Charite & Humboldt Univ, Mind Brain Inst, Berlin Sch Mind & Brain, Berlin, Germany.; Nierhaus, T (reprint author), Free Univ Berlin, Neurocomputat & Neuroimaging Unit, Dept Educ & Psychol, Berlin, Germany. EM till.nierhaus@fu-berlin.de; daniel.pach@charite.de FU Carstens Foundation; NCCAM, National Institutes of Health [R01-AT004714, R01-AT005280, P01-AT006663, R21-DK097499, R01-AT007550] FX This study had no additional funding. WH received a scholarship from the Carstens Foundation. VN was supported by NCCAM, National Institutes of Health [R01-AT004714, R01-AT005280, P01-AT006663, R21-DK097499, and R01-AT007550]. NR 78 TC 0 Z9 0 U1 6 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 18 PY 2016 VL 10 AR 510 DI 10.3389/fnhum.2016.00510 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DZ5HM UT WOS:000385892600001 PM 27803655 ER PT J AU Perez-Garcia, G Sosa, MAG De Gasperi, R Lashof-Sullivan, M Maudlin-Jeronimo, E Stone, JR Haghighi, F Ahlers, ST Elder, GA AF Perez-Garcia, Georgina Sosa, Miguel A. Gama De Gasperi, Rita Lashof-Sullivan, Margaret Maudlin-Jeronimo, Eric Stone, James R. Haghighi, Fatemeh Ahlers, Stephen T. Elder, Gregory A. TI Exposure to a Predator Scent Induces Chronic Behavioral Changes in Rats Previously Exposed to Low-level Blast: Implications for the Relationship of Blast-Related TBI to PTSD SO FRONTIERS IN NEUROLOGY LA English DT Article DE animal models; blast; postconcussion syndrome; post-traumatic stress disorder; rat; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; ANIMAL-MODEL; OVERPRESSURE; VETERANS; RISK; CARE AB Blast-related mild traumatic brain injury (mTBI) has been unfortunately common in veterans who served in the recent conflicts in Iraq and Afghanistan. The postconcussion syndrome associated with these mTBIs has frequently appeared in combination with post-traumatic stress disorder (PTSD). The presence of PTSD has complicated diagnosis, since clinically, PTSD and the postconcussion syndrome of mTBI have many overlapping symptoms. In particular, establishing how much of the symptom complex can be attributed to the psychological trauma associated with PTSD in contrast to the physical injury of traumatic brain injury has proven difficult. Indeed, some have suggested that much of what is now being called blast-related postconcussion syndrome is better explained by PTSD. The relationship between the postconcussion syndrome of mTBI and PTSD is complex. Association of the two disorders might be viewed as additive effects of independent psychological and physical traumas suffered in a war zone. However, we previously found that rats exposed to repetitive low-level blast exposure in the absence of a psychological stressor developed a variety of anxiety and PTSD-related behavioral traits that were present months following the last blast exposure. Here, we show that a single predator scent challenge delivered 8 months after the last blast exposure induces chronic anxiety related changes in blast-exposed rats that are still present 45 days later. These observations suggest that in addition to independently inducing PTSD-related traits, blast exposure sensitizes the brain to react abnormally to a subsequent psychological stressor. These studies have implications for conceptualizing the relationship between blast-related mTBI and PTSD and suggest that blast-related mTBI in humans may predispose to the later development of PTSD in reaction to subsequent psychological stressors. C1 [Perez-Garcia, Georgina; Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Perez-Garcia, Georgina; Sosa, Miguel A. Gama; De Gasperi, Rita; Haghighi, Fatemeh] James J Peters Dept Vet Affairs Med Ctr, Res & Dev Serv, Bronx, NY USA. [Perez-Garcia, Georgina; Sosa, Miguel A. Gama; De Gasperi, Rita; Haghighi, Fatemeh; Elder, Gregory A.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Sosa, Miguel A. Gama; De Gasperi, Rita; Haghighi, Fatemeh; Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Lashof-Sullivan, Margaret; Maudlin-Jeronimo, Eric; Ahlers, Stephen T.] Naval Med Res Ctr, Dept Neurotrauma Operat & Undersea Med, Silver Spring, MD USA. [Stone, James R.] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA USA. [Stone, James R.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA. [Haghighi, Fatemeh] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Elder, Gregory A.] James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY 10468 USA. RP Elder, GA (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA.; Elder, GA (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA.; Elder, GA (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Elder, GA (reprint author), James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY 10468 USA. EM gregory.elder@va.gov FU NMRC [0000B999.0000.000.A1503]; Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Award [1I01RX000996-01] FX This work was supported by NMRC work unit number 0000B999.0000.000.A1503 and by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Award 1I01RX000996-01. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. ML-S, EM-J, and SA are military service members (or employees of the U.S. Government). This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that copyright protection under this title is not available for any work of the United States Government. Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. NR 39 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD OCT 18 PY 2016 VL 7 AR 176 DI 10.3389/fneur.2016.00176 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DZ2BL UT WOS:000385647000001 PM 27803688 ER PT J AU Roszko, KL Bi, RD Mannstadt, M AF Roszko, Kelly L. Bi, Ruiye D. Mannstadt, Michael TI Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2 SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE autosomal-dominant hypocalcemia; CASR; calcium metabolism; GNA11; G11; calcilytics; YM254890; hypocalcemia ID CALCIUM-SENSING RECEPTOR; PARATHYROID-HORMONE 1-34; APICAL K+ CHANNELS; MUTATIONS; HYPERCALCEMIA; IDENTIFICATION; ABNORMALITIES; METABOLISM; DISORDERS; PHOSPHATE AB Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH) which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH) type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion are suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (G alpha 11) have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of G alpha 11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in G alpha 11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2. C1 [Mannstadt, Michael] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Mannstadt, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM mannstadt@mgh.harvard.edu FU NIDDK NIH HHS [T32 DK007028, R01 DK100584] NR 34 TC 1 Z9 1 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD OCT 18 PY 2016 VL 7 AR 458 DI 10.3389/fphys.2016.00458 PG 7 WC Physiology SC Physiology GA DY9PS UT WOS:000385466900001 PM 27803672 ER PT J AU Van der Kraak, L Goel, G Ramanan, K Kaltenmeier, C Zhang, L Normolle, DP Freeman, GJ Tang, D Nason, KS Davison, JM Luketich, JD Dhupar, R Lotze, MT AF Van der Kraak, Lauren Goel, Gaurav Ramanan, Krishnaveni Kaltenmeier, Christof Zhang, Lin Normolle, Daniel P. Freeman, Gordon J. Tang, Daolin Nason, Katie S. Davison, Jon M. Luketich, James D. Dhupar, Rajeev Lotze, Michael T. TI 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE 5-Fluorouracil; B7-H1; PD-L1; PD-1; Digestive cancers; Checkpoint blockade; Immunotherapy ID COLON-CANCER; COLORECTAL-CANCER; CARCINOMA; APOPTOSIS; PATHWAY; LINES; MICROENVIRONMENT; IMMUNOTHERAPY; PROGRESSION; BLOCKADE AB Background: Resistance to chemotherapy is a major obstacle in the effective treatment of cancer patients. B7-homolog 1, also known as programmed death ligand-1 (PD-L1), is an immunoregulatory protein that is overexpressed in several human cancers. Interaction of B7-H1 with programmed death 1 (PD-1) prevents T-cell activation and proliferation, sequestering the T-cell receptor from the cell membrane, inducing T-cell apoptosis, thereby leading to cancer immunoresistance. B7-H1 upregulation contributes to chemoresistance in several types of cancer, but little is known with respect to changes associated with 5-fluorouracil (5-FU) or gastrointestinal cancers. Methods: HCT 116 p53(+/+), HCT 116 p53(-/-) colorectal cancer (CRC) and OE33 esophageal adenocarcinoma (EAC) cells were treated with increasing doses of 5-FU (0.5 uM, 5 uM, 50 uM, 500 uM) or interferon gamma (IFN-gamma, 10 ng/mL) in culture for 24 h and B7-H1 expression was quantified using flow cytometry and western blot analysis. We also evaluated B7-H1 expression, by immunohistochemistry, in tissue collected prior to and following neoadjuvant therapy in 10 EAC patients. Results: B7-H1 expression in human HCT 116 p53(+/+) and HCT 116 p53(-/-) CRC cells lines, while low at baseline, can be induced by treatment with 5-FU. OE33 baseline B7-H1 expression exceeded CRC cell maximal expression and could be further increased in a dose dependent manner following 5-FU treatment in the absence of immune cells. We further demonstrate tumor B7-H1 expression in esophageal adenocarcinoma patient-derived pre-treatment biopsies. While B7-H1 expression was not enhanced in post-treatment esophagectomy specimens, this may be due to the limits of immunohistochemical quantification. Conclusions: B7-H1/PD-L1 expression can be increased following treatment with 5-FU in gastrointestinal cancer cell lines, suggesting alternative mechanisms to classic immune-mediated upregulation. This suggests that combining 5-FU treatment with PD-1/B7-H1 blockade may improve treatment in patients with gastrointestinal adenocarcinoma. C1 [Van der Kraak, Lauren; Nason, Katie S.; Luketich, James D.; Dhupar, Rajeev] Univ Pittsburgh, Dept Cardiothorac Surg, Pittsburgh, PA USA. [Goel, Gaurav] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. [Goel, Gaurav] Univ Kentucky, Markey Canc Ctr, Div Med Oncol, Lexington, KY USA. [Ramanan, Krishnaveni; Kaltenmeier, Christof; Tang, Daolin; Lotze, Michael T.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA. [Zhang, Lin] Univ Pittsburgh, Sch Med, Inst Canc, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Normolle, Daniel P.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Freeman, Gordon J.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Davison, Jon M.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Lotze, Michael T.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15260 USA. [Lotze, Michael T.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. RP Lotze, MT (reprint author), Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA.; Lotze, MT (reprint author), Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15260 USA.; Lotze, MT (reprint author), Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. EM lotzemt@upmc.edu OI GOEL, GAURAV/0000-0002-1688-8644 FU NCI NIH HHS [K07 CA151613, P30 CA047904] NR 34 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD OCT 18 PY 2016 VL 4 AR 65 DI 10.1186/s40425-016-0163-8 PG 8 WC Oncology SC Oncology GA DY9LV UT WOS:000385456200007 PM 27777774 ER PT J AU Tetteh, PW Kretzschmar, K Begthel, H van den Born, M Korving, J Morsink, F Farin, H van Es, JH Offerhaus, GJA Clevers, H AF Tetteh, Paul W. Kretzschmar, Kai Begthel, Harry van den Born, Maaike Korving, Jeroen Morsink, Folkert Farin, Henner van Es, Johan H. Offerhaus, G. Johan A. Clevers, Hans TI Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mouse model; gastrointestinal tract; colorectal cancer; Car1; differentiated epithelial cells ID COLORECTAL-CANCER; STEM-CELLS; INTESTINAL EPITHELIUM; EXPRESSION; GENE; MICE; INFLAMMATION; MUTATIONS; MODELS; MARKER AB Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1(CreER) knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1(CreER) KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4. Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1(CreER) KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions. C1 [Tetteh, Paul W.; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; Farin, Henner; van Es, Johan H.; Clevers, Hans] Royal Netherlands Acad Arts & Sci ( KNAW), Hubrecht Inst Dev Biol & Stem Cell Res, NL-3584 CT Utrecht, Netherlands. [Tetteh, Paul W.; Kretzschmar, Kai; Begthel, Harry; van den Born, Maaike; Korving, Jeroen; Farin, Henner; van Es, Johan H.; Clevers, Hans] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Morsink, Folkert; Offerhaus, G. Johan A.] Univ Med Ctr Utrecht, Dept Pathol, NL-3584 CX Utrecht, Netherlands. [Tetteh, Paul W.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. [Farin, Henner] Georg Speyer Haus Inst Tumor Biol & Expt Therapy, D-60596 Frankfurt, Germany. RP Clevers, H (reprint author), Royal Netherlands Acad Arts & Sci ( KNAW), Hubrecht Inst Dev Biol & Stem Cell Res, NL-3584 CT Utrecht, Netherlands.; Clevers, H (reprint author), Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. EM h.clevers@hubrecht.eu FU Netherlands Organization for Scientific Research; European Molecular Biology Organization (EMBO); Human Frontier Science Program; EMBO long-term fellowship; Leducq Foundation Transatlantic Networks of Excellence grant; Cardiovasculair Onderzoek Nederland (CVON)-Human Stem Cells for Cardiac Repair (HUSTCARE) grants FX P.W.T. was supported by a Netherlands Organization for Scientific Research personal grant. K.K. is supported by long-term fellowships from the European Molecular Biology Organization (EMBO) and the Human Frontier Science Program. H.F. was supported by an EMBO long-term fellowship. J.H.v.E. was supported by a Leducq Foundation Transatlantic Networks of Excellence grant. M.v.d.B. and H.B. were supported by Cardiovasculair Onderzoek Nederland (CVON)-Human Stem Cells for Cardiac Repair (HUSTCARE) grants. NR 41 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2016 VL 113 IS 42 BP 11859 EP 11864 DI 10.1073/pnas.1614057113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1PN UT WOS:000385610400070 PM 27708166 ER PT J AU Pulivarthy, SR Lion, M Kuzu, G Matthews, AGW Borowsky, ML Morris, J Kingston, RE Dennis, JH Tolstorukov, MY Oettinger, MA AF Pulivarthy, Sandhya R. Lion, Mattia Kuzu, Guray Matthews, Adam G. W. Borowsky, Mark L. Morris, John Kingston, Robert E. Dennis, Jonathan H. Tolstorukov, Michael Y. Oettinger, Marjorie A. TI Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epigenetics; V(D)J recombination; nucleosome positioning; chromatin; lymphocytes ID ANTIGEN RECEPTOR LOCI; HEAVY-CHAIN LOCUS; PRO-B CELLS; CCCTC-BINDING FACTOR; GENE REARRANGEMENT; IGH LOCUS; NONCODING TRANSCRIPTION; 3-DIMENSIONAL STRUCTURE; EPIGENETIC CONTROL; PLANT HOMEODOMAIN AB We show that the physical distribution of nucleosomes at antigen receptor loci is subject to regulated cell type-specific and lineage-specific positioning and correlates with the accessibility of these gene segments to recombination. At the Ig heavy chain locus (IgH), a nucleosome in pro-B cells is generally positioned over each IgH variable (VH) coding segment, directly adjacent to the recombination signal sequence (RSS), placing the RSS in a position accessible to the recombination activating gene (RAG) recombinase. These changes result in establishment of a specific chromatin organization at the RSS that facilitates accessibility of the genomic DNA for the RAG recombinase. In contrast, in mouse embryonic fibroblasts the coding segment is depleted of nucleosomes, which instead cover the RSS, thereby rendering it inaccessible. Pro-T cells exhibit a pattern intermediate between pro-B cells and mouse embryonic fibroblasts. We also find large-scale variations of nucleosome density over hundreds of kilobases, delineating chromosomal domains within IgH, in a cell type-dependent manner. These findings suggest that developmentally regulated changes in nucleosome location and occupancy, in addition to the known chromatin modifications, play a fundamental role in regulating V(D)J recombination. Nucleosome positioning-which has previously been observed to vary locally at individual enhancers and promoters-may be a more general mechanism by which cells can regulate the accessibility of the genome during development, at scales ranging from several hundred base pairs to many kilobases. C1 [Pulivarthy, Sandhya R.; Lion, Mattia; Kuzu, Guray; Matthews, Adam G. W.; Borowsky, Mark L.; Morris, John; Kingston, Robert E.; Dennis, Jonathan H.; Tolstorukov, Michael Y.; Oettinger, Marjorie A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Pulivarthy, Sandhya R.; Lion, Mattia; Matthews, Adam G. W.; Borowsky, Mark L.; Morris, John; Kingston, Robert E.; Dennis, Jonathan H.; Oettinger, Marjorie A.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Matthews, Adam G. W.] Wellesley Coll, Dept Biol Sci, Wellesley, MA 02481 USA. [Matthews, Adam G. W.] Wellesley Coll, Program Biochem, Wellesley, MA 02481 USA. [Dennis, Jonathan H.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Pulivarthy, Sandhya R.] Northrop Grumann Corp, Milford Mill, MD 21244 USA. [Borowsky, Mark L.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Morris, John] Black Duck Software, Burlington, MA 01803 USA. RP Tolstorukov, MY; Oettinger, MA (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Oettinger, MA (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM tolstorukov@molbio.mgh.harvard.edu; oettinger@molbio.mgh.harvard.edu FU National Institutes of Health [GM048026, AI083510, GM048405, DA033773] FX The authors thank Anne E. Corcoran for insightful discussions and critical reading of the manuscript. This work was supported by National Institutes of Health Grants GM048026 (to M.A.O.), AI083510 (to M.A.O.), GM048405 (to R.E.K.), and DA033773 (to J.H.D.). NR 71 TC 0 Z9 0 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2016 VL 113 IS 42 BP E6427 EP E6436 DI 10.1073/pnas.1605543113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1PN UT WOS:000385610400016 PM 27698124 ER PT J AU Zhang, XM Mormino, EC Sun, NB Sperling, RA Sabuncu, MR Yeo, BTT AF Zhang, Xiuming Mormino, Elizabeth C. Sun, Nanbo Sperling, Reisa A. Sabuncu, Mert R. Yeo, B. T. Thomas CA Alzheimer's Dis Neuroimaging Initi TI Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mental disorder subtypes; Alzheimer's disease subtypes; Alzheimer's disease heterogeneity; voxel-based morphometry; unsupervised machine learning ID HUMAN CEREBRAL-CORTEX; NEUROIMAGING INITIATIVE ADNI; VOXEL-BASED MORPHOMETRY; FUNCTIONAL CONNECTIVITY; NATIONAL INSTITUTE; HIERARCHICAL ORGANIZATION; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; DEFINED SUBTYPES; COMPOSITE SCORE AB We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxel-wise structural MRIs of late-onset Alzheimer's disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid-positive (A beta+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in A beta+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research. C1 [Zhang, Xiuming; Sun, Nanbo; Yeo, B. T. Thomas] Natl Univ Singapore, Dept Elect & Comp Engn, Agcy Sci Technol & Res, Singapore Inst Neurotechnol,Clin Imaging Res Ctr, Singapore 117599, Singapore. [Zhang, Xiuming; Sun, Nanbo; Yeo, B. T. Thomas] Natl Univ Singapore, Memory Networks Program, Singapore 117599, Singapore. [Mormino, Elizabeth C.; Sperling, Reisa A.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, Boston, MA 02129 USA. [Sabuncu, Mert R.; Yeo, B. T. Thomas] Massachusetts Gen Hosp, Harvard Med Sch, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Sabuncu, Mert R.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02138 USA. [Yeo, B. T. Thomas] Duke Natl Univ Singapore, Grad Sch Med, Ctr Cognit Neurosc, Singapore 169857, Singapore. RP Yeo, BTT (reprint author), Natl Univ Singapore, Dept Elect & Comp Engn, Agcy Sci Technol & Res, Singapore Inst Neurotechnol,Clin Imaging Res Ctr, Singapore 117599, Singapore.; Yeo, BTT (reprint author), Natl Univ Singapore, Memory Networks Program, Singapore 117599, Singapore.; Yeo, BTT (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA.; Yeo, BTT (reprint author), Duke Natl Univ Singapore, Grad Sch Med, Ctr Cognit Neurosc, Singapore 169857, Singapore. EM thomas.yeo@nus.edu.sg OI Yeo, B.T. Thomas/0000-0002-0119-3276 FU National University of Singapore (NUS) Tier 1; Singapore Ministry of Education Tier 2 Grant [MOE2014-T2-2-016]; NUS Strategic Research Grant [DPRT/944/09/14]; NUS School of Medicine Aspiration Fund [R185000271720]; Singapore National Medical Research Council [CBRG14nov007, NMRC/CG/013/2013]; NUS Young Investigator Award; NIH [1K25EB013649-01, 1R21AG050122-01A1, P01AG036694, F32AG044054]; Center for Functional Neuroimaging Technologies [P41EB015896]; Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital [1S10RR023401, 1S10RR019307, 1S10RR023043]; ADNI (NIH Grant) [U01 AG024904]; Department of Defense (DOD) ADNI (DOD Grant) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; Transition Therapeutics; Canadian Institutes of Health Research FX We thank Maxwell Bertolero, Mark D'Esposito, Rik Ossenkoppele, Daniel Alexander, and Christopher Asplund for their constructive comments as well as Gia Ngo, Muhammad Anwar, Ryan Fong, and Xilin Jiang for assistance with public release of code and data. This work was supported by National University of Singapore (NUS) Tier 1; Singapore Ministry of Education Tier 2 Grant MOE2014-T2-2-016; NUS Strategic Research Grant DPRT/944/09/14; NUS School of Medicine Aspiration Fund R185000271720; Singapore National Medical Research Council Grant CBRG14nov007, NMRC/CG/013/2013; NUS Young Investigator Award; and NIH Grants 1K25EB013649-01, 1R21AG050122-01A1, P01AG036694, and F32AG044054. The research also used resources provided by Center for Functional Neuroimaging Technologies Grant P41EB015896 and instruments supported by Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043 from the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital. Data collection and sharing for this project was funded by the ADNI (NIH Grant U01 AG024904) and the Department of Defense (DOD) ADNI (DOD Grant W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Data used in preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. NR 48 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 18 PY 2016 VL 113 IS 42 BP E6535 EP E6544 DI 10.1073/pnas.1611073113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1PN UT WOS:000385610400027 PM 27702899 ER PT J AU Kobeissy, FH Hansen, K Neumann, M Fu, SP Jin, KL Liu, JL AF Kobeissy, Firas H. Hansen, Katharina Neumann, Melanie Fu, Shuping Jin, Kulin Liu, Jialing TI Deciphering the Role of Emx1 in Neurogenesis: A Neuroproteomics Approach SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE cofilin; VEGF; neural stem cell; 2D-PAGE/MS-MS; Boyden chamber assay ID ENDOTHELIAL GROWTH-FACTOR; NEURAL STEM-CELLS; ACTIN-DEPOLYMERIZING FACTOR; CEREBRAL-CORTEX; NEUROVASCULAR NICHE; BRAIN-DEVELOPMENT; ACIDIC CALPONIN; MUTANT MICE; NEURONAL DIFFERENTIATION; NEURITE OUTGROWTH AB Emx1 has long been implicated in embryonic brain development. Previously we found that mice null of Emx1 gene had smaller dentate gyri and reduced neurogenesis, although the molecular mechanisms underlying this defect was not well understood. To decipher the role of Emx1 gene in neural regeneration and the timing of its involvement, we determine the frequency of neural stem cells (NSCs) in embryonic and adult forebrains of Emx1 wild type (WT) and knock out (KO) mice in the neurosphere assay. Emx1 gene deletion reduced the frequency and self-renewal capacity of NSCs of the embryonic brain but did not affect neuronal or glial differentiation. Emx1 KO NSCs also exhibited a reduced migratory capacity in response to serum or vascular endothelial growth factor (VEGF) in the Boyden chamber migration assay compared to their WT counterparts. A thorough comparison between NSC lysates from Emx1 WT and KO mice utilizing 2D-PAGE coupled with tandem mass spectrometry revealed 38 proteins differentially expressed between genotypes, including the F-actin depolymerization factor Cofilin. A global systems biology and cluster analysis identified several potential mechanisms and cellular pathways implicated in altered neurogenesis, all involving Cofilin1. Protein interaction network maps with functional enrichment analysis further indicated that the differentially expressed proteins participated in neural-specific functions including brain development, axonal guidance, synaptic transmission, neurogenesis, and hippocampal morphology, with VEGF as the upstream regulator intertwined with Cofilin1 and Emx1 Functional validation analysis indicated that apart from the overall reduced level of phosphorylated Cofilin1 (p-Cofilin1) in the Emx1 KO NSCs compared to WT NSCs as demonstrated in the western blot analysis. VEGF was able to induce more Cofilin1 phosphorylation and FLK expression only in the latter. Our results suggest that a defect in Cofilin1 phosphorylation induced by VEGF or other growth factors might contribute to the reduced neurogenesis in the Emx1 null mice during brain development. C1 [Kobeissy, Firas H.] Univ Florida, Dept Psychiat, Ctr Neuroprote & Biomarkers Res, Gainesville, FL 32611 USA. [Hansen, Katharina; Neumann, Melanie; Fu, Shuping; Liu, Jialing] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Hansen, Katharina; Neumann, Melanie; Fu, Shuping; Liu, Jialing] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Fu, Shuping] Nanjing Univ Chihese Med, Minister Educ, Key Lab Acupuncture & Med Res, Nanjing, Jiangsu, Peoples R China. [Jin, Kulin] Univ North Texas, Hlth Sci Ctr, Pharmacol & Neurosci, Ft Worth, TX USA. RP Liu, JL (reprint author), Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA.; Liu, JL (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM jialing.liu@ucsf.edu RI kobeissy, firas/E-7042-2017 OI kobeissy, firas/0000-0002-5008-6944 FU NIH grant [R01 NS071050, I01RX000655]; National Natural Science Foundation of China [81403479] FX This work was supported by NIH grant R01 NS071050 (JL), VA merit award I01RX000655 (JL), and National Natural Science Foundation of China No.81403479 (SF). NR 93 TC 0 Z9 0 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD OCT 17 PY 2016 VL 9 AR 98 DI 10.3389/fnmol.2016.00098 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DY9GV UT WOS:000385442800001 PM 27799894 ER PT J AU Wong, JC Dutton, SBB Collins, SD Schachter, S Escayg, A AF Wong, Jennifer C. Dutton, Stacey B. B. Collins, Stephen D. Schachter, Steven Escayg, Andrew TI Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scnla Mutant Mice SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE huperzine A; Scn1a; Dravet syndrome; genetic epilepsy with febrile seizures plus; seizure ID SEVERE MYOCLONIC EPILEPSY; ANTIEPILEPTIC DRUG DEVELOPMENT; HYPERTHERMIA-INDUCED SEIZURES; SODIUM-CHANNEL GENE; DE-NOVO MUTATIONS; DRAVET-SYNDROME; MOUSE MODEL; FEBRILE SEIZURES; CHOLINESTERASE INHIBITOR; GABAERGIC INTERNEURONS AB De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Na-v,1.1)are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a(+/-)) and GEFS+ (Scn1a(RH/+)). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Sonla(RH/+) mutants. Finally, we determined that muscarinic and GABA(A) receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEES+, and more broadly, in other forms of refractory epilepsy. C1 [Wong, Jennifer C.; Dutton, Stacey B. B.; Escayg, Andrew] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Dutton, Stacey B. B.] Agnes Scott Coll, Dept Biol, Atlanta, GA USA. [Collins, Stephen D.] Biscayne Pharmaceut, Miami, FL USA. [Schachter, Steven] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. [Schachter, Steven] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Escayg, A (reprint author), Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. EM aescayg@emory.edu FU National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health [R01NS072221, R21NS098776]; Training Translational Research in Neurology [T32 2T32NS00748016] FX The authors would like to acknowledge Dr. William Catterall for providing the ScnIa+/- mutant mice. The authors would also like to thank Cheryl Strauss for editorial assistance. This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health [R01NS072221, R21NS098776 (AE)] and the Training Translational Research in Neurology T32 [2T32NS00748016 (JW)]. The content is solely the responsibility of the authors and does not necessarily represent the views of the NR 80 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD OCT 17 PY 2016 VL 7 AR 357 DI 10.3389/fphar.2016.00357 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY9IS UT WOS:000385447800001 PM 27799911 ER PT J AU Kitsak, M Sharma, A Menche, J Guney, E Ghiassian, SD Loscalzo, J Barabasi, AL AF Kitsak, Maksim Sharma, Amitabh Menche, Joerg Guney, Emre Ghiassian, Susan Dina Loscalzo, Joseph Barabasi, Albert-Laszlo TI Tissue Specificity of Human Disease Module SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; PROTEIN INTERACTION NETWORK; ALZHEIMERS-DISEASE; SCALE MAP; GENES; EXPRESSION; COMPLEXES; PHENOTYPE; GENOTYPE; MEDICINE AB Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations. C1 [Kitsak, Maksim; Sharma, Amitabh; Menche, Joerg; Guney, Emre; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Networks Res, 110 Forsyth St,111 Dana Res Ctr, Boston, MA 02115 USA. [Kitsak, Maksim; Sharma, Amitabh; Menche, Joerg; Guney, Emre; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, 110 Forsyth St,111 Dana Res Ctr, Boston, MA 02115 USA. [Kitsak, Maksim; Sharma, Amitabh; Menche, Joerg; Guney, Emre; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, CCSB, 450 Brookline Ave, Boston, MA 02215 USA. [Kitsak, Maksim; Sharma, Amitabh; Menche, Joerg; Guney, Emre; Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Sharma, Amitabh] Harvard Med Sch, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Menche, Joerg; Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, Nador U 9, H-1051 Budapest, Hungary. [Menche, Joerg] Austrian Acad Sci, CeMM Res Ctr Mol Med, Lazarettgasse 14,AKH BT 25-3, A-1090 Vienna, Austria. [Guney, Emre] Inst Res Biomed, Barcelona 08028, Spain. [Ghiassian, Susan Dina; Barabasi, Albert-Laszlo] DZZOM Inc, 111 Huntington Ave, Boston, MA 02119 USA. [Loscalzo, Joseph; Barabasi, Albert-Laszlo] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Budapest Univ Technol & Econ, Dept Theoret Phys, H-1111 Budapest, Hungary. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Networks Res, 110 Forsyth St,111 Dana Res Ctr, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Northeastern Univ, Dept Phys, 110 Forsyth St,111 Dana Res Ctr, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Dana Farber Canc Inst, CCSB, 450 Brookline Ave, Boston, MA 02215 USA.; Barabasi, AL (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA.; Barabasi, AL (reprint author), Cent European Univ, Ctr Network Sci, Nador U 9, H-1051 Budapest, Hungary.; Barabasi, AL (reprint author), DZZOM Inc, 111 Huntington Ave, Boston, MA 02119 USA.; Barabasi, AL (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Barabasi, AL (reprint author), Budapest Univ Technol & Econ, Dept Theoret Phys, H-1111 Budapest, Hungary. EM barabasi@gmail.com RI Menche, Jorg/G-3994-2015; Guney, Emre/B-2568-2017 OI Menche, Jorg/0000-0002-1583-6404; Guney, Emre/0000-0002-3466-6535 FU NHLBI [PO1-HL083069, R37-HL061795, RC2-HL101543, U01-HL108630]; NIH [P50-HG004233, U01-HG001715]; NHGRI [UO1-HG007690]; NIGMS [P50-GM107618] FX We thank M. Vidal, A. Kamburov and R. Wang for many discussions of the manuscript; and K. Albrecht for assistance in figure design. This work was supported by NIH grants P50-HG004233, U01-HG001715, and UO1-HG007690 from NHGRI, P50-GM107618 from NIGMS and PO1-HL083069, R37-HL061795, RC2-HL101543, and U01-HL108630 from NHLBI. NR 39 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 17 PY 2016 VL 6 AR 35241 DI 10.1038/srep35241 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY8CE UT WOS:000385355300001 PM 27748412 ER PT J AU Shin, JW Kim, KH Chao, MJ Atwal, RS Gillis, T MacDonald, ME Gusella, JF Lee, JM AF Shin, Jun Wan Kim, Kyung-Hee Chao, Michael J. Atwal, Ranjit S. Gillis, Tammy MacDonald, Marcy E. Gusella, James F. Lee, Jong-Min TI Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9 SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPANDED CAG REPEAT; MUTANT HUNTINGTIN; DETERMINES AGE; CAS9 NUCLEASES; GENE HOMOLOG; MICE; EXPANSION; CRISPR-CAS9; EXPRESSION; HAPLOTYPE AB A comprehensive genetics-based precision medicine strategy to selectively and permanently inactivate only mutant, not normal allele, could benefit many dominantly inherited disorders. Here, we demonstrate the power of our novel strategy of inactivating the mutant allele using haplotype-specific CRISPR/Cas9 target sites in Huntington's disease (HD), a late-onset neurodegenerative disorder due to a toxic dominant gain-of-function CAG expansionmutation. Focusing on improving allele specificity, we combined extensive knowledge of huntingtin (HTT) gene haplotype structure with a novel personalized allele-selective CRISPR/Cas9 strategy based on Protospacer Adjacent Motif (PAM)-altering SNPs to target patient-specific CRISPR/Cas9 sites, aiming at the mutant HTT allele-specific inactivation for a given diplotype. As proof-of-principle, simultaneously using two CRISPR/Cas9 guide RNAs (gRNAs) that depend on PAM sites generated by SNP alleles on the mutant chromosome, we selectively excised similar to 44 kb DNA spanning promoter region, transcription start site, and the CAG expansion mutation of the mutant HTT gene, resulting in complete inactivation of the mutant allele without impacting the normal allele. This excision on the disease chromosome completely prevented the generation of mutant HTT mRNA and protein, unequivocally indicating permanent mutant allele-specific inactivation of the HD mutant allele. The perfect allele selectivity with broad applicability of our strategy in disorders with diverse disease haplotypes should also support precision medicine through inactivation of many other gain-of-function mutations. C1 [Shin, Jun Wan; Kim, Kyung-Hee; Chao, Michael J.; Atwal, Ranjit S.; Gillis, Tammy; MacDonald, Marcy E.; Gusella, James F.; Lee, Jong-Min] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Shin, Jun Wan; Kim, Kyung-Hee; Chao, Michael J.; Atwal, Ranjit S.; MacDonald, Marcy E.; Lee, Jong-Min] Harvard Med Sch, Dept Neurol, Boston, MA USA. [MacDonald, Marcy E.; Lee, Jong-Min] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA. [Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. EM jlee51@mgh.harvard.edu FU Harvard NeuroDiscovery Center; CHDI Foundation; National Institute of Neurological Disorders and Stroke [U01NS082079, R01NS091161] FX This research was supported by Harvard NeuroDiscovery Center, CHDI Foundation and grants from the National Institute of Neurological Disorders and Stroke (U01NS082079 and R01NS091161). NR 39 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2016 VL 25 IS 20 BP 4566 EP 4576 DI 10.1093/hmg/ddw286 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EN1ZM UT WOS:000395809100017 PM 28172889 ER PT J AU Nishida, T Goto, O Raut, CP Yahagi, N AF Nishida, Toshirou Goto, Osamu Raut, Chandrajit Premanand Yahagi, Naohisa TI Diagnostic and Treatment Strategy for Small Gastrointestinal Stromal Tumors SO CANCER LA English DT Review DE endoscopic ultrasonography (EUS); gastrointestinal stromal tumor (GIST); high-risk features; laparoscopic surgery; submucosal tumor (SMT) ID ENDOSCOPIC SUBMUCOSAL DISSECTION; FINE-NEEDLE-ASPIRATION; LONG-TERM OUTCOMES; ESOPHAGOGASTRIC JUNCTION; SUBEPITHELIAL LESIONS; LAPAROSCOPIC RESECTION; COOPERATIVE SURGERY; MESENCHYMAL TUMORS; MUSCULARIS PROPRIA; GIST AB Gastrointestinal stromal tumors (GISTs) are considered to be potentially malignant mesenchymal tumors of the gastrointestinal tract. Clinically relevant GISTs are rare; however, subclinical GISTs (mini-GISTs) (1-2 cm) and pathologic GISTs (micro-GISTs) (<1 cm) are frequently reported. Most mini-GISTs and almost all micro-GISTs of the stomach may exhibit benign clinical behavior, and only mini-GISTs with high-risk features may progress. For this review, a provisional algorithm was used to propose diagnostic and treatment strategies for patients with small GISTs. Because surgery is the only potentially curative treatment, in its application for small GISTs, the principles of sarcoma surgery should be maintained, and cost effectiveness should be considered. Indications for surgery include GISTs measuring >= 2 cm, symptomatic GISTs, and mini-GISTs with high-risk features (irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, and tumor progression during follow-up); however, a preoperative pathologic diagnosis is infrequently obtained. For small intestinal and colorectal GISTs, surgery is indicated irrespective of size because of their greater malignant potential. Otherwise, mini-GISTs without high-risk features, micro-GISTs, and small submucosal tumors measuring <5 cm without high-risk features may be followed by periodical endoscopic ultrasonography. Although surgical approaches and operative methods are selected according to tumor size, location, growth pattern, and surgical teams, laparoscopic surgery has produced similar oncologic outcomes and is less invasiveness compared with open surgery. After resection, pathologic examination for diagnosis and risk assessment is mandatory, and genotyping is also recommended for high-risk GISTs. Endoscopic resection techniques, although feasible, are not routinely indicated for most mini-GISTs or micro-GISTs. (C) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. C1 [Nishida, Toshirou] Natl Canc Ctr, Dept Surg, Tokyo, Japan. [Goto, Osamu; Yahagi, Naohisa] Keio Univ, Div Res & Dev Minimally Invas Treatment, Ctr Canc, Sch Med, Tokyo, Japan. [Raut, Chandrajit Premanand] Harvard Med Sch, Brigham & Womens Hosp, Ctr Sarcoma & Bone Oncol, Div Surg Oncol,Dana Farber Canc Inst, Boston, MA USA. RP Nishida, T (reprint author), Natl Canc Ctr, Dept Surg, Chuo Ku, 5-5-1 Tsukiji, Tokyo 1040045, Japan. EM tnishida@ncc.go.jp FU Japanese Ministry of Education, Culture, Sports, Science and Technology [16H05419]; National Cancer Center Research and Development Fund [26-A-21]; Uehara Memorial Foundation FX This work is supported in part by a Grant-in-Aid (16H05419) for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; by grant 26-A-21 from the National Cancer Center Research and Development Fund; and by a grant from the Uehara Memorial Foundation. NR 49 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2016 VL 122 IS 20 BP 3110 EP 3118 DI 10.1002/cncr.30239 PG 9 WC Oncology SC Oncology GA EC6ZF UT WOS:000388284500006 PM 27478963 ER PT J AU Markt, SC Lago-Hernandez, CA Miller, RE Mahal, BA Bernard, B Albiges, L Frazier, LA Beard, CJ Wright, AA Sweeney, CJ AF Markt, Sarah C. Lago-Hernandez, Carlos A. Miller, Rowan E. Mahal, Brandon A. Bernard, Brandon Albiges, Laurence Frazier, Lindsay A. Beard, Clair J. Wright, Alexi A. Sweeney, Christopher J. TI Insurance Status and Disparities in Disease Presentation, Treatment, and Outcomes for Men With Germ Cell Tumors SO CANCER LA English DT Article DE cancer; disparities; germ cell tumors; insurance; outcomes ID AFFORDABLE CARE ACT; PREVIOUSLY UNINSURED ADULTS; ONCOLOGY POLICY STATEMENT; MEDICARE COVERAGE; AMERICAN SOCIETY; YOUNG-ADULTS; CANCER; HEALTH; SURVIVAL; STAGE AB BACKGROUND: People aged 26 to 34 years represent the greatest proportion of the uninsured, and they have the highest incidence of testicular cancers. The aim of this study was to investigate the association between insurance status and cancer outcomes in men diagnosed with germ cell tumors. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 10,211 men diagnosed with germ cell gonadal neoplasms from 2007 to 2011. Associations between insurance status and characteristics at diagnosis and receipt of treatment were examined with log-binomial regression. The association between insurance status and mortality was assessed with Cox proportional hazards regression. RESULTS: Uninsured patients had an increased risk of metastatic disease at diagnosis (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.38) in comparison with insured patients, as did Medicaid patients (RR, 1.62; 95% CI, 1.51-1.74). Among men with metastatic disease, uninsured and Medicaid patients were more likely to be diagnosed with intermediate/poor-risk disease (RR for uninsured patients, 1.22; 95% CI, 1.04-1.44; RR for Medicaid patients, 1.39; 95% CI, 1.23-1.57) and were less likely to undergo lymph node dissection (RR for uninsured patients, 0.74; 95% CI, 0.57-0.94; RR for Medicaid patients, 0.76; 95% CI, 0.63-0.92) in comparison with insured patients. Men without insurance were more likely to die of their disease (hazard ratio [HR], 1.88; 95% CI, 1.29-2.75) in comparison with insured men, as were those with Medicaid (HR, 1.51; 95% CI, 1.08-2.10). CONCLUSIONS: Patients without insurance and patients with Medicaid have an increased risk of presenting with advanced disease and dying of the disease in comparison with those who have insurance. Future studies should examine whether implementation of the Patient Protection and Affordable Care Act reduces these disparities. (C) 2016 American Cancer Society. C1 [Lago-Hernandez, Carlos A.; Miller, Rowan E.; Mahal, Brandon A.; Bernard, Brandon; Albiges, Laurence; Sweeney, Christopher J.] Dana Farber Brigham & Womens Canc Ctr, Lank Ctr Genitourinary Oncol, Dept Med Oncol, 450 Brookline Ave,Suite D1230, Boston, MA 02115 USA. [Markt, Sarah C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Frazier, Lindsay A.] Dana Farber Childrens Canc Ctr, Boston, MA USA. [Beard, Clair J.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Wright, Alexi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wright, Alexi A.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. RP Sweeney, CJ (reprint author), Dana Farber Brigham & Womens Canc Ctr, Lank Ctr Genitourinary Oncol, Dept Med Oncol, 450 Brookline Ave,Suite D1230, Boston, MA 02115 USA. EM christopher_sweeney@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health through a training grant [T32 CA09001]; National Cancer Institute [K07 CA166210] FX Sarah C. Markt is supported by the National Cancer Institute of the National Institutes of Health through a training grant (T32 CA09001). Alexi A. Wright is also supported by the National Cancer Institute (K07 CA166210). NR 30 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2016 VL 122 IS 20 BP 3127 EP 3135 DI 10.1002/cncr.30159 PG 9 WC Oncology SC Oncology GA EC6ZF UT WOS:000388284500008 PM 27500561 ER PT J AU D'Agostino, NM Edelstein, K Zhang, N Recklitis, CJ Brinkman, TM Srivastava, D Leisenring, WM Robison, LL Armstrong, GT Krull, KR AF D'Agostino, Norma Mammone Edelstein, Kim Zhang, Nan Recklitis, Christopher J. Brinkman, Tara M. Srivastava, Deokumar Leisenring, Wendy M. Robison, Leslie L. Armstrong, Gregory T. Krull, Kevin R. TI Comorbid Symptoms of Emotional Distress in Adult Survivors of Childhood Cancer SO CANCER LA English DT Article DE Brief Symptom Inventory 18; comorbidity; latent profile analysis; psychosocial late effect; quality of life ID LONG-TERM SURVIVORS; QUALITY-OF-LIFE; PSYCHOLOGICAL DISTRESS; POSTTRAUMATIC-STRESS; SUICIDE IDEATION; OUTCOMES; RISK; INVENTORY-18 AB BACKGROUND: Childhood cancer survivors are at risk for emotional distress symptoms, but symptom comorbidity has not been previously examined. This study examined distress profiles for adult survivors of childhood cancer diagnosed between 1970 and 1999. METHODS: Self-reported depression, anxiety, and somatization symptoms from Brief Symptom Inventory 18 were examined in survivors (n = 16,079) and siblings (n = 3085) from the Childhood Cancer Survivor Study. A latent profile analysis identified clusters of survivors with individual and comorbid symptoms. Disease, treatment, and demographic predictors of distress comorbidity patterns were examined with multinomial logistic regressions. RESULTS: Four clinically relevant profiles were identified: low distress on all subscales (asymptomatic, 62%), high distress on all subscales (comorbid distress, 11%), elevated somatization (somatic symptoms, 13%), and elevated depression and anxiety (affective distress, 14%). Compared with siblings, fewer survivors were asymptomatic (62% vs 74%, P<.0001), and more had comorbid distress (11% vs 5%, P<.0001). Survivors of leukemia (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.12-1.61), central nervous system tumors (OR, 1.30; 95% CI, 1.05-1.61), and sarcoma (OR, 1.26; 95% CI, 1.01-1.57) had a greater risk of comorbid distress than survivors of solid tumors. Psychoactive medications were associated with comorbid distress (P<.0001), and this suggested that this group was refractory to traditional medical management. Comorbid distress was associated with poor perceived health (OR, 31.7; 95% CI, 23.1-43.3), headaches (OR, 3.2; 95% CI, 2.8-3.7), and bodily pain (OR, 4.0; 95% CI, 3.2-5.0). CONCLUSIONS: A significant proportion of survivors are at risk for comorbid distress, which may require extensive treatment approaches beyond those used for individual symptoms. (C) 2016 American Cancer Society. C1 [D'Agostino, Norma Mammone; Edelstein, Kim] Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. [Zhang, Nan; Brinkman, Tara M.; Srivastava, Deokumar; Robison, Leslie L.; Armstrong, Gregory T.; Krull, Kevin R.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Recklitis, Christopher J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Leisenring, Wendy M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP D'Agostino, NM (reprint author), Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM norma.dagostino@uhn.ca FU National Cancer Institute [CA55727]; Cancer Center Support (Core) Grant [CA21765]; American Lebanese-Syrian Associated Charities; Ontario Ministry of Health and Long-Term Care; Princess Margaret Cancer Foundation FX This work was supported by the National Cancer Institute (CA55727 to Gregory T. Armstrong, principal investigator). Support for St. Jude Children's Research Hospital was provided by a Cancer Center Support (Core) Grant (CA21765 to C. Roberts, principal investigator) and the American Lebanese-Syrian Associated Charities. Support for the Princess Margaret Cancer Centre was provided by the Ontario Ministry of Health and Long-Term Care and the Princess Margaret Cancer Foundation. NR 31 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2016 VL 122 IS 20 BP 3215 EP 3224 DI 10.1002/cncr.30171 PG 10 WC Oncology SC Oncology GA EC6ZF UT WOS:000388284500019 PM 27391586 ER PT J AU Halasz, LM Uno, H Punglia, RS AF Halasz, Lia M. Uno, Hajime Punglia, Rinaa S. TI Reply to Comparative Effectiveness of Stereotactic Radiosurgery Versus Whole-Brain Radiation Therapy for Patients With Brain Metastases From Breast or Non-Small Cell Lung Cancer SO CANCER LA English DT Letter ID ONCOLOGY GROUP; STRATEGIES C1 [Halasz, Lia M.] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Halasz, LM (reprint author), Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2016 VL 122 IS 20 BP 3244 EP 3245 DI 10.1002/cncr.30187 PG 3 WC Oncology SC Oncology GA EC6ZF UT WOS:000388284500023 PM 27391929 ER PT J AU McArdel, SL Brown, DR Sobel, RA Sharpe, AH AF McArdel, Shannon L. Brown, Daniel R. Sobel, Raymond A. Sharpe, Arlene H. TI Anti-CD48 Monoclonal Antibody Attenuates Experimental Autoimmune Encephalomyelitis by Limiting the Number of Pathogenic CD4(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; NATURAL-KILLER; GAMMA-CHAIN; LIGAND CD48; MURINE CD2; IN-VIVO; RECEPTOR; IMMUNITY; MICE AB CD48 (SLAMF2) is an adhesion and costimulatory molecule constitutively expressed on hematopoietic cells. Polymorphisms in CD48 have been linked to susceptibility to multiple sclerosis (MS), and altered expression of the structurally related protein CD58 (LFA-3) is associated with disease remission in MS. We examined CD48 expression and function in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that a subpopulation of CD4(+) T cells highly upregulated CD48 expression during EAE and were enriched for pathogenic CD4(+) T cells. These CD48(++)CD4(+) T cells were predominantly CD44(+) and Ki67(+), included producers of IL-17A, GM-CSF, and IFN-gamma, and were most of the CD4(+) T cells in the CNS. Administration of anti-CD48 mAb during EAE attenuated clinical disease, limited accumulation of lymphocytes in the CNS, and reduced the number of pathogenic cytokine-secreting CD4(+) T cells in the spleen at early time points. These therapeutic effects required CD48 expression on CD4(+) T cells but not on APCs. Additionally, the effects of anti-CD48 were partially dependent on FcgRs, as anti-CD48 did not ameliorate EAE or reduce the number of cytokine-producing effector CD4(+) T cells in Fc epsilon r1 gamma(-/-) mice or in wild-type mice receiving anti-CD16/CD32 mAb. Our data suggest that anti-CD48 mAb exerts its therapeutic effects by both limiting CD4(+) T cell proliferation and preferentially eliminating pathogenic CD48(++) CD4(+) T cells during EAE. Our findings indicate that high CD48 expression is a feature of pathogenic CD4(+) T cells during EAE and point to CD48 as a potential target for immunotherapy. C1 [McArdel, Shannon L.; Brown, Daniel R.; Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [McArdel, Shannon L.; Brown, Daniel R.; Sharpe, Arlene H.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [McArdel, Shannon L.; Brown, Daniel R.; Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Brown, Daniel R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Sobel, Raymond A.] Palo Alto Vet Adm Hlth Care Syst, Palo Alto, CA 94304 USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. RP Sharpe, AH (reprint author), Harvard Med Sch, 77 Ave Louis Pasteur,NRB-837, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU NIAID NIH HHS [P01 AI065687] NR 45 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2016 VL 197 IS 8 BP 3038 EP 3048 DI 10.4049/jimmunol.1600706 PG 11 WC Immunology SC Immunology GA EC2PF UT WOS:000387965100008 PM 27581174 ER PT J AU Chen, L Zhao, LJ Alt, FW Krangel, MS AF Chen, Liang Zhao, Lijuan Alt, Frederick W. Krangel, Michael S. TI An Ectopic CTCF Binding Element Inhibits Tcrd Rearrangement by Limiting Contact between V delta and D delta Gene Segments SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KAPPA INTERVENING REGION; HEAVY-CHAIN GENE; V(D)J RECOMBINATION; CHROMATIN ARCHITECTURE; LOCUS CONTRACTION; ALPHA REPERTOIRES; ENHANCER; GENOME; ACCESSIBILITY; INSULATOR AB Chromatin looping mediated by the CCCTC binding factor (CTCF) regulates V(D)J recombination at Ag receptor loci. CTCF-mediated looping can influence recombination signal sequence (RSS) accessibility by regulating enhancer activation of germline promoters. CTCF-mediated looping has also been shown to limit directional tracking of the RAG recombinase along chromatin, and to regulate long-distance interactions between RSSs, independent of the RAG recombinase. However, in all prior instances in which CTCF-mediated looping was shown to influence V(D)J recombination, it was not possible to fully resolve the relative contributions to the V(D)J recombination phenotype of changes in accessibility, RAG tracking, and RAG-independent long-distance interactions. In this study, to assess mechanisms by which CTCF-mediated looping can impact V(D)J recombination, we introduced an ectopic CTCF binding element (CBE) immediately downstream of E delta in the murine Tcra-Tcrd locus. The ectopic CBE impaired inversional rearrangement of Trdv5 in the absence of measurable effects on Trdv5 transcription and chromatin accessibility. The ectopic CBE also limited directional RAG tracking from the Tcrd recombination center, demonstrating that a single CBE can impact the distribution of RAG proteins along chromatin. However, such tracking cannot account for Trdv5-to-Trdd2 inversional rearrangement. Rather, the defect in Trdv5 rearrangement could only be attributed to a reconfigured chromatin loop organization that limited RAG-independent contacts between the Trdv5 and Trdd2 RSSs. We conclude that CTCF can regulate V(D)J recombination by segregating RSSs into distinct loop domains and inhibiting RSS synapsis, independent of any effects on transcription, RSS accessibility, and RAG tracking. C1 [Chen, Liang; Krangel, Michael S.] Duke Univ, Med Ctr, Dept Immunol, Campus Box 3010, Durham, NC 27710 USA. [Zhao, Lijuan; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Zhao, Lijuan; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Zhao, Lijuan; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Krangel, MS (reprint author), Duke Univ, Med Ctr, Dept Immunol, Campus Box 3010, Durham, NC 27710 USA. EM krang001@mc.duke.edu FU NIAID NIH HHS [R01 AI020047]; NIGMS NIH HHS [R01 GM041052, R37 GM041052] NR 41 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2016 VL 197 IS 8 BP 3188 EP 3197 DI 10.4049/jimmunol.1601124 PG 10 WC Immunology SC Immunology GA EC2PF UT WOS:000387965100022 PM 27613698 ER PT J AU Garcia-Diaz, M Huang, YY Hamblin, MR AF Garcia-Diaz, Maria Huang, Ying-Ying Hamblin, Michael R. TI Use of fluorescent probes for ROS to tease apart Type I and Type II photochemical pathways in photodynamic therapy SO METHODS LA English DT Article DE Photodynamic therapy; Singlet oxygen; Hydroxyl radical; Singlet oxygen sensor green; Hydroxyphenyl fluorescein; Fullerenes; Bacteriochlorins; Phenothiazinium salts ID STABLE SYNTHETIC BACTERIOCHLORINS; SINGLET OXYGEN LUMINESCENCE; SPIN-RESONANCE SPECTROSCOPY; REACTIVE OXYGEN; ESCHERICHIA-COLI; MALIGNANT-TUMORS; METHYLENE-BLUE; LIVING CELLS; RADICALS; VIVO AB Photodynamic therapy involves the excitation of a non-toxic dye by harmless visible light to produce a long-lived triplet state that can interact with molecular oxygen to produce reactive oxygen species (ROS), which can damage biomolecules and kill cells. ROS produced by electron transfer (Type 1) include superoxide, hydrogen peroxide and hydroxyl radical (Ha), while singlet oxygen (O-1(2)) is produced by energy transfer. Diverse methods exist to distinguish between these two pathways, some of which are more specific or more sensitive than others. In this review we cover the use of two fluorescence probes: singlet oxygen sensor green (SOSG) detects O-1(2); and 4-hydroxyphenyl-fluorescein (HPF) that detects Ha. Interesting data was collected concerning the photochemical pathways of functionalized fullerenes compared to tetrapyrroles, stable synthetic bacteriochlorins with and without central metals, phenothiazinium dyes interacting with inorganic salts such as azide. (C) 2016 Elsevier Inc. All rights reserved. C1 [Garcia-Diaz, Maria] Univ Copenhagen, Dept Pharm, Uinv Pk 2, DK-2100 Copenhagen, Denmark. [Huang, Ying-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Ying-Ying; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01AI050875] FX MRH was supported by US NIH R01AI050875. NR 75 TC 1 Z9 1 U1 21 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD OCT 15 PY 2016 VL 109 BP 158 EP 166 DI 10.1016/j.ymeth.2016.06.025 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA9TW UT WOS:000386988600018 PM 27374076 ER PT J AU Wiley, CA Bissel, SJ Lesniak, A Dixon, CE Franks, J Stolz, DB Sun, M Wang, GJ Switzer, R Kochanek, PM Murdoch, G AF Wiley, Clayton A. Bissel, Stephanie J. Lesniak, Andrew Dixon, C. Edward Franks, Jonathan Stolz, Donna Beer Sun, Ming Wang, Guoji Switzer, Robert Kochanek, Patrick M. Murdoch, Geoffrey TI Ultrastructure of Diaschisis Lesions after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE axonal injury; controlled cortical impact; electron microscopy; light microscopy; TBI ID CROSSED CEREBELLAR ATROPHY; CONTROLLED CORTICAL IMPACT; LATERAL GENICULATE-NUCLEUS; AXONAL INJURY; HEAD-INJURY; NEUROFILAMENT COMPACTION; NEURONAL DEGENERATION; CEREBRAL HEMIATROPHY; CELL-DEATH; APOPTOSIS AB We used controlled cortical impact in mice to model human traumatic brain injury (TBI). Local injury was accompanied by distal diaschisis lesions that developed within brain regions anatomically connected to the injured cortex. At 7 days after injury, histochemistry documented broadly distributed lesions, particularly in the contralateral cortex and ipsilateral thalamus and striatum. Reactive astrocytosis and microgliosis were noted in multiple neural pathways that also showed silver-stained cell processes and bodies. Wisteria floribunda agglutinin (WFA) staining, a marker of perineuronal nets, was substantially diminished in the ipsilateral, but less so in the contralateral cortex. Contralateral cortical silver positive diaschisis lesions showed loss of both phosphorylated and unphosphorylated neurofilament staining, but overall preservation of microtubule-associated protein (MAP)-2 staining. Thalamic lesions showed substantial loss of MAP-2 and unphosphorylated neurofilaments in addition to moderate loss of phosphorylated neurofilament. One animal demonstrated contralateral cerebellar degeneration at 7 days post-injury. After 21 days, the gliosis had quelled, however persistent silver staining was noted. Using a novel serial section technique, we were able to perform electron microscopy on regions fully characterized at the light microscopy level. Cell bodies and processes that were silver positive at the light microscopy level showed hydropic disintegration consisting of: loss of nuclear heterochromatin; dilated somal and neuritic processes with a paucity of filaments, tubules, and mitochondria; and increased numbers of electron-dense membranous structures. Importantly the cell membrane itself was still intact 3 weeks after injury. Although the full biochemical nature of these lesions remains to be deciphered, the morphological preservation of damaged neurons and processes raises the question of whether this is a reversible process. C1 [Wiley, Clayton A.; Bissel, Stephanie J.; Lesniak, Andrew; Wang, Guoji; Murdoch, Geoffrey] Univ Pittsburgh, Dept Pathol, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Dixon, C. Edward; Kochanek, Patrick M.] Univ Pittsburgh, Dept Neurosurg, Anesthesiol, Phys Med, Pittsburgh, PA 15213 USA. [Kochanek, Patrick M.] Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA. [Kochanek, Patrick M.] Univ Pittsburgh, Rehabil & Crit Care Med, Pittsburgh, PA 15213 USA. [Franks, Jonathan; Stolz, Donna Beer; Sun, Ming] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA 15213 USA. [Dixon, C. Edward; Kochanek, Patrick M.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Dixon, C. Edward; Kochanek, Patrick M.] Safar Ctr Resuscitat Res, Pittsburgh, PA USA. [Switzer, Robert] NeuroSci Associates, Knoxville, TN USA. RP Wiley, CA (reprint author), Univ Pittsburgh, Dept Pathol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM wileyca@upmc.edu FU NINDS NIH HHS [R01 NS079061] NR 63 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD OCT 15 PY 2016 VL 33 IS 20 BP 1866 EP 1882 DI 10.1089/neu.2015.4272 PG 17 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EA6YO UT WOS:000386775300007 PM 26914973 ER PT J AU Xing, CH McCarthy, JM Dupuis, J Cupples, LA Meigs, JB Lin, XH Allen, AS AF Xing, Chuanhua McCarthy, Janice M. Dupuis, Josee Cupples, L. Adrienne Meigs, James B. Lin, Xihong Allen, Andrew S. TI Robust analysis of secondary phenotypes in case-control genetic association studies SO STATISTICS IN MEDICINE LA English DT Article DE case-control; estimating equation; inverse-probability-weighted; secondary phenotype; genetic association study ID BODY-MASS INDEX; FASTING BLOOD-GLUCOSE; ADULT HUMAN HEIGHT; COMMON VARIANT; LOCI; INITIATION; CHILDHOOD; OBESITY; DISEASE; RISK AB The case-control study is a common design for assessing the association between genetic exposures and a disease phenotype. Though association with a given (case-control) phenotype is always of primary interest, there is often considerable interest in assessing relationships between genetic exposures and other (secondary) phenotypes. However, the case-control sample represents a biased sample from the general population. As a result, if this sampling framework is not correctly taken into account, analyses estimating the effect of exposures on secondary phenotypes can be biased leading to incorrect inference. In this paper, we address this problem and propose a general approach for estimating and testing the population effect of a genetic variant on a secondary phenotype. Our approach is based on inverse probability weighted estimating equations, where the weights depend on genotype and the secondary phenotype. We show that, though slightly less efficient than a full likelihood-based analysis when the likelihood is correctly specified, it is substantially more robust to model misspecification, and can out-perform likelihood-based analysis, both in terms of validity and power, when the model is misspecified. We illustrate our approach with an application to a case-control study extracted from the Framingham Heart Study. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Xing, Chuanhua; Dupuis, Josee; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [McCarthy, Janice M.; Allen, Andrew S.] Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Dupuis, Josee; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Lin, Xihong] Harvard Univ, Dept Biostat, Cambridge, MA 01238 USA. [Allen, Andrew S.] Duke Univ, Ctr Human Genome Variat, Durham, NC 27710 USA. RP Allen, AS (reprint author), Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. EM andrew.s.allen@duke.edu OI Dupuis, Josee/0000-0003-2871-3603 FU NIH [R01 DK078616, R01 MH084680] FX JBM and JD acknowledge funding through NIH grant R01 DK078616. ASA and CX acknowledge funding through NIH grant R01 MH084680. NR 20 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2016 VL 35 IS 23 BP 4226 EP 4237 DI 10.1002/sim.6976 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DW5YC UT WOS:000383722600010 PM 27241694 ER PT J AU Barton, JP De Leonardis, E Coucke, A Cocco, S AF Barton, J. P. De Leonardis, E. Coucke, A. Cocco, S. TI ACE: adaptive cluster expansion for maximum entropy graphical model inference SO BIOINFORMATICS LA English DT Article AB Motivation: Graphical models are often employed to interpret patterns of correlations observed in data through a network of interactions between the variables. Recently, Ising/Potts models, also known as Markov random fields, have been productively applied to diverse problems in biology, including the prediction of structural contacts from protein sequence data and the description of neural activity patterns. However, inference of such models is a challenging computational problem that cannot be solved exactly. Here, we describe the adaptive cluster expansion (ACE) method to quickly and accurately infer Ising or Potts models based on correlation data. ACE avoids overfitting by constructing a sparse network of interactions sufficient to reproduce the observed correlation data within the statistical error expected due to finite sampling. When convergence of the ACE algorithm is slow, we combine it with a Boltzmann Machine Learning algorithm (BML). We illustrate this method on a variety of biological and artificial datasets and compare it to state-of-the-art approximate methods such as Gaussian and pseudo-likelihood inference. Results: We show that ACE accurately reproduces the true parameters of the underlying model when they are known, and yields accurate statistical descriptions of both biological and artificial data. Models inferred by ACE more accurately describe the statistics of the data, including both the constrained low-order correlations and unconstrained higher-order correlations, compared to those obtained by faster Gaussian and pseudo-likelihood methods. These alternative approaches can recover the structure of the interaction network but typically not the correct strength of interactions, resulting in less accurate generative models. C1 [Barton, J. P.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Barton, J. P.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Barton, J. P.] Massachusetts Inst Technol & Harvard, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [De Leonardis, E.; Cocco, S.] Ecole Normale Super, CNRS, Lab Phys Stat, Paris, France. [De Leonardis, E.; Coucke, A.; Cocco, S.] Univ P&M Curie, Paris, France. [De Leonardis, E.; Coucke, A.] Sorbonne Univ, Computat & Quantitat Biol, UPMC, UMR 7238, Paris, France. [Coucke, A.] Ecole Normale Super, CNRS, Phys Theor Lab, Paris, France. RP Barton, JP (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Barton, JP (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Barton, JP (reprint author), Massachusetts Inst Technol & Harvard, Ragon Inst, Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Cocco, S (reprint author), Ecole Normale Super, CNRS, Lab Phys Stat, Paris, France.; Cocco, S (reprint author), Univ P&M Curie, Paris, France. EM jpbarton@mit.edu; cocco@lps.ens.fr FU Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; Institute des Systemes Complexes (ISC-PIF); Region Ile-de-France; Coevstat [ANR-13-BS04-0012-01] FX J.B. is funded by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard. A.C. is funded by the Institute des Systemes Complexes (ISC-PIF) and the Region Ile-de-France. S.C. is funded by ANR-13-BS04-0012-01 (Coevstat). NR 43 TC 6 Z9 6 U1 7 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD OCT 15 PY 2016 VL 32 IS 20 BP 3089 EP 3097 DI 10.1093/bioinformatics/btw328 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DZ7CD UT WOS:000386020700006 PM 27329863 ER PT J AU Younossi, ZM Stepanova, M Sulkowski, M Foster, GR Reau, N Mangia, A Patel, K Brau, N Roberts, SK Afdhal, N Nader, F Henry, L Hunt, S AF Younossi, Zobair M. Stepanova, Maria Sulkowski, Mark Foster, Graham R. Reau, Nancy Mangia, Alessandra Patel, Keyur Brau, Norbert Roberts, Stuart K. Afdhal, Nezam Nader, Fatema Henry, Linda Hunt, Sharon TI Ribavirin-Free Regimen With Sofosbuvir and Velpatasvir Is Associated With High Efficacy and Improvement of Patient-Reported Outcomes in Patients With Genotypes 2 and 3 Chronic Hepatitis C: Results From Astral-2 and-3 Clinical Trials SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE health-related quality of life; fatigue; work productivity; hepatitis C; direct-acting antivirals ID QUALITY-OF-LIFE; TELAPREVIR COMBINATION TREATMENT; TREATMENT-NAIVE PATIENTS; WORK PRODUCTIVITY; ANTIVIRAL REGIMENS; INSULIN-RESISTANCE; PLUS SOFOSBUVIR; VIRUS-INFECTION; LIVER-DISEASE; HCV AB Background. Until recently, the approved treatment regimens for patients with hepatitis C virus (HCV) genotypes (GTs) 2 and 3 contain sofosbuvir (SOF) and ribavirin (RBV) for 12 or 24 weeks. The impact of RBV-free pan-genotypic regimen with SOF and velpatasvir (SOF/VEL) on patient-reported outcomes (PROs) of patients with genotype 2 and 3 has not been described. Methods. PROs data were collected from participants of ASTRAL-2 and ASTRAL-3 studies before, during, and after treatment using 4 PRO instruments (Short Form-36, Chronic Liver Disease Questionnaire-HCV, Functional Assessment of Chronic Illness Therapy-Fatigue, and Work Productivity and Activity Index: Specific Health Problem), and compared between the SOF/VEL and SOF + RBV groups. Results. A total of 818 HCV patients were included: 78% treatment naive, 25% cirrhosis. The rates of nearly all adverse events were lower in the RBV-free SOF/VEL group (all P<.03). The SOF/VEL group also experienced improvement of their PROs by treatment week 4 (+1.8% on average across all PROs), which continued throughout treatment (+4.1%) and post-treatment (+5.5%). In contrast, those in the SOF + RBV group had a modest decline in their PROs starting at treatment week 4 (up to -3.7%), which lasted until the end of treatment (up to -6.4%). In multiple regression analysis, the association of a treatment regimen with end-of-treatment PROs was significant for nearly all PROs; the average beta was +5.0% for the use of SOF/VEL (reference: SOF + RBV). Conclusions. Patients receiving ribavirin-free SOF/VEL reported significantly better PRO scores during treatment compared with those receiving the RBV-containing regimen. Furthermore, the interferon-and ribavirin-free SOF/VEL regimen resulted in a rapid improvement of PROs in HCV GTs 2 and 3 patients during treatment and after achieving sustained virologic response. C1 [Younossi, Zobair M.; Nader, Fatema; Henry, Linda; Hunt, Sharon] Inova Fairfax Hosp, Dept Med, Ctr Liver Dis, Falls Church, VA USA. [Stepanova, Maria] Ctr Outcomes Res Liver Dis, Washington, DC USA. [Sulkowski, Mark] Johns Hopkins Univ, Baltimore, MD USA. [Foster, Graham R.] Queen Mary Univ London, London, England. [Reau, Nancy] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Mangia, Alessandra] Casa Sollievo Sofferenza Hosp, San Giovanni Rotondo, Italy. [Patel, Keyur] Univ Toronto Hlth Network, Toronto, ON, Canada. [Brau, Norbert] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Roberts, Stuart K.] Alfred Hlth, Melbourne, Vic, Australia. [Roberts, Stuart K.] Monash Univ, Melbourne, Vic, Australia. [Afdhal, Nezam] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Younossi, ZM (reprint author), Betty & Guy Beatty Ctr Integrated Res, Claude Moore Hlth Educ & Res Bldg,3300 Gallows Rd, Falls Church, VA 22042 USA. EM zobair.younossi@inova.org FU Gilead Sciences FX M. S., G. F., N. R., A. M., K. P., N. B., S. K. R., and N. A. have received research support and/or on advisory board or consultant to Gilead Sciences. NR 45 TC 5 Z9 5 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2016 VL 63 IS 8 BP 1042 EP 1048 DI 10.1093/cid/ciw496 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ7KN UT WOS:000386044400010 PM 27444413 ER PT J AU Mukerji, SS Locascio, JJ Misra, V Lorenz, DR Holman, A Dutta, A Penugonda, S Wolinsky, SM Gabuzda, D AF Mukerji, Shibani S. Locascio, Joseph J. Misra, Vikas Lorenz, David R. Holman, Alex Dutta, Anupriya Penugonda, Sudhir Wolinsky, Steven M. Gabuzda, Dana TI Lipid Profiles and APOE4 Allele Impact Midlife Cognitive Decline in HIV-Infected Men on Antiretroviral Therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV-1; aging; APOE; cholesterol; cognitive decline ID APOLIPOPROTEIN E4 GENOTYPE; VASCULAR RISK-FACTORS; NEUROCOGNITIVE DISORDERS; ALZHEIMER-DISEASE; DEMENTIA; EPSILON-4; AGE; ASSOCIATION; IMPAIRMENT; ACTIVATION AB Background. Dyslipidemia and apolipoprotein E4 (APOE epsilon 4) allele are risk factors for age-related cognitive decline, but how these risks are modified by human immunodeficiency virus (HIV) infection is unclear. Methods. In a longitudinal nested study from the Multicenter AIDS Cohort Study, 273 HIV type 1-infected (HIV+) men aged 50-65 years with baseline HIV RNA <400 copies/mL and on continuous antiretroviral therapy (ART) in >= 95% of follow-up visits were matched by sociodemographic variables to 516 HIV-uninfected (HIV-) controls. The association between lipid markers (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), APOE genotype, and cognitive decline in HIV infection was examined using mixed-effects models. Results. The median baseline age of participants was 51, 81% were white, and 89% had education >12 years. HIV+ men had similar baseline total cholesterol and LDL-C, but lower HDL-C and higher triglycerides than controls (P<.001). Higher total cholesterol and LDL-C were associated with faster rates of cognitive decline (P<.01), whereas higher HDL-C attenuated decline (P=.02) in HIV+ men. In HIV+ men with elevated cholesterol, statin use was associated with a slower estimated rate of decline (P=.02). APOE epsilon 4 genotype accelerated cognitive decline in HIV+ but not HIV- men (P=.01), with trajectories diverging from HIV - epsilon 4 carriers after age 50. Total cholesterol levels did not modify the association of epsilon 4 genotype with decline (P=.9). Conclusions. Elevated cholesterol and APOE e4 genotype are independent risk factors for cognitive decline in ART-adherent HIV+ men aged >50 years. Treatment of dyslipidemia may be an effective strategy to reduce cognitive decline in older HIV+ individuals. C1 [Mukerji, Shibani S.; Misra, Vikas; Lorenz, David R.; Holman, Alex; Dutta, Anupriya; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Mukerji, Shibani S.; Locascio, Joseph J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Penugonda, Sudhir; Wolinsky, Steven M.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Ctr Life Sci, Dept Canc Immunol & Virol, 1010,450 Brookline Ave, Boston, MA 02215 USA. EM dana_gabuzda@dfci.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, UM1-AI35043]; National Cancer Institute, National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH); Johns Hopkins University Clinical and Translational Science Award [UL1-TR000424]; NIMH [RO1 MH097659]; NIDA [RO1 DA028994]; National Institute on Aging [T32-AG000222]; NIH Clinical and Translational Science Award [1UL1-TR001102] FX The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (grant numbers U01-AI35039, U01-AI35040; U01-AI35041; U01-AI35042; and UM1-AI35043), with additional co-funding from the National Cancer Institute, National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH). MACS data collection is also supported by UL1-TR000424 (Johns Hopkins University Clinical and Translational Science Award). The website is located at http://www.statepi.jhsph.edu/macs/macs.html. This work was supported by the NIMH (RO1 MH097659) and NIDA (RO1 DA028994) to D. G. Training and educational support for S. S. M. and A. D. was provided by National Institute on Aging award T32-AG000222. Additional support for S. S. M. included the Harvard Catalyst Master's Program in Clinical and Translational Investigation funded by the NIH Clinical and Translational Science Award Program (1UL1-TR001102), and Catalyst Biostatistical Consultation with contributions from Harvard Medical School and affiliated hospitals. NR 38 TC 1 Z9 1 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2016 VL 63 IS 8 BP 1130 EP 1139 DI 10.1093/cid/ciw495 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ7KN UT WOS:000386044400023 PM 27448678 ER PT J AU Chalmers, JD Reyes, LF Aliberti, S Restrepo, MI AF Chalmers, James D. Reyes, Luis F. Aliberti, Stefano Restrepo, Marcos I. TI Empirical Coverage of Methicillin-Resistant Staphylococcus aureus in Community-Acquired Pneumonia: Those Who Do Not Remember the Past Are Doomed to Repeat It SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID CARE-ASSOCIATED PNEUMONIA; PATHOGENS C1 [Chalmers, James D.] Univ Dundee, Sch Med, Dundee DD1 4HN, Scotland. [Reyes, Luis F.; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. [Reyes, Luis F.; Restrepo, Marcos I.] Audie L Murphy Mem VA Hosp, South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Aliberti, Stefano] Univ Milan, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy. [Aliberti, Stefano] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Cardiothorac Unit, Milan, Italy. [Aliberti, Stefano] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Adult Cyst Fibrosis Ctr, Milan, Italy. RP Restrepo, MI (reprint author), Audie L Murphy Mem VA Hosp, South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM restrepom@uthscsa.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2016 VL 63 IS 8 BP 1145 EP U182 DI 10.1093/cid/ciw464 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ7KN UT WOS:000386044400028 PM 27402822 ER PT J AU Walter, ND de Jong, BC Garcia, BJ Dolganov, GM Worodria, W Byanyima, P Musisi, E Huang, L Chan, ED Van, TT Antonio, M Ayorinde, A Kato-Maeda, M Nahid, P Leung, AM Yen, A Fingerlin, TE Kechris, K Strong, M Voskuil, MI Davis, JL Schoolnik, GK AF Walter, Nicholas D. de Jong, Bouke C. Garcia, Benjamin J. Dolganov, Gregory M. Worodria, William Byanyima, Patrick Musisi, Emmanuel Huang, Laurence Chan, Edward D. Van, Tran T. Antonio, Martin Ayorinde, Abigail Kato-Maeda, Midori Nahid, Payam Leung, Ann M. Yen, Andrew Fingerlin, Tasha E. Kechris, Katerina Strong, Michael Voskuil, Martin I. Davis, J. Lucian Schoolnik, Gary K. TI Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/physiology; sputum/microbiology; tuberculosis; pulmonary/epidemiology; acquired immunodeficiency syndrome/immunology ID NITRIC-OXIDE; TRANSCRIPTIONAL ADAPTATION; ALTERNATIVE ACTIVATION; PULMONARY TUBERCULOSIS; DORMANCY REGULON; GENE-EXPRESSION; LUNG GRANULOMAS; DOSR REGULON; MOUSE MODEL; MACROPHAGES AB Background. It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis in vivo. We evaluated the impact of host immunity by comparing M. tuberculosis and human gene transcription in sputum between human immunodeficiency virus (HIV)-infected and uninfected patients with tuberculosis. Methods. We collected sputum specimens before treatment from Gambians and Ugandans with pulmonary tuberculosis, revealed by positive results of acid-fast bacillus smears. We quantified expression of 2179 M. tuberculosis genes and 234 human immune genes via quantitative reverse transcription-polymerase chain reaction. We summarized genes from key functional categories with significantly increased or decreased expression. Results. A total of 24 of 65 patients with tuberculosis were HIV infected. M. tuberculosis DosR regulon genes were less highly expressed among HIV-infected patients with tuberculosis than among HIV-uninfected patients with tuberculosis (Gambia, P < .0001; Uganda, P = .037). In profiling of human genes from the same sputa, HIV-infected patients had 3.4-fold lower expression of IFNG (P = .005), 4.9-fold higher expression of ARG1 (P = .0006), and 3.4-fold higher expression of IL10 (P = .0002) than in HIV-uninfected patients with tuberculosis. Conclusions. M. tuberculosis in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by NO, carbon monoxide, and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages, with consequent decreased NO expression and/or by poor granuloma formation with consequent decreased hypoxic stress. C1 [Walter, Nicholas D.; Chan, Edward D.] Denver Vet Affairs Med Ctr, Pulm Sect, Denver, CO USA. [Walter, Nicholas D.; Garcia, Benjamin J.; Fingerlin, Tasha E.; Strong, Michael] Integrated Ctr Genes Environm & Hlth, Denver, CO USA. [Chan, Edward D.] Natl Jewish Hlth, Dept Acad Affairs & Med, Denver, CO USA. [Walter, Nicholas D.; Chan, Edward D.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Anschutz Med Campus, Aurora, CO USA. [Garcia, Benjamin J.; Strong, Michael] Univ Colorado Denver, Computat Biosci Program, Anschutz Med Campus, Aurora, CO USA. [Voskuil, Martin I.] Univ Colorado Denver, Dept Immunol & Microbiol, Anschutz Med Campus, Aurora, CO USA. [Kechris, Katerina] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. [de Jong, Bouke C.] NYU, New York, NY USA. [Dolganov, Gregory M.; Van, Tran T.; Schoolnik, Gary K.] Stanford Univ, Med Ctr, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Leung, Ann M.] Stanford Univ, Med Ctr, Dept Radiol, Stanford, CA 94305 USA. [Huang, Laurence; Kato-Maeda, Midori; Nahid, Payam] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Huang, Laurence] Univ Calif San Francisco, HIV AIDS Div, San Francisco, CA 94143 USA. [Yen, Andrew] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Davis, J. Lucian] Yale Sch Med, Dept Epidemiol Microbial Dis, New Haven, CT USA. [Davis, J. Lucian] Yale Sch Med, Dept Pulm Crit Care & Sleep Med, New Haven, CT USA. [de Jong, Bouke C.] Inst Trop Med, Antwerp, Belgium. [de Jong, Bouke C.; Antonio, Martin; Ayorinde, Abigail] MRC Labs, Serrekunda, Gambia. [Worodria, William; Byanyima, Patrick; Musisi, Emmanuel] Makerere Univ, UCSF Res Collaborat, Kampala, Uganda. RP Walter, ND (reprint author), Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Res 2, Anschutz Med Campus,Box C272,9th Flr, Aurora, CO 80045 USA. EM nicholas.walter@ucdenver.edu FU European Research Council [INTERRUPTB 311725]; National Institutes of Health [UL1 RR025780, 2T15LM009451-06, R21AI101714, K23AI080147, K24HL087713, R01HL090335, 5R01AI104589, 2RO1 AI061505]; Veteran's Administration [CDA1IK2CX000914-01A1]; Boettcher Foundation Webb Waring Award FX This work was supported by the European Research Council Starting (grant INTERRUPTB 311725 to B. C. d. J.), the National Institutes of Health (grants UL1 RR025780 and 2T15LM009451-06 [to B. J. G.], R21AI101714 [to J. L. D.], K23AI080147 [to J. L. D.], K24HL087713 [to L. H.], R01HL090335 [to L. H.], 5R01AI104589 [to P. N.], and 2RO1 AI061505 [to M. I. V.]), the Veteran's Administration (CDA1IK2CX000914-01A1 to N. D. W.), and a Boettcher Foundation Webb Waring Award (to M. S.). NR 42 TC 2 Z9 2 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 IS 8 BP 1205 EP 1211 DI 10.1093/infdis/jiw364 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8UL UT WOS:000386147200016 PM 27534685 ER PT J AU Elphinstone, RE Conroy, AL Hawkes, M Hermann, L Namasopo, S Warren, HS John, CC Liles, WC Kain, KC AF Elphinstone, Robyn E. Conroy, Andrea L. Hawkes, Michael Hermann, Laura Namasopo, Sophie Warren, H. Shaw John, Chandy C. Liles, W. Conrad Kain, Kevin C. TI Alterations in Systemic Extracellular Heme and Hemopexin Are Associated With Adverse Clinical Outcomes in Ugandan Children With Severe Malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE severe malaria; heme; hemopexin; metabolic acidosis; anemia; respiratory distress; acute kidney injury; pediatric ID ACUTE KIDNEY INJURY; PLASMODIUM-FALCIPARUM MALARIA; AFRICAN CHILDREN; CEREBRAL MALARIA; RANDOMIZED-TRIAL; DISEASE; PATHOGENESIS; ACTIVATION; PRODUCTS; THERAPY AB Background. Malaria remains a major cause of global mortality. Extracellular heme, released during malaria-induced hemolysis, mediates a number of pathogenic processes associated with vascular and organ injury. Hemopexin (hpx) facilitates the degradation of extracellular heme. In this study, we explore the hypothesis that dysregulation of the heme-hpx axis is associated with disease severity, acute kidney injury (AKI), and outcome. Methods. Plasma levels of hemin and hpx (at admission, day 3, and day 14) were assessed in children with severe malaria in Jinja, Uganda. Results. The ratio of heme to hpx was higher at admission and decreased with recovery (median, 0.043 [interquartile range {IQR}, 0.007-0.239] on day 1, 0.024 [IQR, 0.005-0.126] on day 3, and 0.008 [IQR, 0.002-0.022] on day 14; P < .001). Ratios of heme to hpx at admission were higher in children with as compared to those without severe anemia (median, 0.124 [IQR, 0.024-0.431] vs 0.016 [IQR, 0.003-0.073]; P < .0001), children with as compared to those without respiratory distress (median, 0.063 [IQR, 0.017-0.413] vs 0.020 [IQR, 0.004-0.124]; P < .01), and children with as opposed to those without stage 3 AKI (median, 0.354 [IQR, 0.123-2.481] vs 0.037 [IQR, 0.005-0.172], P < .01). The heme to hpx ratio at admission was associated with 6-month mortality (median, 0.148 [IQR, 0.042-0.500] vs 0.039 [IQR, 0.007-0.172]; P = .012). Conclusions. The ratio of heme to hpx is associated with disease severity and adverse clinical outcomes in Ugandan children, and dysregulation of the heme axis may contribute to malaria pathogenesis. C1 [Elphinstone, Robyn E.; Conroy, Andrea L.; Hawkes, Michael; Hermann, Laura; Kain, Kevin C.] Toronto Gen Hosp, Sandra Rotman Ctr Global Hlth, Univ Hlth Network, Toronto, ON, Canada. [Elphinstone, Robyn E.; Kain, Kevin C.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A1, Canada. [Kain, Kevin C.] Univ Toronto, Trop Dis Unit, Div Infect Dis, Dept Med, Toronto, ON M5S 1A1, Canada. [Hawkes, Michael] Univ Alberta, Div Pediat Infect Dis, Edmonton, AB, Canada. [Conroy, Andrea L.; John, Chandy C.] Indiana Univ, Dept Pediat, Indianapolis, IN 46204 USA. [Warren, H. Shaw] Massachusetts Gen Hosp, Dept Pediat, Infect Dis Unit, Boston, MA 02114 USA. [Liles, W. Conrad] Univ Washington, Dept Med, Seattle, WA USA. [Namasopo, Sophie] Jinja Reg Referral Hosp, Dept Pediat, Jinja, Uganda. RP Kain, KC (reprint author), MaRS Ctr, Sandra Rotman Ctr, Suite 10-351,Toronto Med Discovery Tower, Toronto, ON M5G 1L7, Canada. EM kevin.kain@uhn.ca FU Canadian Institute for Health Research (CIHR) [MOP-13721, MOP-136813, MOP-115160]; CIHR Foundation; clinician-scientist training award; Vanier Canada Graduate Scholarship; Canada Research Chair in Molecular Parasitology FX This work was supported by the Canadian Institute for Health Research (CIHR; MOP-13721, MOP-136813, MOP-115160, and CIHR Foundation grant to K. C. K.; MD/PhD studentship to R. E. E.; post-PhD fellowships to A. L. C. and L. H.; and clinician-scientist training award to M. H.); a Vanier Canada Graduate Scholarship (to R. E. E.); a kind donation from Kim Kertland; a kind donation from the Tesari Foundation; and a Canada Research Chair in Molecular Parasitology (to K. C. K.). NR 46 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2016 VL 214 IS 8 BP 1268 EP 1275 DI 10.1093/infdis/jiw357 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DZ8UL UT WOS:000386147200025 PM 27515862 ER PT J AU Corbo, JM Delellis, TM Hill, LG Rindfuss, SL Nashelsky, J AF Corbo, Jason M. Delellis, Teresa M. Hill, Lucas G. Rindfuss, Sarah L. Nashelsky, Joan TI ACE Inhibitors or ARBs to Prevent CKD in Patients with Microalbuminuria SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID DIABETES-MELLITUS C1 [Corbo, Jason M.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Delellis, Teresa M.] Univ Manchester, Coll Pharm Nat & Hlth Sci, Ft Wayne, IN USA. [Hill, Lucas G.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Rindfuss, Sarah L.] West Penn Hosp, Care Partner Clin, Allegheny Hlth Network, Pittsburgh, PA USA. [Nashelsky, Joan] Univ Iowa, Ctr Human Rights, Iowa City, IA USA. RP Corbo, JM (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM jason.Corbo@gmail.com NR 9 TC 0 Z9 0 U1 3 U2 3 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD OCT 15 PY 2016 VL 94 IS 8 BP 652 EP 653 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA DZ5PR UT WOS:000385914500006 PM 27929222 ER PT J AU Halpern, SD French, B Small, DS Saulsgiver, K Harhay, MO Audrain-McGovern, J Loewenstein, G Asch, DA Volpp, KG AF Halpern, Scott D. French, Benjamin Small, Dylan S. Saulsgiver, Kathryn Harhay, Michael O. Audrain-McGovern, Janet Loewenstein, George Asch, David A. Volpp, Kevin G. TI Heterogeneity in the Effects of Reward- and Deposit-based Financial Incentives on Smoking Cessation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE financial incentives; smoking cessation; behavior change; heterogeneity of treatment effect ID INSTRUMENTAL VARIABLES; TRIALS; SMOKERS; IDENTIFICATION; ABSTINENCE; DEPENDENCE; OUTCOMES; HEALTH; MODEL; RATES AB Rationale: Targeting different smoking cessation programs to smokers most likely to quit when using them could reduce the burden of lung disease. Objectives: To identify smokers most likely to quit using pure reward-based financial incentives or incentive programs requiring refundable deposits to become eligible for rewards. Methods: We conducted prespecified secondary analyses of a randomized trial in which 2,538 smokers were assigned to an $800 reward contingent on sustained abstinence from smoking, a refundable $150 deposit plus a $650 reward, or usual care. Measurements and Main Results: Using logistic regression, we identified characteristics of smokers that were most strongly associated with accepting their assigned intervention and ceasing smoking for 6 months. We assessed modification of the acceptance, efficacy, and effectiveness of reward and deposit programs by 11 prospectively selected demographic, smoking-related, and psychological factors. Predictors of sustained smoking abstinence differed among participants assigned to reward-versus deposit-based incentives. However, greater readiness to quit and less steep discounting of future rewards were consistently among the most important predictors. Deposit-based programs were uniquely effective relative to usual care among men, higher-income participants, and participants who more commonlyfailed to pay their bills (all interaction P values < 0.10). Relative to rewards, deposits were more effective among black persons (P = 0.022) and those who more commonly failed to pay their bills (P = 0.082). Relative to rewards, deposits were more commonly accepted by higher-income participants, men, white persons, and those who less commonly failed to pay their bills (all P < 0.05). Conclusions: Heterogeneity among smokers in their acceptance and response to different forms of incentives suggests potential benefits of targeting behavior-change interventions based on patient characteristics. C1 [Halpern, Scott D.; Asch, David A.; Volpp, Kevin G.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Halpern, Scott D.; French, Benjamin; Small, Dylan S.; Saulsgiver, Kathryn; Audrain-McGovern, Janet; Loewenstein, George; Asch, David A.; Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent & Behav Econ, Perelman Sch Med, Philadelphia, PA 19104 USA. [Halpern, Scott D.; French, Benjamin; Saulsgiver, Kathryn; Harhay, Michael O.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Halpern, Scott D.; Asch, David A.; Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Audrain-McGovern, Janet] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Small, Dylan S.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin G.] Univ Penn, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Loewenstein, George] Carnegie Mellon Univ, Ctr Behav Decis Res, Pittsburgh, PA 15213 USA. [Asch, David A.; Volpp, Kevin G.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Halpern, SD (reprint author), Univ Penn, Perelman Sch Med, 719 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM shalpern@exchange.upenn.edu OI Harhay, Michael/0000-0002-0553-674X FU National Institutes of Health [R01CA159932, RC2AG036592, F31HL127947] FX Supported by National Institutes of Health grants R01CA159932 (S.D.H.), RC2AG036592 (D.A.A. and K.G.V.), and F31HL127947 (M.O.H.) and by in-kind support from CVS Health. NR 38 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD OCT 15 PY 2016 VL 194 IS 8 BP 981 EP 988 DI 10.1164/rccm.201601-0108OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DY7VU UT WOS:000385338200013 PM 27064456 ER PT J AU Putcha, N Crainiceanu, C Norato, G Samet, J Quan, SF Gottlieb, DJ Redline, S Punjabi, NM AF Putcha, Nirupama Crainiceanu, Ciprian Norato, Gina Samet, Jonathan Quan, Stuart F. Gottlieb, Daniel J. Redline, Susan Punjabi, Naresh M. TI Influence of Lung Function and Sleep-disordered Breathing on All-Cause Mortality A Community-based Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sleep apnea; impaired lung function; mortality ID OBSTRUCTIVE PULMONARY-DISEASE; FOLLOW-UP; BUSSELTON-HEALTH; OVERLAP SYNDROME; POPULATION; APNEA; INDEX; RISK AB Rationale: Whether sleep-disordered breathing (SDB) severity and diminished lung function act synergistically to heighten the risk of adverse health outcomes remains a topic of significant debate. Objectives: The current study sought to determine whether the association between lower lung function and mortality would be stronger in those with increasing severity of SDB in a community based cohort of middle-aged and older adults. Methods: Full montage home sleep testing and spirometry data were analyzed on 6,173 participants of the Sleep Heart Health Study. Proportional hazards models were used to calculate risk for all-cause mortality, with FEV1 and apnea-hypopnea index (AHI) as the primary exposure indicators along with several potential confounders. Measurements and Main Results: All-cause mortality rate was 26.9 per 1,000 person-years in those with SDB (AHI events/h) and 18.2 per 1,000 person-years in those without (AHI <5 events/h). For every 200-ml decrease in FEV1, all-cause mortality increased by 11.0% in those without SDB (hazard ratio, 1.11; 95% confidence interval, 1.08-1.13). In contrast, for every 200-ml decrease in FEVI, all-cause mortality increased by only 6.0% in participants with SDB (hazard ratio, 1.06; 95% confidence interval, 1.04-1.09). Additionally, the incremental influence of lung function on all -cause mortality was less with increasing severity of SDB (P value for interaction between AHI and FEV1, 0.004). Conclusions: Lung function was associated with risk for all -cause mortality. The incremental contribution of lung function to mortality diminishes with increasing severity of SDB. C1 [Putcha, Nirupama; Crainiceanu, Ciprian; Norato, Gina; Punjabi, Naresh M.] Johns Hopkins Univ, Baltimore, MD USA. [Samet, Jonathan] Univ Southern Calif, Los Angeles, CA USA. [Quan, Stuart F.] Univ Arizona, Tucson, AZ USA. [Quan, Stuart F.; Gottlieb, Daniel J.; Redline, Susan] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Redline, Susan] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. RP Punjabi, NM (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM npunjabi@jhmi.edu FU NHLBI [U01HL53940, U01HL53941, U01HL53938, U01HL53916, U01HL53934, U01HL53931, U01HL53937, U01HL64360, U01HL63463, U01HL63429]; National Institutes of Health [K23-HL123594, R01 HL075078, R01 HL117167]; Johns Hopkins University School of Medicine Clinician Scientist Award FX The Sleep Heart Health Study was supported by NHLBI cooperative agreements U01HL53940 (University of Washington), U01HL53941 (Boston University), U01HL53938 (University of Arizona), U01HL53916 (University of California, Davis), U01HL53934 (University of Minnesota), U01HL53931 (New York University), U01HL53937 and U01HL64360 (Johns Hopkins University), U01HL63463 (Case Western Reserve University), and U01HL63429 (Missouri Breaks Research). N.P. is supported by National Institutes of Health grant K23-HL123594 and the Johns Hopkins University School of Medicine Clinician Scientist Award. N.M.P. is supported by National Institutes of Health grants R01 HL075078 and R01 HL117167. NR 22 TC 1 Z9 1 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD OCT 15 PY 2016 VL 194 IS 8 BP 1007 EP 1014 DI 10.1164/rccm.201511-2178OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DY7VU UT WOS:000385338200016 PM 27105053 ER PT J AU Manoach, DS Pan, JQ Purcell, SM Stickgold, R AF Manoach, Dara S. Pan, Jen Q. Purcell, Shaun M. Stickgold, Robert TI Reduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition? SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Cognition; Endophenotype; Genetics; Memory; Schizophrenia; Sleep; Spindles ID THALAMIC RETICULAR NUCLEUS; DEPENDENT MEMORY CONSOLIDATION; GENOME-WIDE ASSOCIATION; DIRECT-CURRENT STIMULATION; MAJOR DEPRESSIVE DISORDER; PLACEBO-CONTROLLED TRIAL; DE-NOVO MUTATIONS; SLOW-WAVE SLEEP; PSYCHIATRIC-DISORDERS; STAGE-2 SLEEP AB Although schizophrenia (SZ) is defined by waking phenomena, abnormal sleep is a common feature. In particular, there is accumulating evidence of a sleep spindle deficit. Sleep spindles, a defining thalamocortical oscillation of non-rapid eye movement stage 2 sleep, correlate with IQ and are thought to promote long-term potentiation and enhance memory consolidation. We review evidence that reduced spindle activity in SZ is an endophenotype that impairs sleep-dependent memory consolidation, contributes to symptoms, and is a novel treatment biomarker. Studies showing that spindles can be pharmacologically enhanced in SZ and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in patients with SZ may improve cognition. Spindle activity is highly heritable, and recent large-scale genome-wide association studies have identified SZ risk genes that may contribute to spindle deficits and illuminate their mechanisms. For example, the SZ risk gene CACNA1l encodes a calcium channel that is abundantly expressed in the thalamic spindle generator and plays a critical role in spindle activity based on a mouse knockout. Future genetic studies of animals and humans can delineate the role of this and other genes in spindles. Such cross-disciplinary research, by forging empirical links in causal chains from risk genes to proteins and cellular functions to endophenotypes, cognitive impairments, symptoms, and diagnosis, has the potential to advance the mechanistic understanding, treatment, and prevention of SZ. This review highlights the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of SZ and implicates reduced sleep spindles as a potentially treatable mechanism. C1 [Manoach, Dara S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Purcell, Shaun M.] Harvard Med Sch, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Analyt & Translat Genet Unit, Boston, MA USA. [Manoach, Dara S.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Manoach, Dara S.; Pan, Jen Q.; Purcell, Shaun M.; Stickgold, Robert] Broad Inst Harvard & Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Stickgold, Robert] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA USA. RP Manoach, DS (reprint author), Massachusetts Gen Hosp, 149 13th St,Room 1-111, Boston, MA 02129 USA. EM dara@nmr.mgh.harvard.edu FU National Institutes of Health [K24MH099421, R01 MH092638, R01MH048832, R21MH099448]; Stanley Research Center FX This work was supported by the National Institutes of Health Grant Nos. K24MH099421 (DSM), R01 MH092638 (DSM, RS), R01MH048832 (RS), and R21MH099448 (JQP) and Stanley Research Center (JQP). NR 150 TC 5 Z9 5 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2016 VL 80 IS 8 BP 599 EP 608 DI 10.1016/j.biopsych.2015.10.003 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0ED UT WOS:000385509400006 PM 26602589 ER PT J AU Eryilmaz, H AF Eryilmaz, Hamdi TI Revisiting the Inverted-U Hypothesis of Working Memory Activation in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID PREFRONTAL CORTEX; PERFORMANCE; DYSFUNCTION; NETWORK; BRAIN; TASK; FMRI C1 [Eryilmaz, Hamdi] Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2606, Charlestown, MA 02129 USA. [Eryilmaz, Hamdi] Harvard Med Sch, Charlestown, MA USA. RP Eryilmaz, H (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2606, Charlestown, MA 02129 USA. EM hamdi.eryilmaz@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2016 VL 80 IS 8 BP E67 EP E68 DI 10.1016/j.biopsych.2016.08.015 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DZ0ED UT WOS:000385509400012 PM 27663068 ER PT J AU Payabyab, EC Balasubramaniam, S Edgerly, M Velarde, M Merino, MJ Venkatesan, AM Leuva, H Litman, T Bates, SE Fojo, T AF Payabyab, Eden C. Balasubramaniam, Sanjeeve Edgerly, Maureen Velarde, Margarita Merino, Maria J. Venkatesan, Aradhana M. Leuva, Harshraj Litman, Thomas Bates, Susan E. Fojo, Tito TI Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters SO CLINICAL CANCER RESEARCH LA English DT Article ID ADRENAL-CORTICAL CARCINOMA; LONG-TERM SURVIVAL; LAPAROSCOPIC ADRENALECTOMY; GENOMIC CHARACTERIZATION; ONCOLOGIC OUTCOMES; ADJUVANT MITOTANE; PHASE-II; STAGE-I; THERAPY; TUMORS AB The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocortical cancer is no exception. Mitotane, an older agent considered "adrenolytic," is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resection. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex disease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful outcomes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical cancer, we raise one critical clinical issue-the risk of peritoneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peritoneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dissemination, a complication of laparoscopy that is uniformly fatal. (C) 2016 AACR. C1 [Payabyab, Eden C.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Payabyab, Eden C.] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Balasubramaniam, Sanjeeve] USDA, Div Oncol Prod 1, OHOP, CDER, Silver Spring, MD USA. [Edgerly, Maureen; Velarde, Margarita] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Div Diagnost Imaging, Houston, TX 77030 USA. [Leuva, Harshraj; Bates, Susan E.; Fojo, Tito] James J Peters Vet Adm Med Ctr, Bronx, NY USA. [Litman, Thomas] Univ Copenhagen, Med Biostat, Copenhagen, Denmark. [Bates, Susan E.; Fojo, Tito] Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA. RP Fojo, T (reprint author), Columbia Univ, Dept Med, Med Ctr, Div Med Oncol, New York, NY 10032 USA.; Fojo, T (reprint author), James J Peters VA Med Ctr, Bronx, NY 10468 USA. EM atf2116@cumc.columbia.edu OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 NR 57 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 4989 EP 5000 DI 10.1158/1078-0432.CCR-16-1570 PG 12 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700007 PM 27742785 ER PT J AU Sestak, I Zhang, Y Schroeder, BE Schnabel, CA Dowsett, M Cuzick, J Sgroi, D AF Sestak, Ivana Zhang, Yi Schroeder, Brock E. Schnabel, Catherine A. Dowsett, Mitch Cuzick, Jack Sgroi, Dennis TI Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor-Positive Lymph Node-Negative Early-Stage Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID LATE-DISTANT RECURRENCE; ESTROGEN-RECEPTOR; GENE-EXPRESSION; ONCOTYPE DX; PAM50 RISK; PREDICTION; ASSAY; TAMOXIFEN; TRANSATAC; IHC4 AB Purpose: Previous results from the TransATAC study demonstrated that both the Breast Cancer Index (BCI) and the Oncoty-peDX Recurrence Score (RS) added significant prognostic information to clinicopathologic factors over a 10-year period. Here, we examined cross-stratification between BCI and RS to directly compare their prognostic accuracy at the individual patient level. Experimental Design: A total of 665 patients with hormone receptor-positive (HR+) and lymph node-negative disease were included in this retrospective analysis. BCI and RS risk groups were determined using predefined clinical cut-off points. Kaplan-Meier estimates of 10-year risk of distant recurrence (DR) and log-rank tests were used to examine cross-stratification between BCI and RS. Results: As previously reported, both RS and BCI were significantly prognostic in years 0 to 10. BCI provided significant additional prognostic information to the Clinical Treatment Score (CTS) plus RS (Delta LR-chi(2) = 11.09; P < 0.001), whereas no additional prognostic information was provided by RS to CTS plus BCI (Delta LR-chi(2) = 2.22; P = 0.1). Restratification by BCI of the low and intermediate RS risk groups led to subgroups with significantly different DR rates (P < 0.001 and P = 0.003, respectively). In contrast, restratified subgroups created by RS of BCI risk groups did not differ significantly. Conclusions: In this retrospective analysis, BCI demonstrated increased prognostic accuracy versus RS. Notably, BCI identified subsets of RS low and RS intermediate risk patients with significant and clinically relevant rates of DR. These results indicate that additional subsets of women with HR+, lymph node-negative breast cancer identified by BCI may be suitable candidates for adjuvant chemotherapy or extended endocrine therapy. (C) 2016 AACR. C1 [Sestak, Ivana; Cuzick, Jack] Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, Charterhouse Sq, London EC1M 6BQ, England. [Zhang, Yi; Schroeder, Brock E.; Schnabel, Catherine A.] bioTheranostics, San Diego, CA USA. [Dowsett, Mitch] Royal Marsden Hosp, Inst Canc Res, London, England. [Dowsett, Mitch] Royal Marsden Hosp, Acad Dept Biochem, London, England. [Sgroi, Dennis] Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02114 USA. [Sgroi, Dennis] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. RP Sestak, I (reprint author), Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, Charterhouse Sq, London EC1M 6BQ, England. EM i.sestak@qmul.ac.uk FU AstraZeneca; National Institute for Health Research Biomedical Research at the Royal Marsden (London, United Kingdom); Cancer Research UK [C569/A16891] FX This work was supported by Cancer Research UK (C569/A16891), AstraZeneca, and the National Institute for Health Research Biomedical Research at the Royal Marsden (London, United Kingdom). NR 20 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 5043 EP 5048 DI 10.1158/1078-0432.CCR-16-0155 PG 6 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700012 PM 27252417 ER PT J AU Almhanna, K Kalebic, T Cruz, C Faris, JE Ryan, DP Jung, J Wyant, T Fasanmade, AA Messersmith, W Rodon, J AF Almhanna, Khaldoun Kalebic, Thea Cruz, Cristina Faris, Jason E. Ryan, David P. Jung, JungAh Wyant, Tim Fasanmade, Adedigbo A. Messersmith, Wells Rodon, Jordi TI Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID HEAT-STABLE ENTEROTOXIN; CONTINUAL REASSESSMENT METHOD; BRENTUXIMAB VEDOTIN SGN-35; GROWTH-FACTOR RECEPTOR; COLORECTAL-CANCER; HEMATOLOGIC MALIGNANCIES; TRASTUZUMAB EMTANSINE; C GCC; CELLS; EXPRESSION AB Purpose: To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti-guanylyl cyclase C (GCC) antibody-drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies. Experimental Design: Adult patients with GCC-expressing gastrointestinal malignancies (H-score >= 10) were eligible for inclusion. TAK-264 was administered as a 30-minute intravenous infusion once every 3 weeks for up to 17 cycles. Dose escalation proceeded using a Bayesian continual reassessment method. At the maximum tolerated dose (MTD), 25 patients with metastatic colorectal cancer were enrolled in a prespecified dose expansion cohort. Results: Forty-one patients were enrolled, including 35 (85%) with metastatic colorectal cancer. During dose escalation (0.3-2.4 mg/kg), four of 19 patients experienced dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 mg/kg. Patients received a median of two cycles of TAK-264 (range, 1-12); nine received >= four cycles. Common drug-related adverse events (AEs) included nausea and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and neutropenia (each 27%); grade >= 3 AEs included neutropenia (22%), hypokalemia, and febrile neutropenia (each 7%). Peripheral neuropathy was reported in four (10%) patients. Pharmacokinetic data showed approximately dose proportional systemic exposure and a mean plasma half-life of around 4 days, supporting the dosing schedule. Overall, 39 patients were response-evaluable; three experienced durable stable disease; and one with gastric adenocarcinoma had a partial response. GCC expression did not appear to correlate with treatment duration. Conclusions: These findings suggest that TAK-264 has a manageable safety profile, with preliminary evidence of potential antitumor activity in specific gastrointestinal malignancies. Further investigation is underway. (C) 2016 AACR. C1 [Almhanna, Khaldoun] H Lee Moffitt Canc Ctr & Res Inst, Dept Gastrointestinal Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Kalebic, Thea; Jung, JungAh; Wyant, Tim; Fasanmade, Adedigbo A.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Cruz, Cristina; Rodon, Jordi] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona, Spain. [Cruz, Cristina; Rodon, Jordi] Univ Autonoma Barcelona, Barcelona, Spain. [Faris, Jason E.; Ryan, David P.] Massachusetts Gen Hosp, Hematol Oncol, Boston, MA 02114 USA. [Messersmith, Wells] Univ Colorado, Ctr Canc, Div Med Oncol, Aurora, CO USA. RP Almhanna, K (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Gastrointestinal Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Khaldoun.Almhanna@moffitt.org FU Millennium Pharmaceuticals Inc. FX This study was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. NR 37 TC 1 Z9 1 U1 9 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 5049 EP 5057 DI 10.1158/1078-0432.CCR-15-2474 PG 9 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700013 PM 27178743 ER PT J AU Gerstner, ER Zhang, Z Fink, JR Muzi, M Hanna, L Greco, E Prah, M Schmainda, KM Mintz, A Kostakoglu, L Eikman, EA Ellingson, BM Ratai, EM Sorensen, AG Barboriak, DP Mankoff, DA AF Gerstner, Elizabeth R. Zhang, Zheng Fink, James R. Muzi, Mark Hanna, Lucy Greco, Erin Prah, Melissa Schmainda, Kathleen M. Mintz, Akiva Kostakoglu, Lale Eikman, Edward A. Ellingson, Benjamin M. Ratai, Eva-Maria Sorensen, A. Gregory Barboriak, Daniel P. Mankoff, David A. CA ACRIN 6684 Trial Grp TI ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using F-18-FMISO PET and MRI SO CLINICAL CANCER RESEARCH LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-VOLUME; ANTIANGIOGENIC TREATMENT; MALIGNANT GLIOMAS; DCE-MRI; SURVIVAL; FLUOROMISONIDAZOLE; RADIOTHERAPY; MULTIFORME; CONTRAST AB Purpose: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. Experimental Design: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (k(trans)) as well as F-18-Fluoromisonidazole (F-18-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. Results: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment F-18-FMISO SUVpeak (P = 0.048), mean k(trans) (P = 0.024), and median k(trans) (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median k(trans) (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59-0.91], nRCBV (AUC = 0.72; 95% CI, 0.56-0.89), and nCBF (AUC = 0.72; 95% CI, 0.56-0.89) were predictive of survival at 1 year. Conclusions: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and F-18-FMISO PET. (C) 2016 AACR. C1 [Gerstner, Elizabeth R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Gerstner, Elizabeth R.; Ratai, Eva-Maria] Martinos Ctr Biomed Res, Charlestown, MA USA. [Zhang, Zheng; Hanna, Lucy] Brown Univ, Providence, RI 02912 USA. [Fink, James R.; Muzi, Mark] Univ Washington, Seattle, WA 98195 USA. [Prah, Melissa; Schmainda, Kathleen M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Mintz, Akiva] Wake Forest Sch Med, Winston Salem, NC USA. [Kostakoglu, Lale] Mt Sinai Med Ctr, New York, NY 10029 USA. [Eikman, Edward A.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Ellingson, Benjamin M.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Ratai, Eva-Maria] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Sorensen, A. Gregory] Siemens Healthcare, Malvern, PA USA. [Barboriak, Daniel P.] Duke Univ, Med Ctr, Durham, NC USA. [Mankoff, David A.] Univ Penn, Philadelphia, PA 19104 USA. RP Gerstner, ER (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM egerstner@mgh.harvard.edu FU NCI [U01 CA079778]; American Recovery and Reinvestment Act (ARRA) FX ACRIN received funding from the NCI through the grant U01 CA079778. This trial was also supported by the American Recovery and Reinvestment Act (ARRA). NR 37 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 5079 EP 5086 DI 10.1158/1078-0432.CCR-15-2529 PG 8 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700016 PM 27185374 ER PT J AU Ballard, P Yates, JWT Yang, ZF Kim, DW Yang, JCH Cantarini, M Pickup, K Jordan, A Hickey, M Grist, M Box, M Johnstrom, P Varnas, K Malmquist, J Thress, KS Janne, PA Cross, D AF Ballard, Peter Yates, James W. T. Yang, Zhenfan Kim, Dong-Wan Yang, James Chih-Hsin Cantarini, Mireille Pickup, Kathryn Jordan, Angela Hickey, Mike Grist, Matthew Box, Matthew Johnstrom, Peter Varnas, Katarina Malmquist, Jonas Thress, Kenneth S. Janne, Pasi A. Cross, Darren TI Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; UNBOUND BRAIN; GEFITINIB; ERLOTINIB; RECEPTOR; PET; BARRIER; DISEASE; CHEMOTHERAPY AB Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). Results: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [C-11] osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [C-11] rociletinib and [C-11] gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. (C) 2016 AACR. C1 [Ballard, Peter; Pickup, Kathryn; Jordan, Angela; Grist, Matthew; Box, Matthew] AstraZeneca, iMED Oncol, Macclesfield, Cheshire, England. [Yates, James W. T.; Cross, Darren] AstraZeneca, iMED Oncol, Cambridge, England. [Yang, Zhenfan] AstraZeneca, Asia & Emerging Markets iMED, Shanghai, Peoples R China. [Kim, Dong-Wan] Seoul Natl Univ Hosp, Dept Internal Med, Seoul, South Korea. [Yang, James Chih-Hsin] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Cantarini, Mireille] AstraZeneca, Global Med Dev, Macclesfield, Cheshire, England. [Hickey, Mike] AstraZeneca, Cambridge, England. [Johnstrom, Peter] AstraZeneca Translat Sci Ctr, Stockholm, Sweden. [Johnstrom, Peter; Varnas, Katarina; Malmquist, Jonas] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Thress, Kenneth S.] AstraZeneca, iMED Oncol, Gatehouse Pk, Waltham, MA USA. [Janne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ballard, P (reprint author), AstraZeneca, iMED Oncol, Macclesfield, Cheshire, England.; Cross, D (reprint author), AstraZeneca, iMED Oncol, Cambridge, England. EM pbdmpk@gmail.com; Darren.Cross@astrazeneca.com FU AstraZeneca FX This research was funded by AstraZeneca. NR 47 TC 15 Z9 16 U1 7 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2016 VL 22 IS 20 BP 5130 EP 5140 DI 10.1158/1078-0432.CCR-16-0399 PG 11 WC Oncology SC Oncology GA DZ1WP UT WOS:000385632700021 PM 27435396 ER PT J AU Tache, Y AF Tache, Yvette TI The vagal anti-inflammatory pathways to the viscera: from basic understanding to therapeutic implications SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID VAGUS NERVE-STIMULATION C1 [Tache, Yvette] Univ Calif Los Angeles, David Geffen Sch Med, Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Tache, Yvette] VA Greater Los Angeles Healthcare Syst, Digest Dis Res Ctr, Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Tache, Y (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA.; Tache, Y (reprint author), VA Greater Los Angeles Healthcare Syst, Digest Dis Res Ctr, Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ytache@mednet.ucla.edu NR 11 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD OCT 15 PY 2016 VL 594 IS 20 BP 5769 EP 5770 DI 10.1113/JP271540 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DY8RV UT WOS:000385399100006 PM 27739076 ER PT J AU Ailon, T Torabi, R Fisher, CG Rhines, LD Clarke, MJ Bettegowda, C Boriani, S Yamada, YJ Kawahara, N Varga, PP Shin, JH Saghal, A Gokaslan, ZL AF Ailon, Tamir Torabi, Radmehr Fisher, Charles G. Rhines, Laurence D. Clarke, Michelle J. Bettegowda, Chetan Boriani, Stefano Yamada, Yoshiya J. Kawahara, Norio Varga, Peter P. Shin, John H. Saghal, Arjun Gokaslan, Ziya L. TI Management of Locally Recurrent Chordoma of the Mobile Spine and Sacrum: A Systematic Review SO SPINE LA English DT Article DE adjuvant; chordoma; en bloc resection; locally recurrent; morbidity; neoadjuvant; primary tumor; radiation therapy; recurrence; relapse; spine; surgery; systematic review ID PROGNOSTIC-FACTORS; RADIATION-THERAPY; MALIGNANT-TUMORS; CHONDROSARCOMAS; RECOMMENDATIONS; RADIOTHERAPY; GUIDELINES; EXPERIENCE; SURGERY AB Study Design.Systematic review.Objective.To determine evidence-based guidelines for the management of locally recurrent spinal chordoma.Summary of Background Data.Chordoma of the spine is a low-grade malignant tumor with a strong propensity for local recurrence. Salvage therapy is challenging due to its relentless nature and refractoriness to adjuvant therapies. There are currently no guidelines regarding the best management of recurrent chordoma.Methods.We combined the results of a systematic review with expert opinion to address the following research questions: (1) For locally recurrent chordoma of the spine without systemic disease, if surgery is planned, should en bloc resection be attempted if technically feasible with acceptable morbidity? (2) For locally recurrent chordoma without systemic disease, in which wide en bloc excision is not possible, what is the treatment of choice? (2) Should adjuvant or neoadjuvant radiation therapy be used in the treatment of locally recurrent chordoma?Results.A total of nine surgical and seven radiation therapy articles met study criteria. Evidence quality was low or very low. Recurrent disease is associated with predominantly poor outcome, regardless of treatment modality. As for primary chordoma, resection with wide margins appears to confer an advantage with respect to local control, although this effect is attenuated in the setting of relapse. Postoperative radiation therapy likely reduces the rate of further relapse.Conclusion.(1) For locally recurrent chordoma of the spine without systemic disease, when surgery is planned, wide en bloc resection should be performed if technically feasible with acceptable morbidity. Strong recommendation, Low Quality of Evidence. (2) For locally recurrent chordoma without systemic disease, in which wide en bloc excision is not possible, partial resection is the treatment of choice. Weak recommendation, Very Low Quality of Evidence. (3) For the treatment of locally recurrent chordoma, high-dose conformal radiation therapy should be administered postoperatively to reduce the risk of further recurrence, and may be considered as a primary therapy. Strong recommendation, Very Low Quality of Evidence.Level of Evidence: 2 C1 [Ailon, Tamir; Fisher, Charles G.] Univ British Columbia, Dept Orthopaed, Div Spine, 818 W 10th Ave, Vancouver, BC, Canada. [Ailon, Tamir; Fisher, Charles G.] Vancouver Gen Hosp, 818 W 10th Ave, Vancouver, BC, Canada. [Torabi, Radmehr; Gokaslan, Ziya L.] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Dept Neurosurg, Providence, RI 02903 USA. [Rhines, Laurence D.] Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Neurosurg, Houston, TX 77030 USA. [Clarke, Michelle J.] Mayo Clin, Dept Neurol Surg, Rochester, MN USA. [Bettegowda, Chetan] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD USA. [Boriani, Stefano] Rizzoli Inst Bologna, Dept Degenerat & Oncol Spine Surg, Bologna, Italy. [Yamada, Yoshiya J.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Kawahara, Norio] Kanazawa Med Univ, Dept Orthopaed Surg, Uchinada, Ishikawa, Japan. [Varga, Peter P.] Natl Ctr Spinal Disorders, Budapest, Hungary. [Shin, John H.] Harvard Univ, Dept Neurosurg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Saghal, Arjun] Univ Toronto, Sunnybrook Odette Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. RP Ailon, T (reprint author), Univ British Columbia, Dept Orthopaed, Div Spine, 818 W 10th Ave, Vancouver, BC, Canada.; Ailon, T (reprint author), Vancouver Gen Hosp, 818 W 10th Ave, Vancouver, BC, Canada. EM tamir.ailon@vch.ca OI Shin, John/0000-0001-7490-8108 FU AOSpine International FX AOSpine International funds were received in support of this work. NR 30 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2016 VL 41 IS 20 SU S BP S193 EP S198 DI 10.1097/BRS.0000000000001812 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DZ0JV UT WOS:000385525600006 PM 27753782 ER PT J AU Chang, JH Shin, JH Yamada, YJ Mesfin, A Fehlings, MG Rhines, LD Sahgal, A AF Chang, Joe H. Shin, John H. Yamada, Yoshiya J. Mesfin, Addisu Fehlings, Michael G. Rhines, Laurence D. Sahgal, Arjun TI Stereotactic Body Radiotherapy for Spinal Metastases: What are the Risks and How Do We Minimize Them? SO SPINE LA English DT Article DE epidural disease; myelopathy; spine; stereotactic body radiotherapy; vertebral compression fracture ID VERTEBRAL COMPRESSION FRACTURE; RENAL-CELL CARCINOMA; INSTABILITY NEOPLASTIC SCORE; RADIATION-THERAPY; CLINICAL ARTICLE; HELICAL TOMOTHERAPY; PHASE-II; RADIOSURGERY; OUTCOMES; DISEASE AB Study Design.Systematic literature review.Objectives.To summarize the risks of 3 key complications of stereotactic body radiotherapy (SBRT) for spinal metastases, that is, radiation myelopathy (RM), vertebral compression fracture (VCF), and epidural disease progression, and to discuss strategies for minimizing them.Summary of Background Data.RM, VCF and epidural disease progression are now recognized as important risks following SBRT for spine metastases. It is unclear at this stage exactly how large these risks are and what strategies can be employed to minimize these risks.Methods.A systematic review of the literature using MEDLINE and a review of the bibliographies of reviewed articles on SBRT for spinal metastases were conducted.Results.The initial literature search revealed a total of 376 articles, of which 38 were pertinent to the study objectives. The risk of RM following SBRT was found to be dependent on the maximum dose to the spinal cord and estimated to be 5% if the recommended published thecal sac dose constraints are adhered to. The crude risk of VCF was 13.7% (range: 0.7%-40.5%), and, on average, 45% were surgically salvaged. It has been shown that the risk of VCF is dependent on several anatomic and tumor-related factors including the SBRT dose per fraction. The crude risk of local failure at 1 year was 21.4% (range: 12%-27%) of which 67% (range: 38%-96%) occurred within the epidural space. The grade of epidural disease has been shown to be associated with the risk of local failure.Conclusion.The risk of RM after spinal SBRT is low in particular if recommended dose metrics are adhered to. There is a significant risk of both VCF and epidural disease progression after spinal SBRT. These risks can potentially be minimized by identifying the risk factors for these complications, and performing careful radiotherapy and surgical planning.Level of Evidence: 2 C1 [Chang, Joe H.; Sahgal, Arjun] Univ Toronto, Dept Radiat Oncol, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Shin, John H.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Yamada, Yoshiya J.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Mesfin, Addisu] Univ Rochester, Dept Orthopaed Surg, Rochester, NY USA. [Fehlings, Michael G.] Univ Toronto, Dept Neurosurg, Toronto, ON, Canada. [Fehlings, Michael G.] Univ Toronto, Spinal Program, Toronto Western Hosp, Toronto, ON, Canada. [Rhines, Laurence D.] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. RP Sahgal, A (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Radiat Oncol, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM arjun.sahgal@sunnybrook.ca OI Shin, John/0000-0001-7490-8108 FU AOSpine International FX AOSpine International funds were received in support of this work. NR 53 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2016 VL 41 IS 20 SU S BP S238 EP S245 DI 10.1097/BRS.0000000000001823 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DZ0JV UT WOS:000385525600013 PM 27488294 ER PT J AU Laufer, I Zuckerman, SL Bird, JE Bilsky, MH Lazary, A Quraishi, NA Fehlings, MG Sciubba, DM Shin, JH Mesfin, A Sahgal, A Fisher, CG AF Laufer, Ilya Zuckerman, Scott L. Bird, Justin E. Bilsky, Mark H. Lazary, Aron Quraishi, Nasir A. Fehlings, Michael G. Sciubba, Daniel M. Shin, John H. Mesfin, Addisu Sahgal, Arjun Fisher, Charles G. TI Predicting Neurologic Recovery after Surgery in Patients with Deficits Secondary to MESCC: Systematic Review SO SPINE LA English DT Article DE ambulation; bladder; MESCC; metastasis; neurologic outcome; prognosis; recovery; spinal cord compression; spine; surgery; systematic review; tumor ID SPINAL-CORD COMPRESSION; SURGICAL DECOMPRESSION; METASTASES; SURVIVAL; OUTCOMES; CANCER AB Study Design.Systematic literature review and expert surveyObjective.The aim of this study was to determine factors associated with neurologic improvement in patients with neurologic deficits secondary to metastatic epidural spinal cord compression (MESCC). Clear understanding of these factors will guide surgical decision-making by helping to elucidate which patients are more likely to benefit from surgery and how surgeons can increase the probability of neurologic and functional restoration.Summary of Background Data.Surgical spinal cord decompression has been shown to improve neurologic function in patients with symptomatic MESCC. However, prognostication of neurologic improvement after surgery remains challenging, owing to sparse data and complexity of these patients.Methods.PubMed and Embase databases were searched for relevant publications. PRISMA Statement guided publication selection and data reporting. GRADE guidelines were used for evidence quality evaluation and recommendation formulation.Results.Low-quality evidence supports the use of the duration and severity of neurologic deficit as predictors of neurological recovery in patients with MESCC. Low-quality evidence supports the use of thoracic level of compression and previous irradiation as adverse predictors of neurological recovery. Nearly all of the AOSpine Knowledge Forum Tumor members who responded to the survey agreed that ambulation with assistance represented a successful surgical result and that duration of ambulation loss and the severity of weakness should be considered when trying to predict whether surgery would result in restoration of ambulation.Conclusions.Review of literature and expert opinion support the importance of duration of ambulation loss and the severity of neurologic deficit (muscle strength, bladder function) in prediction of neurologic recovery among patients with symptomatic MESCC. Efforts to reduce the duration of ambulation loss and to prevent progression of neurologic deficits should be made to improve the probability of neurologic recovery.Level of Evidence: 2 C1 [Laufer, Ilya; Bilsky, Mark H.] Mem Sloan Kettering Canc Ctr, Dept Neurol Surg, 1275 York Ave, New York, NY 10065 USA. [Zuckerman, Scott L.] Vanderbilt Univ, Sch Med, Dept Neurol Surg, Nashville, TN 37212 USA. [Bird, Justin E.] Univ Texas MD Anderson Canc Ctr, Div Surg, Dept Orthopaed Oncol, Houston, TX 77030 USA. [Lazary, Aron] Natl Ctr Spinal Disorders, Budapest, Hungary. [Quraishi, Nasir A.] Univ Nottingham Hosp, Ctr Spinal Studies & Surg, Queens Med Ctr Campus, Nottingham, England. [Fehlings, Michael G.] Univ Toronto, Dept Surg, Div Neurosurg, Toronto, ON, Canada. [Fehlings, Michael G.] Toronto Western Hosp, Toronto, ON, Canada. [Sciubba, Daniel M.] Johns Hopkins Univ, Sch Med, Dept Neurol Surg, Baltimore, MD USA. [Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Mesfin, Addisu] Univ Rochester, Med Ctr, Dept Orthopaed Surg & Oncol, Rochester, NY 14642 USA. [Sahgal, Arjun] Sunnybrook Hlth Sci Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Fisher, Charles G.] Univ British Columbia, Div Spine, Dept Orthopaed, Vancouver, BC, Canada. [Fisher, Charles G.] Vancouver Gen Hosp, Vancouver, BC, Canada. RP Laufer, I (reprint author), Mem Sloan Kettering Canc Ctr, Dept Neurol Surg, 1275 York Ave, New York, NY 10065 USA. EM lauferi@mskcc.org OI Shin, John/0000-0001-7490-8108 FU AOSpine International FX AOSpine International funds were received in support of this work. NR 19 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2016 VL 41 IS 20 SU S BP S224 EP S230 DI 10.1097/BRS.0000000000001827 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DZ0JV UT WOS:000385525600011 PM 27488300 ER PT J AU Mesfin, A Sciubba, DM Dea, N Nater, A Bird, JE Quraishi, NA Fisher, CG Shin, JH Fehlings, MG Kumar, N Clarke, MJ AF Mesfin, Addisu Sciubba, Daniel M. Dea, Nicolas Nater, Anick Bird, Justin E. Quraishi, Nasir A. Fisher, Charles G. Shin, John H. Fehlings, Michael G. Kumar, Naresh Clarke, Michelle J. TI Changing the Adverse Event Profile in Metastatic Spine Surgery: An Evidence-Based Approach to Target Wound Complications and Instrumentation Failure SO SPINE LA English DT Article DE implant failure; instrumentation failure; metastatic spine disease; metastatic spine tumor; prevention of infection; prevention of instrumentation failure; surgical site infection; wound complication ID SOFT-TISSUE RECONSTRUCTION; SURGICAL SITE INFECTION; POSTEROLATERAL TRANSPEDICULAR APPROACH; PEDICLE SCREW FIXATION; QUALITY-OF-LIFE; RISK-FACTORS; CORD COMPRESSION; VERTEBRAL BODY; POSTERIOR INSTRUMENTATION; CEMENT AUGMENTATION AB Study Design.Systematic review.Objective.To identify risk factors and preventive methods for wound complications and instrumentation failure after metastatic spine surgery.Summary of Background Data.We focused on two postoperative complications of metastatic spine tumor surgery: wound complications and instrumentation failure and preventive measures.Methods.We performed a systematic review of the literature from 1980 to 2015. The articles were analyzed for the presence of documented infection and/or wound complications and instrumentation failure.Results.Forty articles met our inclusion criteria for wound complications and prevention. There is very low level of evidence that preoperative radiation, preoperative neurological deficit, revision procedures, and posterior approaches can contribute to wound complications (infections, wound dehiscence). There is very low level of evidence that plastic surgery soft tissue reconstruction, intrawound vancomycin powder, and percutaneous pedicle screws may prevent postoperative wound complications. Fourteen articles met our inclusion criteria for instrumentation failure. There is very low level of evidence that constructs greater than six levels, positive sagittal balance, preoperative radiation, and history of chest wall resection can contribute to implant failures.Conclusion.center dot For patients undergoing revision metastatic spine tumor surgery, plastic surgery should perform the soft tissue reconstruction (strong recommendation/very low quality of evidence).center dot For patients undergoing metastatic spine tumor surgery, plastic surgery may perform immediate soft tissue reconstruction (weak recommendation/very low quality of evidence).center dot For patients undergoing metastatic spine tumor surgery, intrawound vancomycin can be applied to decrease the risk of postoperative wound infections (weak recommendation/very low quality of evidence).center dot For patients undergoing metastatic spine tumor surgery, percutaneous pedicle screws can be placed to decrease the risk of postoperative wound complications (weak recommendation/very low quality of evidence).center dot Instrumentation failure risk factors include constructs greater than six levels, positive sagittal balance, preoperative radiation, and history of chest wall resections (weak recommendation/very low quality of evidence).Level of Evidence: N/A C1 [Mesfin, Addisu] Univ Rochester, Sch Med & Dent, Dept Orthopaed Surg, 601 Elmwood Ave,Box 665, Rochester, NY 14610 USA. [Sciubba, Daniel M.] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD USA. [Dea, Nicolas] Univ Sherbrooke, Dept Neurosurg, Sherbrooke, PQ, Canada. [Nater, Anick; Fehlings, Michael G.] Univ Toronto, Div Neurosurg, Toronto, ON, Canada. [Bird, Justin E.] Univ Texas MD Anderson Canc Ctr, Dept Orthopaed Surg, Houston, TX 77030 USA. [Quraishi, Nasir A.] Nothingham Univ Hosp, Ctr Spinal Studies & Surg, Nottingham, England. [Fisher, Charles G.] Univ British Columbia, Dept Orthopaed Surg, Vancouver, BC, Canada. [Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kumar, Naresh] Natl Univ Singapore Hosp, Dept Orthopaed Surg, Singapore, Singapore. [Clarke, Michelle J.] Mayo Clin, Dept Neurosurg, Rochester, MN USA. RP Mesfin, A (reprint author), Univ Rochester, Sch Med & Dent, Orthopaed Surg & Neurosurg, 601 Elmwood Ave,Box 665, Rochester, NY 14610 USA. EM Addisu_mesfin@urmc.rochester.edu FU AOSpine International FX AOSpine International funds were received in support of this work. NR 64 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2016 VL 41 IS 20 SU S BP S262 EP S270 DI 10.1097/BRS.0000000000001817 PG 9 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DZ0JV UT WOS:000385525600016 ER PT J AU Zuckerman, SL Laufer, I Sahgal, A Yamada, YJ Schmidt, MH Chou, D Shin, JH Kumar, N Sciubba, DM AF Zuckerman, Scott L. Laufer, Ilya Sahgal, Arjun Yamada, Yoshiya J. Schmidt, Meic H. Chou, Dean Shin, John H. Kumar, Naresh Sciubba, Daniel M. TI When Less Is More: The indications for MIS Techniques and Separation Surgery in Metastatic Spine Disease SO SPINE LA English DT Article DE endoscopy; epidural spinal cord compression; metastatic spinal cord compression; minimally invasive surgery; mini-open; pathologic fracture; percutaneous instrumentation; separation surgery; spinal metastases; stereotactic radiosurgery; thoracoscopy; tubular retractor; VATS; video-assisted thoracoscopic surgery ID STEREOTACTIC BODY RADIOTHERAPY; PERCUTANEOUS PEDICLE SCREW; CLINICAL ARTICLE; SINGLE-FRACTION; MINI-OPEN; THORACOLUMBAR SPINE; THORACIC SPINE; THORACOSCOPIC APPROACH; CEMENT AUGMENTATION; SOLITARY METASTASES AB Study Design.Systematic review.Objective.The aim of this study was to review the techniques, indications, and outcomes of minimally invasive surgery (MIS) and separation surgery with subsequent radiosurgery in the treatment of patients with metastatic spine disease.Summary of Background Data.The utilization of MIS techniques in patients with spine metastases is a growing area within spinal oncology. Separation surgery represents a novel paradigm where radiosurgery provides long-term control after tumor is surgically separated from the neural elements.Methods.PubMed, Embase, and CINAHL databases were systematically queried for literature reporting MIS techniques or separation surgery in patients with metastatic spine disease. PRISMA guidelines were followed.Results.Of the initial 983 articles found, 29 met inclusion criteria. Twenty-five articles discussed MIS techniques and were grouped according to the primary objective: percutaneous stabilization (8), tubular retractors (4), mini-open approach (8), and thoracoscopy/endoscopy (5). The remaining 4 studies reported separation surgery. Indications were similar across all studies and included patients with instability, refractory pain, or neurologic compromise. Intraoperative variables, outcomes, and complications were similar in MIS studies compared to traditional approaches, and some MIS studies showed a statistically significant improvement in outcomes. Studies of mini-open techniques had the strongest evidence for superiority.Conclusions.Low-quality evidence currently exists for MIS techniques and separation surgery in the treatment of metastatic spine disease. Given the early promising results, the next iteration of research should include higher-quality studies with sufficient power, and will be able to provide higher-level evidence on the outcomes of MIS approaches and separation surgery.Level of Evidence: N/A C1 [Zuckerman, Scott L.] Vanderbilt Univ, Sch Med, Dept Neurol Surg, Med Ctr North T-4224, Nashville, TN 37212 USA. [Laufer, Ilya] Mem Sloan Kettering Canc Ctr, Dept Neurol Surg, 1275 York Ave, New York, NY 10021 USA. [Sahgal, Arjun] Sunnybrook Hlth Sci Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Yamada, Yoshiya J.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Schmidt, Meic H.] Univ Utah, Dept Neurol Surg, Salt Lake City, UT USA. [Chou, Dean] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kumar, Naresh] Natl Univ Singapore Hosp, Univ Spine Ctr, Univ Orthopaed Hand & Reconstruct Microsurg Clust, Singapore, Singapore. [Sciubba, Daniel M.] Johns Hopkins Sch Med, Dept Neurol Surg, Baltimore, MD USA. RP Zuckerman, SL (reprint author), Vanderbilt Univ, Sch Med, Dept Neurol Surg, Med Ctr North T-4224, Nashville, TN 37212 USA. EM scott.zuckerman@vanderbilt.edu FU AOSpine International FX AOSpine International funds were received in support of this work. NR 71 TC 1 Z9 1 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2016 VL 41 IS 20 SU S BP S246 EP S253 DI 10.1097/BRS.0000000000001824 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DZ0JV UT WOS:000385525600014 PM 27753784 ER PT J AU Dai, N Zhang, XL Zhang, Y Hou, L Li, WM Fan, B Zhang, TS Xu, YW AF Dai, Neng Zhang, Xianlin Zhang, Yi Hou, Lei Li, WeiMing Fan, Bing Zhang, TianSong Xu, YaWei TI Enhanced diagnostic utility achieved by myocardial blood analysis: A meta-analysis of noninvasive cardiac imaging in the detection of functional coronary artery disease SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Cardiac imaging; Coronary artery disease; Noninvasive imaging; Fractional flow reserve ID FRACTIONAL FLOW RESERVE; EMISSION-COMPUTED-TOMOGRAPHY; CARDIOVASCULAR MAGNETIC-RESONANCE; AMERICAN-HEART-ASSOCIATION; REFERENCE-STANDARD; FOLLOW-UP; PERFUSION; PERFORMANCE; STRESS; STENOSIS AB Aim: The aim of this study is to determine the diagnostic utility of 6 cardiac imaging modalities using fractional flow reserve (FFR) as the reference standard. Methods: Studies reporting diagnostic performance of computed tomographic perfusion imaging (CTP), fractional flow reserve derived from computed tomography (FFRCT), cardiac magnetic resonance (CMR), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and dobutamine stress echocardiography (DSE) for diagnosis of ischemia-causing lesions were included. Results: On vessel-based and patient-based analyses, CMR, PET, CTP and FFRCT exhibited comparable sensitivity (per-vessel: 87% vs. 86% vs. 89% vs. 86%; per-patient: 88% vs. 90% vs. 88% vs. 90%, P > 0.05) and specificity (per-vessel: 89% vs. 88% vs. 89% vs. 83%; per-patient: 84% vs. 84% vs. 87% vs. 75%, P > 0.05); whereas SPECT yielded significantly lower sensitivity (per-vessel: 72%; per-patient: 78%, P < 0.05) and specificity (per-vessel: 79%; per-patient: 79%, P < 0.05) and DES yielded significantly lower sensitivity (per-vessel: 62%, per-patient: 69%, P < 0.05). On the other hand, within the same imaging modality, myocardial blood flow (MBF) derived by CTP had a higher sensitivity (90% vs. 80%, P = 0.048) but lower specificity (77% vs. 93%, P = 0.02) than that of perfusion defect (PD). Moreover, MBF derived by CMR had a lower specificity than that of PD (60% vs. 93%, P = 0.02), while coronary flow reserve (CRF) derived by PET had a lower specificity than that of MBF (81% vs. 89%, P = 0.005). Conclusion: CMR, PET, CTP and FFRCT expressed similar and high accuracy in detecting functional CAD, whereas different analysis methods for each imaging modality may vary their diagnostic utility. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Dai, Neng; Zhang, Xianlin; Zhang, Yi; Hou, Lei; Li, WeiMing; Xu, YaWei] Tongji Univ, Peoples Hosp 10, Dept Cardiol, 301 Middle Yanchang Rd, Shanghai 200072, Peoples R China. [Dai, Neng] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA USA. [Fan, Bing] Fudan Univ, ZhongShan Hosp, Dept Cardiol, 180 Fenglin Rd, Shanghai, Peoples R China. [Zhang, TianSong] JingAn Dist Ctr Hosp, Dept TCM, 259 Xikang Rd, Shanghai 200040, Peoples R China. RP Xu, YW (reprint author), Tongji Univ, Peoples Hosp 10, Dept Cardiol, 301 Middle Yanchang Rd, Shanghai 200072, Peoples R China.; Fan, B (reprint author), Fudan Univ, ZhongShan Hosp, Dept Cardiol, 180 Fenglin Rd, Shanghai, Peoples R China.; Zhang, TS (reprint author), JingAn Dist Ctr Hosp, Dept TCM, 259 Xikang Rd, Shanghai 200040, Peoples R China. EM fanbingzs@126.com; ztsdoctor@126.com; xuyaweish@aliyun.com FU China Scholarship Council [2014OS66014261]; Medical Related Science and Technology Project of Shanghai Municipal Science and Technology Commission [14411963100] FX This study was funded, in part, by the China Scholarship Council (2014OS66014261) and by the Medical Related Science and Technology Project of Shanghai Municipal Science and Technology Commission (No. 14411963100). NR 37 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 15 PY 2016 VL 221 BP 665 EP 673 DI 10.1016/j.ijcard.2016.07.031 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9DA UT WOS:000384692600130 PM 27423088 ER PT J AU Tromp, J Meyer, S Mentz, RJ O'Connor, CM Metra, M Dittrich, HC Ponikowski, P Teerlink, JR Cotter, G Davison, B Cleland, JGF Givertz, MM Bloomfield, DM van Veldhuisen, DJ Hillege, HL Voors, AA van der Meer, P AF Tromp, Jasper Meyer, Sven Mentz, Robert J. O'Connor, Christopher M. Metra, Marco Dittrich, Howard C. Ponikowski, Piotr Teerlink, John R. Cotter, Gad Davison, Beth Cleland, John G. F. Givertz, Michael M. Bloomfield, Daniel M. van Veldhuisen, Dirk J. Hillege, Hans L. Voors, Adriaan A. van der Meer, Peter TI Acute heart failure in the young: Clinical characteristics and biomarker profiles SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Heart failure; Age; Young; Biomarker ID PRESERVED EJECTION FRACTION; GELATINASE-ASSOCIATED LIPOCALIN; SELECTIVE ADHESION MOLECULE; ENDOTHELIAL GROWTH-FACTOR; OLDER-ADULTS; AGE; COMORBIDITIES; DYSFUNCTION; OUTCOMES; TRIAL AB Background: Young patients (<50 years) exhibit specific characteristics in chronic heart failure (HF), but their phenotype in acute heart failure (AHF) is not well described. Methods and results: 2033 patients of the PROTECT trialwere divided into two groups: young patients (<= 50 years) and older patients (>50 years). Biomarkers from different pathophysiological domains were available in 1266 patients. Patients were compared with regard to clinical characteristics, biomarker profiles, and in-hospital (worsening renal function [WRF] and decongestion) and post-discharge (180-day survival) outcome. Young patients (n = 121) were mostly men, had fewer comorbidities with better renal function, and more often had a reduced ejection fraction. At admission, young patients were more likely to have jugular venous distension, but less rales and dyspnea compared with older patients. During hospitalization, young patients received higher loop diuretic doses and were decongested earlier than older patients. WRF occurred less frequently in young patients (5.9% vs. 13.3%, p = 0.020) and they were more often discharged alive. At 180 days, the mortality of young patients was lower than that of the older patients (9.9% vs. 18.1, p = 0.021). Biomarker levels indicative of inflammation and renal damage were lower in the young, although they exhibited higher BNP levels than older patients. Conclusions: Despite use of higher diuretic doses, young patients with AHF less often developed WRF during hospitalization and had better outcomes than older patients. Differences in biomarker levels between the age groups suggest distinct underlying pathophysiologies. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Tromp, Jasper; Meyer, Sven; van Veldhuisen, Dirk J.; Hillege, Hans L.; Voors, Adriaan A.; van der Meer, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Meyer, Sven] Carl von Ossietzky Univ Oldenburg, European Med Sch Oldenburg Groningen, Heart Ctr Oldenburg, Dept Cardiol, Oldenburg, Germany. [Mentz, Robert J.] Duke Univ, Med Ctr, Durham, NC USA. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Metra, Marco] Univ Brescia, Brescia, Italy. [Dittrich, Howard C.] Univ Iowa, Carver Coll Med, Cardiovasc Res Ctr, Iowa City, IA USA. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. [Teerlink, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cotter, Gad; Davison, Beth] Momentum Res, Durham, NC USA. [Cleland, John G. F.] Univ Hull, Kingston Upon Hull, Yorks, England. [Givertz, Michael M.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Bloomfield, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. RP van der Meer, P (reprint author), Univ Med Ctr Groningen, Dept Cardiol, AB31,Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM p.van.der.meer@umcg.nl RI Ponikowski, Piotr/O-6454-2015 OI Ponikowski, Piotr/0000-0002-3391-7064 FU Amgen; Bayer; Cytokinetics; Medtronic; Merck; Novartis; St. Jude; Trevena; NovaCardia FX Dr. Cleland was on the Steering Committee for the PROTECT trial, served on the advisory board for MSD, and received payments for both. Dr. O'Connor is a consultant to Merck. Dr. Ponikowski has received honoraria from Merck; Dr. Davison and Dr. Cotter are employees of Momentum Research Inc., which was contracted to perform work on the study by Merck. Dr. Metra have received honoraria and reimbursements from NovaCardia, sponsors of the study, and Merck. Dr. Givertz has received institutional research support and served on a scientific Advisory Board for Merck. Dr. Teerlink has received research grants and consultation fees from: Amgen, Bayer, Cytokinetics, Medtronic, Merck, Novartis, St. Jude, Trevena. Dr. Bloomfield is an employee of Merck. Dr. Dittrich served as a consultant to Merck. Dr. Voors has received speaker and consultancy fees from Merck. All other authors have reported that they have no conflict of interest to declare and that they take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. NR 33 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 15 PY 2016 VL 221 BP 1067 EP 1072 DI 10.1016/j.ijcard.2016.06.339 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9DA UT WOS:000384692600201 PM 27448534 ER PT J AU Charidimou, A Inamura, S Nomura, T Kanno, A Kim, SN Imaizumi, T AF Charidimou, Andreas Inamura, Shigeru Nomura, Tatsufumi Kanno, Aya Kim, Sang Nyon Imaizumi, Toshio TI Cerebral microbleeds and white matter hyperintensities in cardioembolic stroke patients due to atrial fibrillation: single-centre longitudinal study SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Cerebral microbleeds; Atrial fibrillation; Intracerebral haemorrhage; Cerebral amyloid angiopathy ID SMALL VESSEL DISEASE; BRAIN MICROBLEEDS; PREVALENCE; RISK; METAANALYSIS; ASSOCIATION; RECURRENCE; HEMORRHAGE; STANDARDS; DESIGN AB Cerebral microbleeds (CMBs) are a potential predictor of future stroke risk with clinical relevance for antithrombotic treatments, especially in ischaemic stroke patients with atrial fibrillation. However, prospective data on CMBs and risk of stroke in this particular stroke population remain scarce. We therefore performed a single centre longitudinal study to investigate CMBs and white matter hyperintensities (WMH) and the risk of future stroke. Consecutive acute stroke patients, admitted during 2008-2012 for presumed cardioembolic stroke due to non valvular atrial fibrillation with available follow-up for the occurrence of recurrent stroke were included in our study. The rate of future stroke between patients with vs. without CMBs and moderate to severe WMH at baseline MRI was compared in separate survival and multivariable Cox regression analyses. A total of 119 cardioembolic stroke patients (49% female, median age: 76; IQR: 68-82 years) were included. CMBs were found at baseline in 26/119 (21.8%; 95% CI: 14.8-30.4%) patients. Moderate to severe WMH were present in 27/119 (22.7%; 95% CI: 15.5-313%) cases. During a median follow-up time of 17 months (IQR: 3-50 months), 17 of 119 patients experienced a symptomatic stroke: 14 patients had an ischaemic stoke and 3 had intracerebral haemorrhage. The overall incidence rate for ischaemic stroke and intracerebral haemorrhage was 4.2 (95% CI: 2.3-7.1) and 0.9 (95% CI: 0.5-2.6) per 1000 patient-year of follow-up respectively. In multivariable Cox regression analysis the hazard ratio for total CMB number and the risk of stroke during follow-up was 1.05 (95% CI: 0.99-1.11; p = 0.137, per each additional CMB increase), after adjusting for CHAD2S. A similar regression analysis demonstrated that moderate to severe WMHS were independently associated with increased risk of symptomatic stroke at follow-up, after adjusting for CHAD2S (HR: 2.99; 95% CI: 1.01-830; p = 0.036). Despite the small sample size, our study provides useful data to guide power calculations and likely effect sizes relevant for ongoing and future larger studies and clinical trials. (C) 2016 Elsevier B.V. All rights reserved. C1 [Charidimou, Andreas] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Ctr Stroke Res, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. [Inamura, Shigeru; Nomura, Tatsufumi; Kanno, Aya; Kim, Sang Nyon; Imaizumi, Toshio] Kushiro City Gen Hosp, Dept Neurosurg, Kushiro, Hokkaido, Japan. RP Charidimou, A (reprint author), Harvard Med Sch, J Kistler Stroke Res Ctr, Massachusetts Gen Hosp, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM andreas.charidimou.09@ucl.ac.uk NR 24 TC 2 Z9 2 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2016 VL 369 BP 263 EP 267 DI 10.1016/j.jns.2016.08.050 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY1NF UT WOS:000384861000049 PM 27653903 ER PT J AU Boulouis, G Charidimou, A Auriel, E Haley, KE van Etten, ES Fotiadis, P Reijmer, Y Ayres, A Schwab, KM Martinez-Ramirez, S Rosand, J Viswanathan, A Goldstein, JN Greenberg, SM Gurol, ME AF Boulouis, Gregoire Charidimou, Andreas Auriel, Eitan Haley, Kellen E. van Etten, Ellis S. Fotiadis, Panagiotis Reijmer, Yael Ayres, Alison Schwab, Kristin M. Martinez-Ramirez, Sergi Rosand, Jonathan Viswanathan, Anand Goldstein, Joshua N. Greenberg, Steven M. Gurol, M. Edip TI Intracranial atherosclerosis and cerebral small vessel disease in intracerebral hemorrhage patients SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Atherosclerosis; Carotid; CT angiography; Intracerebral hemorrhage; Small vessel disease ID CAROTID-ARTERY ATHEROSCLEROSIS; BLOOD-PRESSURE REDUCTION; RISK-FACTOR; AMYLOID ANGIOPATHY; ISCHEMIC-STROKE; CALCIFICATION; ASSOCIATION; MICROBLEEDS; STIFFNESS; DEMENTIA AB Background: The association between cerebral small vessel diseases (cSVD) and intracranial atherosclerosis is debated and conflicting results have been reported. We sought to investigate this association in patients with intracerebral hemorrhage (ICH), due to severe cSVD. Methods: Consecutive ICH patients were divided into those meeting criteria for cerebral amyloid angiopathy (CM) and those with deep hypertensive ICH consistent with hypertensive cSVD (HTN-SVD). White matter hyperintensity volumes (WMH) and microbleed counts (MB) were measured on MRI. CTA was rated for severity of intracranial carotid calcifications and for presence of >50% intracranial stenosis (ICS). Associations of intracranial atherosclerosis severity with type of SVD (CAA vs HTN-cSVD) and with imaging and clinical markers of cSVD burden were analyzed. Results: The cohort included 253 CAA and 90 HTN-SVD patients. In multivariable models, the type of cSVD (CAA vs. HTN-cSVD) was not associated with calcification severity (OR = 1.04, 95% CI [0.62-3.5], p = 037) or presence of ICS (OR = 0.84, 95% CI [021-2.74], p = 0.78). We found no association between intracranial atherosclerosis (calcifications and stenoses) and parenchymal markers of cSVD severity (WMH and MB, adjusted p >= 0.2 for all comparisons) and no association with presence of dementia before ICH (adjusted p 0.2 for both comparisons). Conclusions: We found no association between intracranial atherosclerosis and parenchymal or clinical consequences of cSVD, suggesting that cSVDs while sharing some risk factors are not influenced by upstream larger vessel pathologies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Boulouis, Gregoire; Charidimou, Andreas; Auriel, Eitan; Haley, Kellen E.; van Etten, Ellis S.; Fotiadis, Panagiotis; Reijmer, Yael; Ayres, Alison; Schwab, Kristin M.; Martinez-Ramirez, Sergi; Viswanathan, Anand; Goldstein, Joshua N.; Greenberg, Steven M.; Gurol, M. Edip] Harvard Med Sch, Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Dept Neurol,Stroke Res Ctr, Boston, MA USA. [Rosand, Jonathan; Goldstein, Joshua N.] Harvard Med Sch, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA USA. [Goldstein, Joshua N.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. RP Gurol, ME (reprint author), Massachusetts Gen Hosp, Stroke Serv, 175 Cambridge St 300, Boston, MA 02114 USA. EM edip@mail.harvard.edu OI Ayres, Alison/0000-0002-5492-1695; Boulouis, Gregoire/0000-0001-8422-9205 FU NIH [K23 NS 083711, R01 AG026484]; J. William Fulbright; Monahan Foundation for Biomedical Research Grants FX This work was supported by grants from NIH: K23 NS 083711 (M. E. Gurol); R01 AG026484 (S.M. Greenberg).; Gregoire Boulouis was supported by a J. William Fulbright and a Monahan Foundation for Biomedical Research Grants. NR 41 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD OCT 15 PY 2016 VL 369 BP 324 EP 329 DI 10.1016/j.jns.2016.08.049 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DY1NF UT WOS:000384861000064 PM 27653918 ER PT J AU Oudin, MJ Miller, MA Klazen, JAZ Kosciuk, T Lussiez, A Hughes, SK Tadros, J Bear, JE Lauffenburger, DA Gertler, FB AF Oudin, Madeleine J. Miller, Miles A. Klazen, Joelle A. Z. Kosciuk, Tatsiana Lussiez, Alisha Hughes, Shannon K. Tadros, Jenny Bear, James E. Lauffenburger, Douglas A. Gertler, Frank B. TI Mena(INV) mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID EXTRACELLULAR-MATRIX CUES; MOUSE MAMMARY-TUMORS; CELL-MIGRATION; DIRECTIONAL MIGRATION; PROTEIN MENA; FIBRONECTIN; INTEGRIN; PROGRESSION; INVASION; LAMELLIPODIA AB Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis-the directional movement of cells to soluble cues-and haptotaxis-the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. Mena(INV) has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin alpha 5 beta 1. Here we find that Mena(INV)-driven haptotaxis on fibronectin (FN) gradients requires intact signaling between alpha 5 beta 1 integrin and the epidermal growth factor receptor ( EGFR), which is influenced by PTP1B. Furthermore, we show that MenaINV-driven haptotaxis and ECM reorganization both require the Rab-coupling protein RCP, which mediates alpha 5 beta 1 and EGFR recycling. Finally, MenaINV promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that MenaINV is a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins. C1 [Oudin, Madeleine J.; Klazen, Joelle A. Z.; Kosciuk, Tatsiana; Lussiez, Alisha; Hughes, Shannon K.; Tadros, Jenny; Lauffenburger, Douglas A.; Gertler, Frank B.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Miller, Miles A.; Hughes, Shannon K.; Lauffenburger, Douglas A.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Gertler, Frank B.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Miller, Miles A.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Miller, Miles A.] Harvard Med Sch, Boston, MA 02114 USA. [Bear, James E.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. RP Gertler, FB (reprint author), MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA.; Gertler, FB (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM fgertler@mit.edu FU Department of Defense Breast Cancer Research Program [W81XWH-12-1-0031]; Ludwig Center for Molecular Oncology Postdoctoral Fellowship; Ludwig Center at the Massachusetts Institute of Technology; National Institutes of Health Grant [U54-CA112967]; Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund; Koch Institute NCI Core Grant [P30-CA14051] FX We thank the Microscopy, Flow Cytometry, and Histology facilities in the KI Swanson Biotechnology Center for support. This work was supported by Department of Defense Breast Cancer Research Program W81XWH-12-1-0031 and a Ludwig Center for Molecular Oncology Postdoctoral Fellowship to M.J.O., funds from the Ludwig Center at the Massachusetts Institute of Technology to F.B.G., National Institutes of Health Grant U54-CA112967 to F.B.G. and D.A.L., the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund to F.B.G., and Koch Institute NCI Core Grant P30-CA14051. NR 36 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT 15 PY 2016 VL 27 IS 20 BP 3085 EP 3094 DI 10.1091/mbc.E16-04-0212 PG 10 WC Cell Biology SC Cell Biology GA DY5ZQ UT WOS:000385185000008 PM 27559126 ER PT J AU Joseph, P Tawakol, A AF Joseph, Philip Tawakol, Ahmed TI Imaging atherosclerosis with positron emission tomography SO EUROPEAN HEART JOURNAL LA English DT Review DE Positron emission tomography; Atherosclerosis; Inflammation ID CAROTID PLAQUE INFLAMMATION; PROSTHETIC VALVE ENDOCARDITIS; RANDOMIZED CLINICAL-TRIAL; ACUTE CORONARY SYNDROME; ARTERIAL INFLAMMATION; FDG-PET/CT; F-18-FLUORODEOXYGLUCOSE UPTAKE; CARDIAC SARCOIDOSIS; RISK; EVENTS AB Positron emission tomography (PET) provides a non-invasive method to measure biological processes that are relevant to atherosclerosis, including arterial inflammation and calcification. The vast majority of studies imaging atherosclerosis with PET have utilized the tracer F-18-fluorodeoxyglucose (FDG) to better understand how inflammation contributes to atherosclerosis development, and to test the efficacy of therapeutic interventions aimed at reducing its progression. Additional tracers such as F-18-sodium fluoride (F-18-NaF) provide additional avenues for characterizing atherosclerosis development. This review examines the emerging uses of PET arterial imaging as a marker of vascular inflammation and atherosclerosis, as a prognostic tool, and as a clinical research tool. In addition, we examine emerging methods that should advance arterial imaging with PET. C1 [Joseph, Philip; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Suite 400,165 Cambridge St, Boston, MA 02114 USA. [Joseph, Philip; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Suite 400,165 Cambridge St, Boston, MA 02114 USA. [Joseph, Philip; Tawakol, Ahmed] Harvard Med Sch, Suite 400,165 Cambridge St, Boston, MA 02115 USA. [Joseph, Philip] McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton, ON, Canada. [Joseph, Philip] McMaster Univ, Dept Radiol, Hamilton, ON, Canada. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Suite 400,165 Cambridge St, Boston, MA 02114 USA.; Tawakol, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, Suite 400,165 Cambridge St, Boston, MA 02114 USA.; Tawakol, A (reprint author), Harvard Med Sch, Suite 400,165 Cambridge St, Boston, MA 02115 USA. EM atawakol@mgh.harvard.edu NR 55 TC 6 Z9 6 U1 10 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD OCT 14 PY 2016 VL 37 IS 39 BP 2974 EP + DI 10.1093/eurheartj/ehw147 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EC2YP UT WOS:000387990800008 PM 27125951 ER PT J AU Jadhav, S Russo, S Cottier, S Schneiter, R Cowart, A Greenberg, ML AF Jadhav, Shyamalagauri Russo, Sarah Cottier, Stephanie Schneiter, Roger Cowart, Ashley Greenberg, Miriam L. TI Valproate Induces the Unfolded Protein Response by Increasing Ceramide Levels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ceramide; fatty acid metabolism; lipid metabolism; sphingolipid; unfolded protein response (UPR); inositol ID ENDOPLASMIC-RETICULUM MEMBRANE; SACCHAROMYCES-CEREVISIAE; BIPOLAR DISORDER; INOSITOL-BIOSYNTHESIS; STRESS-RESPONSE; SPHINGOLIPID HOMEOSTASIS; PHOSPHATASE SAC1P; GENE-EXPRESSION; FUMONISIN B-1; YEAST AB Bipolar disorder (BD), which is characterized by depression and mania, affects 1-2% of the world population. Current treatments are effective in only 40-60% of cases and cause severe side effects. Valproate (VPA) is one of the most widely used drugs for the treatment of BD, but the therapeutic mechanism of action of this drug is not understood. This knowledge gap has hampered the development of effective treatments. To identify candidate pathways affected by VPA, we performed a genome-wide expression analysis in yeast cells grown in the presence or absence of the drug. VPA caused up-regulation of FEN1 and SUR4, encoding fatty acid elongases that catalyze the synthesis of very long chain fatty acids (C24 to C26) required for ceramide synthesis. Interestingly, fen1 and sur4 mutants exhibited VPA sensitivity. In agreement with increased fatty acid elongase gene expression, VPA increased levels of phytoceramide, especially those containing C24-C26 fatty acids. Consistent with an increase in ceramide, VPA decreased the expression of amino acid transporters, increased the expression of ER chaperones, and activated the unfolded protein response element (UPRE), suggesting that VPA induces the UPR pathway. These effects were rescued by supplementation of inositol and similarly observed in inositol-starved ino1 cells. Starvation of ino1 cells increased expression of FEN1 and SUR4, increased ceramide levels, decreased expression of nutrient transporters, and induced the UPR. These findings suggest that VPA-mediated inositol depletion induces the UPR by increasing the de novo synthesis of ceramide. C1 [Jadhav, Shyamalagauri; Greenberg, Miriam L.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Russo, Sarah; Cowart, Ashley] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Russo, Sarah; Cowart, Ashley] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Cottier, Stephanie; Schneiter, Roger] Univ Fribourg, Dept Biol, CH-1700 Fribourg, Switzerland. RP Greenberg, ML (reprint author), Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. EM mgreenberg@wayne.edu FU National Institutes of Health [DK081367]; Swiss National Science Foundation; Graduate School of Wayne State University FX This work was supported by National Institutes of Health Grant DK081367 (to M. L. G.), the Swiss National Science Foundation (to R. S.), and the Graduate School of Wayne State University (to S. J.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 55 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 14 PY 2016 VL 291 IS 42 BP 22253 EP 22261 DI 10.1074/jbc.M116.752634 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EA1DL UT WOS:000386332600036 PM 27590340 ER PT J AU Ueno, T Kim, P McGrath, MM Yeung, MY Shimizu, T Jung, K Sayegh, MH Chandraker, AK Abdi, R Yung, SH AF Ueno, Takuya Kim, Pllhan McGrath, Martina M. Yeung, Melissa Y. Shimizu, Tetsunosuke Jung, Keehoon Sayegh, Mohamed H. Chandraker, Anil K. Abdi, Reza Yung, Seok H. TI Live Images of Donor Dendritic Cells Trafficking via CX3CR1 Pathway SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE transplantation; imaging; chemokine; CX3CR1; dendritic cells ID RESPONSES; MONOCYTES AB Background: A number of studies have demonstrated the role of CX3CR1 in regulating the migration of monocytes into peripheral tissue and their transformation into dendritic cell (DC). No data are yet available on the importance of chemokine pathways in regulating homeostasis of DC in heart transplants. Recently, we showed that recipients of heart allografts from CX3CR1(-/-) donors show longer survival. To assess the trafficking of dDC, we have developed and tested a novel in vivo imaging tool in CX3CR1(GFP/+) DC (B6 background) heart graft into BALB/c recipient model. Results: Majority of GFP(+) cells were noted in the middle of cardiac myocyte. However few hours post transplant, they experienced morphological changes including stretching their extensions (3 and 24 h). However, images from 72 h at cardiac graft showed many of GFP(+) cells moved to vessel areas. GFP(+) cells were detected in near vessel wall. Only one GFP(+) cell was observed in three lymph nodes (two mesenteric and one inguinal) (72 h). Conclusion: Our data indicate that immediately post transplant dDC undergo morphological changes and traffic out of the organs via systemic circulation. While, we still noted presence of dDC in the transplanted organs, their trafficking to lymphoid tissue remains to be fully explored. C1 [Ueno, Takuya; McGrath, Martina M.; Yeung, Melissa Y.; Shimizu, Tetsunosuke; Sayegh, Mohamed H.; Chandraker, Anil K.; Abdi, Reza] Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA. [Kim, Pllhan; Jung, Keehoon; Yung, Seok H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA USA. RP Ueno, T (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA 02115 USA. EM ueno.takuya@mgh.harvard.edu FU American Heart Association [11SDG5150000]; JSPS KAKENHI [15K15479]; National Institutes of Health [P41-EB015903]; American Heart Association Scientist Development Grant FX This work was supported by American Heart Association (11SDG5150000), JSPS KAKENHI (15K15479), and National Institutes of Health (P41-EB015903). TU is a recipient of the American Heart Association Scientist Development Grant and Grant-in-Aid for Challenging Exploratory Research. NR 12 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD OCT 14 PY 2016 VL 7 AR 412 DI 10.3389/fimmu.2016.00412 PG 5 WC Immunology SC Immunology GA DY8XM UT WOS:000385415600001 PM 27790214 ER PT J AU Onyango, MA Burkhardt, G Scott, J Rouhani, S Haider, S Greiner, A Albutt, K Mullen, C VanRooyen, M Bartels, S AF Onyango, Monica Adhiambo Burkhardt, Gillian Scott, Jennifer Rouhani, Shada Haider, Sadia Greiner, Ashley Albutt, Katherine Mullen, Colleen VanRooyen, Michael Bartels, Susan TI A Qualitative Analysis of Disclosure Patterns among Women with Sexual Violence-Related Pregnancies in Eastern Democratic Republic of Congo SO PLOS ONE LA English DT Article ID MENTAL-HEALTH; ABORTION; VICTIMS AB The Democratic Republic of the Congo (DRC) has experienced nearly two decades of civil conflict in the Eastern regions of North and South Kivu. This conflict has been notorious for the use of sexual violence as a weapon of war, leading in many cases to pregnancy after rape. The objectives of this analysis were: 1) to describe patterns of sexual violence-related pregnancy (SVRP) disclosure; 2) to consider why survivors chose to disclose to particular individuals; and 3) to examine the dialogue around SVRPs between women with SVRPs and their confidants. In South Kivu Province, Democratic Republic of Congo, two subgroups of sexual violence survivors completed qualitative interviews, those currently raising a child from an SVRP (parenting group, N = 38) and those who had terminated an SVRP (termination group, N = 17). The findings show that a majority of SVRPs were conceived when participants were held in sexual captivity for prolonged periods of time. The SVRPs were disclosed to friends, family members, other sexual violence survivors, community members, spouses, health care providers, or perpetrators. The confidants were most often chosen because they were perceived by the participants as being discreet, trusted, and supportive. The confidants often provided advice about continuing or terminating the SVRP. Trust and discretion are the most important factors determining to whom women with SVRPs disclose their pregnancies. The vital role of confidants in giving support after disclosure cannot be overlooked. Providing opportunities for survivors to safely disclose their SVRPs, including to health care providers, is a necessary first step in allowing them to access safe and comprehensive post-assault care and services. C1 [Onyango, Monica Adhiambo] Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA 02215 USA. [Burkhardt, Gillian; Scott, Jennifer; Rouhani, Shada; Greiner, Ashley; Albutt, Katherine; VanRooyen, Michael; Bartels, Susan] Harvard Humanitarian Initiat, Cambridge, MA USA. [Burkhardt, Gillian] Boston Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA 02118 USA. [Scott, Jennifer] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Scott, Jennifer] Brigham & Womens Hosp, Div Womens Hlth, 75 Francis St, Boston, MA 02115 USA. [Scott, Jennifer; Rouhani, Shada; Albutt, Katherine; VanRooyen, Michael; Bartels, Susan] Harvard Med Sch, Boston, MA USA. [Rouhani, Shada; VanRooyen, Michael] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Haider, Sadia] Univ Illinois, Dept Obstet & Gynecol, Chicago, IL 60612 USA. [Greiner, Ashley; Bartels, Susan] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. [Albutt, Katherine] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mullen, Colleen] Boston Med Ctr, Dept Psychiat, Boston, MA USA. [VanRooyen, Michael] Harvard Sch Publ Hlth, Boston, MA USA. [Bartels, Susan] Queens Univ, Dept Emergency Med, Kingston, ON, Canada. RP Onyango, MA (reprint author), Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA 02215 USA. EM monyango@bu.edu FU Eleanor Miles Shore Foundation [GL Dept] [01025283]; Harvard Humanitarian Initiative; Eleanor Miles Shore Foundation at the Harvard Medical School FX This work was supported by Eleanor Miles Shore Foundation [GL Dept ID 01025283] and the Harvard Humanitarian Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We are grateful to our partners: Centre d'Assistance Medico-Psychosociale (CAMPS), Acteurs Dans le Development et Droit a la Sante Pour Tous (ADES) and Action Pour la Lutte Contre L'Ignorance du SIDA (ALCIS). We would like to thank colleagues at the Harvard Humanitarian Initiative (HHI) as well as Daisy Njebenje, Amani Baro and Ideumbo Kasigwa. This study was funded by the Eleanor Miles Shore Foundation at the Harvard Medical School and by generous donations to Harvard Humanitarian Initiative (HHI). NR 37 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 14 PY 2016 VL 11 IS 10 AR e0164631 DI 10.1371/journal.pone.0164631 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0DG UT WOS:000385507000049 PM 27741262 ER PT J AU Zhang, JT Fiore, A Yun, SH Kim, H Scarcelli, G AF Zhang, Jitao Fiore, Antonio Yun, Seok-Hyun Kim, Hanyoup Scarcelli, Giuliano TI Line-scanning Brillouin microscopy for rapid non-invasive mechanical imaging SO SCIENTIFIC REPORTS LA English DT Article ID LIGHT-SCATTERING; OPTICAL MICROSCOPY; ELASTIC PROPERTIES; GAIN SPECTROSCOPY; VIPA ETALONS; HUMAN EYE; LENS; LIQUIDS; SPECTROMETER; DISPERSION AB Brillouin spectroscopy probes the mechanical properties of material by measuring the optical frequency shift induced by photon-phonon scattering interactions. In traditional configurations, Brillouin spectrometers measure only one point of the sample at a time. This results in long acquisition times for mechanical imaging of large areas. In this work, we demonstrate a parallel detection configuration where the Brillouin shift of hundreds of points in a line can be measured simultaneously. In mm-sized samples, this novel configuration effectively shortens the acquisition time of two-dimensional Brillouin imaging from hours to tens of seconds, thus making it a powerful technology for label-free mechanical characterization of tissue and biomaterials. C1 [Zhang, Jitao; Fiore, Antonio; Scarcelli, Giuliano] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Yun, Seok-Hyun] Harvard Med Sch, Cambridge, MA 02139 USA. [Yun, Seok-Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Yun, Seok-Hyun] Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA. [Kim, Hanyoup] Canon US Life Sci Inc, 9800 Med Ctr Dr,Suite C-120, Rockville, MD 20850 USA. RP Scarcelli, G (reprint author), Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. EM scarc@umd.edu FU National Institutes of Health [K25EB015885, R21EY023043, R01EY025454]; National Science Foundation [CMMI-1537027, CBET-0853773]; Human Frontier Science Program; Canon Innovation Award FX This work was supported in part by the National Institutes of Health (K25EB015885, R21EY023043, R01EY025454); National Science Foundation (CMMI-1537027, CBET-0853773); Human Frontier Science Program (Young Investigator Grant); and Canon Innovation Award. J.Z. would like to thank Mr. Qiannian Jiang from Dongguan Yu Guang Opt & Electronics Tech. Co., Ltd for providing the PMMA lens. NR 42 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 14 PY 2016 VL 6 AR 35398 DI 10.1038/srep35398 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY9IF UT WOS:000385446400002 PM 27739499 ER PT J AU Cavalli, RC Cerdeira, AS Perniconel, E Korkes, HA Burke, SD Rajakumar, A Thadhani, RI Roberts, DJ Bhasinl, M Karumanchi, SA Kopcow, HD AF Cavalli, Ricardo C. Cerdeira, Ana Sofia Perniconel, Elizabeth Korkes, Henri A. Burke, Suzanne D. Rajakumar, Augustine Thadhani, Ravi I. Roberts, Drucilla J. Bhasinl, Manoj Karumanchi, S. Ananth Kopcow, Hernan D. TI Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; UTERINE ARTERY DOPPLER; COLONY-STIMULATING FACTOR; METRIAL GLAND-CELLS; PLACENTAL BED; BLOOD-FLOW; TROPHOBLAST INVASION; GROWTH RESTRICTION; INTERFERON-GAMMA; EARLY-PREGNANCY AB Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as pre-eclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGF beta- 1 and 5-aza-2'-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56 (Bright) idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56 (Dim) idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immu-nocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion. C1 [Cavalli, Ricardo C.; Cerdeira, Ana Sofia; Perniconel, Elizabeth; Korkes, Henri A.; Burke, Suzanne D.; Rajakumar, Augustine; Bhasinl, Manoj; Karumanchi, S. Ananth; Kopcow, Hernan D.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Cerdeira, Ana Sofia] Gulbenkian Programme Adv Med Educ, Lisbon, Portugal. [Burke, Suzanne D.; Rajakumar, Augustine; Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. [Thadhani, Ravi I.] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Boston, MA USA. [Roberts, Drucilla J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Cavalli, Ricardo C.] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Obstet & Gynaecol, BR-05508 Sao Paulo, Brazil. [Cerdeira, Ana Sofia] Univ Oxford, Nuffield Dept Obstet Gynaecol, Oxford, England. [Korkes, Henri A.] Univ Fed Sao Paulo, Dept Obstet, Sao Paulo, Brazil. [Rajakumar, Augustine] Emory Univ, Sch Med, Dept Obstet & Gynaecol, Atlanta, GA USA. RP Kopcow, HD (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. EM kopcowh@gmail.com FU American Heart Association [13GRNT17070111]; Preeclampsia Foundation; Howard Hughes Medical Institute; FAPESP Sao Paulo Research Foundation; CAPES Foundation FX This project was funded by the American Heart Association (http://www.heart.org) Grant in Aid 13GRNT17070111 to HDK, Preeclampsia Foundation (http://www.preeclampsia.org) Vision Grant to ASC, Howard Hughes Medical Institute (http://www.hhmi.org) to SAK, FAPESP Sao Paulo Research Foundation (http://www.fapesp.br/en/) to RCC, CAPES Foundation (http://www.capes.gov.br) to HAK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 1 Z9 1 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 13 PY 2016 VL 11 IS 10 AR e0164353 DI 10.1371/journal.pone.0164353 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CV UT WOS:000385505800056 PM 27736914 ER PT J AU Lin, EW Karakasheva, TA Hicks, PD Bass, AJ Rustgi, AK AF Lin, E. W. Karakasheva, T. A. Hicks, P. D. Bass, A. J. Rustgi, A. K. TI The tumor microenvironment in esophageal cancer SO ONCOGENE LA English DT Review ID SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; REGULATORY T-CELLS; GROWTH-FACTOR-BETA; OXIDATIVE DNA-DAMAGE; DYSPLASIA-ADENOCARCINOMA SEQUENCE; UPPER GASTROINTESTINAL-TRACT; TRANSFORMED BARRETTS CELLS; SUPPRESSOR-CELLS; SIGNALING PATHWAY AB Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus, there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment (TME), which contains diverse cell populations, signaling factors and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Antitumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells and regulatory T cells, as well as immune checkpoints like programmed death-1. Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy. C1 [Lin, E. W.; Karakasheva, T. A.; Hicks, P. D.; Rustgi, A. K.] Univ Penn, Dept Med, Perelman Sch Med, Div Gastroenterol, 951 BRB 421 Curie Blvd, Philadelphia, PA 19104 USA. [Lin, E. W.; Karakasheva, T. A.; Hicks, P. D.; Rustgi, A. K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Bass, A. J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rustgi, A. K.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. RP Rustgi, AK (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Div Gastroenterol, 951 BRB 421 Curie Blvd, Philadelphia, PA 19104 USA. EM anil2@mail.med.upenn.edu FU NCI NIH HHS [P01 CA098101]; NIDDK NIH HHS [P30 DK050306] NR 208 TC 4 Z9 4 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD OCT 13 PY 2016 VL 35 IS 41 BP 5337 EP 5349 DI 10.1038/onc.2016.34 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EA5QU UT WOS:000386677800001 PM 26923327 ER PT J AU Lichtenstein, DA Crispin, AW Sendamarai, AK Campagna, DR Schmitz-Abe, K Sousa, CM Kafina, MD Schmidt, PJ Niemeyer, CM Porter, J May, A Patnaik, MM Heeney, MM Kimmelman, A Bottomley, SS Paw, BH Markianos, K Fleming, MD AF Lichtenstein, Daniel A. Crispin, Andrew W. Sendamarai, Anoop K. Campagna, Dean R. Schmitz-Abe, Klaus Sousa, Cristovao M. Kafina, Martin D. Schmidt, Paul J. Niemeyer, Charlotte M. Porter, John May, Alison Patnaik, Mrinal M. Heeney, Matthew M. Kimmelman, Alec Bottomley, Sylvia S. Paw, Barry H. Markianos, Kyriacos Fleming, Mark D. TI A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia SO BLOOD LA English DT Article ID DEVELOPMENTAL DELAY SIFD; LACTIC-ACIDOSIS; IMMUNODEFICIENCY; MYOPATHY; FEVERS; IRON; GENE AB The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder. C1 [Lichtenstein, Daniel A.; Crispin, Andrew W.; Sendamarai, Anoop K.; Campagna, Dean R.; Schmidt, Paul J.; Markianos, Kyriacos; Fleming, Mark D.] Boston Childrens Hosp, Dept Pathol, Bader 124-1,BCH 3027,300 Longwood Ave, Boston, MA 02115 USA. [Schmitz-Abe, Klaus] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Sousa, Cristovao M.; Kimmelman, Alec] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Kafina, Martin D.; Paw, Barry H.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Kafina, Martin D.; Paw, Barry H.] Boston Childrens Hosp, Boston, MA USA. [Niemeyer, Charlotte M.] Univ Freiburg, Fac Med, Med Ctr, Dept Pediat & Adolescent Med,Div Pediat Hematol &, Freiburg, Germany. [Porter, John] Kings Coll London, Div Haematol, London, England. [May, Alison] Cardiff Univ, Sch Med, Dept Haematol, Cardiff, S Glam, Wales. [Patnaik, Mrinal M.] Mayo Clin, Div Hematol Oncol, Rochester, MN USA. [Heeney, Matthew M.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Kimmelman, Alec] NYU, Langone Canc Ctr, Dept Radiat Oncol, New York, NY USA. [Bottomley, Sylvia S.] Univ Oklahoma, Coll Med, Oklahoma City, OK 73190 USA. RP Fleming, MD (reprint author), Boston Childrens Hosp, Dept Pathol, Bader 124-1,BCH 3027,300 Longwood Ave, Boston, MA 02115 USA. EM mark.fleming@childrens.harvard.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK087992, R01 DK070838]; National Heart, Lung, and Blood Institute [P01 HL03226 2] FX This work was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases DK087992 (M.D.F.) and R01 DK070838 and National Heart, Lung, and Blood Institute P01 HL03226 2 (B.H.P.). NR 14 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 13 PY 2016 VL 128 IS 15 BP 1913 EP 1917 DI 10.1182/blood-2016-05-719062 PG 5 WC Hematology SC Hematology GA DZ3IA UT WOS:000385738500004 PM 27488349 ER PT J AU Nasrallah, R Fast, EM Solaimani, P Knezevic, K Eliades, A Patel, R Thambyrajah, R Unnikrishnan, A Thoms, J Beck, D Vink, CS Smith, A Wong, J Shepherd, M Kent, D Roychoudhuri, R Paul, F Klippert, J Hammes, A Willnow, T Ottgens, BG Dzierzak, E Zon, LI Lacaud, G Kouskoff, V Pimanda, JE AF Nasrallah, Rabab Fast, Eva M. Solaimani, Parham Knezevic, Kathy Eliades, Alexia Patel, Rahima Thambyrajah, Roshana Unnikrishnan, Ashwin Thoms, Julie Beck, Dominik Vink, Chris S. Smith, Aileen Wong, Jason Shepherd, Mairi Kent, David Roychoudhuri, Rahul Paul, Fabian Klippert, Julia Hammes, Annette Willnow, Thomas Ottgens, Bertie G. Dzierzak, Elaine Zon, Leonard I. Lacaud, George Kouskoff, Valerie Pimanda, John E. TI Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes SO BLOOD LA English DT Article ID GENOME-WIDE ANALYSIS; STEM-CELLS; HEMOGENIC ENDOTHELIUM; AORTIC ENDOTHELIUM; PROGENITOR CELLS; RECEPTOR; ZEBRAFISH; BLOOD; GENE; HEMANGIOBLAST AB Enhancers are the primary determinants of cell identity, and specific promoter/enhancer combinations of Endoglin (ENG) have been shown to target blood and endothelium in the embryo. Here, we generated a series of embryonic stem cell lines, each targeted with reporter constructs driven by specific promoter/enhancer combinations of ENG, to evaluate their discriminative potential and value as molecular probes of the corresponding transcriptome. The Eng promoter (P) in combination with the -8/+7/+9-kb enhancers, targeted cells in FLK1 mesoderm that were enriched for blast colony forming potential, whereas the P/-8-kb enhancer targeted TIE2+/c-KIT+/CD41- endothelial cells that were enriched for hematopoietic potential. These fractions were isolated using reporter expression and their transcriptomes profiled by RNA-seq. There was high concordance between our signatures and those from embryos with defects at corresponding stages of hematopoiesis. Of the 6 genes that were upregulated in both hemogenic mesoderm and hemogenic endothelial fractions targeted by the reporters, LRP2, a multiligand receptor, was the only gene that had not previously been associated with hematopoiesis. We show that LRP2 is indeed involved in definitive hematopoiesis and by doing so validate the use of reporter gene-coupled enhancers as probes to gain insights into transcriptional changes that facilitate cell fate transitions. C1 [Nasrallah, Rabab; Knezevic, Kathy; Unnikrishnan, Ashwin; Thoms, Julie; Beck, Dominik; Wong, Jason; Pimanda, John E.] Univ New South Wales Australia, Lowy Canc Res Ctr, Sydney, NSW 2052, Australia. [Nasrallah, Rabab; Knezevic, Kathy; Unnikrishnan, Ashwin; Thoms, Julie; Beck, Dominik; Wong, Jason; Pimanda, John E.] Univ New South Wales Australia, Prince Wales Clin Sch, Sydney, NSW 2052, Australia. [Fast, Eva M.; Zon, Leonard I.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Fast, Eva M.; Zon, Leonard I.] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Howard Hughes Med Inst,Stem Cell Program, Boston, MA USA. [Fast, Eva M.; Zon, Leonard I.] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Solaimani, Parham; Vink, Chris S.; Dzierzak, Elaine] Erasmus Univ, Med Ctr, Dept Cell Biol, Erasmus Med Ctr,Stem Cell Inst, Rotterdam, Netherlands. [Eliades, Alexia; Patel, Rahima; Thambyrajah, Roshana; Lacaud, George; Kouskoff, Valerie] Univ Manchester, Canc Res United Kingdom Manchester Inst, 553 B5093, Manchester M20 4BX, Lancs, England. [Vink, Chris S.; Dzierzak, Elaine] Univ Edinburgh, MRC, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland. [Smith, Aileen; Shepherd, Mairi; Kent, David; Ottgens, Bertie G.] Univ Cambridge, Dept Haematol, Wellcome Trust, Cambridge, England. [Smith, Aileen; Shepherd, Mairi; Kent, David; Ottgens, Bertie G.] Univ Cambridge, MRC, Cambridge Stem Cell Inst, Cambridge, England. [Smith, Aileen; Shepherd, Mairi; Kent, David; Ottgens, Bertie G.] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Roychoudhuri, Rahul] Babraham Inst, Babraham Res Campus, Cambridge, England. [Paul, Fabian; Klippert, Julia; Hammes, Annette; Willnow, Thomas] Max Delbrueck Ctr Mol Med, Berlin, Germany. [Pimanda, John E.] Prince Wales Hosp, Dept Haematol, Sydney, NSW, Australia. [Solaimani, Parham] BeDataDriven BV, The Hague, Netherlands. [Smith, Aileen] GSK Pharmaceut Co, London, England. RP Pimanda, JE (reprint author), Univ New South Wales Australia, Lowy Canc Res Ctr, Sydney, NSW 2052, Australia.; Pimanda, JE (reprint author), Univ New South Wales Australia, Prince Wales Clin Sch, Sydney, NSW 2052, Australia.; Lacaud, G; Kouskoff, V (reprint author), Univ Manchester, Canc Res United Kingdom Manchester Inst, 553 B5093, Manchester M20 4BX, Lancs, England. EM georges.lacaud@cruk.manchester.ac.uk; valerie.kouskoff@cruk.manchester.ac.uk; jpimanda@unsw.edu.au FU National Health and Medical Research Council of Australia; Australian Research Council; Tom Bee Stem Cell Research Fund; Cancer Research UK; Biotechnology and Biological Sciences Research Council; Leukaemia and Lymphoma Research; Leukaemia and Lymphoma Society; Wellcome Trust; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute; National Institutes of Health National Heart, Lung, and Blood Institute [R01 HL04880, P015PO1HL32262-32, 5U01 HL10001-05]; National Institute of Diabetes and Digestive and Kidney Diseases [5P30 DK49216, 5R01 DK53298, R24 DK092760] FX This work was supported by grants from the National Health and Medical Research Council of Australia, Australian Research Council, and the Tom Bee Stem Cell Research Fund (J.E.P.), Cancer Research UK (V.K. and G.L.), the Biotechnology and Biological Sciences Research Council, Leukaemia and Lymphoma Research, The Leukaemia and Lymphoma Society, and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (B.G.). This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (R01 HL04880, P015PO1HL32262-32, and 5U01 HL10001-05) and National Institute of Diabetes and Digestive and Kidney Diseases (5P30 DK49216, 5R01 DK53298, and R24 DK092760) (L.I.Z.). E.M.F. is a Fellow of the Leukemia and Lymphoma Society. NR 55 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 13 PY 2016 VL 128 IS 15 BP 1928 EP 1939 DI 10.1182/blood-2016-02-697870 PG 12 WC Hematology SC Hematology GA DZ3IA UT WOS:000385738500006 PM 27554085 ER PT J AU Villar, J Belda, J Blanco, J Suarez-Sipmann, F Anon, JM Perez-Mendez, L Ferrando, C Parrilla, D Montiel, R Corpas, R Gonzalez-Higueras, E Pestana, D Martinez, D Fernandez, L Soro, M Garcia-Bello, MA Fernandez, RL Kacmarek, RM AF Villar, Jesus Belda, Javier Blanco, Jesus Suarez-Sipmann, Fernando Manuel Anon, Jose Perez-Mendez, Lina Ferrando, Carlos Parrilla, Dacil Montiel, Raquel Corpas, Ruth Gonzalez-Higueras, Elena Pestana, David Martinez, Domingo Fernandez, Lorena Soro, Marina Angel Garcia-Bello, Miguel Lidia Fernandez, Rosa Kacmarek, Robert M. CA NAVa In Acute Resp Failure NAVIAT TI Neurally adjusted ventilatory assist in patients with acute respiratory failure: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Acute respiratory failure; Neurally adjusted ventilatory assist; Ventilator-free days; Lung-protective ventilation; Assist ventilation; Liberation from mechanical ventilation ID PRESSURE-SUPPORT VENTILATION; MECHANICAL VENTILATION; DISTRESS-SYNDROME; ASYNCHRONY; SEDATION; NAVA; VARIABILITY; EFFICACY; INFANTS; SCALE AB Background: Patient-ventilator asynchrony is a common problem in mechanically ventilated patients with acute respiratory failure. It is assumed that asynchronies worsen lung function and prolong the duration of mechanical ventilation (MV). Neurally Adjusted Ventilatory Assist (NAVA) is a novel approach to MV based on neural respiratory center output that is able to trigger, cycle, and regulate the ventilatory cycle. We hypothesized that the use of NAVA compared to conventional lung-protective MV will result in a reduction of the duration of MV. It is further hypothesized that NAVA compared to conventional lung-protective MV will result in a decrease in the length of ICU and hospital stay, and mortality. Methods/design: This is a prospective, multicenter, randomized controlled trial in 306 mechanically ventilated patients with acute respiratory failure from several etiologies. Only patients ventilated for less than 5 days, and who are expected to require prolonged MV for an additional 72 h or more and are able to breathe spontaneously, will be considered for enrollment. Eligible patients will be randomly allocated to two ventilatory arms: (1) conventional lung-protective MV (n = 153) and conventional lung-protective MV with NAVA (n = 153). Primary outcome is the number of ventilator-free days, defined as days alive and free from MV at day 28 after endotracheal intubation. Secondary outcomes are total length of MV, and ICU and hospital mortality. Discussion: This is the first randomized clinical trial examining, on a multicenter scale, the beneficial effects of NAVA in reducing the dependency on MV of patients with acute respiratory failure. C1 [Villar, Jesus; Blanco, Jesus; Suarez-Sipmann, Fernando; Perez-Mendez, Lina; Lidia Fernandez, Rosa] Inst Salud Carlos III, CIBER Enfermedades Resp, Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain. [Villar, Jesus; Lidia Fernandez, Rosa] Hosp Univ Dr Negrin, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Res Unit, Barranco Ballena S-N,4th Floor South Wing, Las Palmas Gran Canaria 35019, Spain. [Villar, Jesus] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr Biomed Sci, 30 Bond St, Toronto, ON M5B 1W8, Canada. [Belda, Javier; Ferrando, Carlos; Soro, Marina] Hosp Clin Univ Valencia, Dept Anesthesiol, Avda Blasco Ibanez 17, Valencia 46010, Spain. [Blanco, Jesus] Hosp Univ Rio Hortega, Intens Care Unit, Calle Dulzaina 2, Valladolid 47012, Spain. [Suarez-Sipmann, Fernando] Univ Uppsala Hosp, Hedenstierna Lab, Dept Surg Sci, Akad Sjukhuset, Ing 40,Tr 3, SE-75185 Uppsala, Sweden. [Manuel Anon, Jose; Gonzalez-Higueras, Elena] Hosp Virgen de La Luz, Intens Care Unit, Hermandad de Donantes Sangre S-N, Cuenca 16002, Spain. [Perez-Mendez, Lina] Hosp Univ NS Candelaria, Res Unit, Div Clin Epidemiol & Biostat, Carretera Gen Rosario 145, Santa Cruz De Tenerife 38010, Spain. [Parrilla, Dacil; Montiel, Raquel] Hosp Univ NS Candelaria, Intens Care Unit, Carretera Gen Rosario 145, Santa Cruz De Tenerife 38010, Spain. [Corpas, Ruth] Hosp Gen NS Prado, Intens Care Unit, Carretera Madrid,Km 114, Talavera De La Reina, Toledo, Spain. [Pestana, David] Hosp Univ Ramon y Cajal, Dept Anesthesiol, Carretera Colmenar Viejo,Km 9,100, Madrid 28034, Spain. [Martinez, Domingo] Hosp Univ Virgen de la Arrixaca, Intens Care Unit, Carretera Madrid Cartagena S-N, Murcia 30120, Spain. [Angel Garcia-Bello, Miguel] Hosp Univ Dr Negrin, Div Biostat, Res Unit, Barranco Ballena S-N, Las Palmas Gran Canaria 35019, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol, 55 Fruit St Gray Bigelow 444, Boston, MA 02144 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain.; Villar, J (reprint author), Hosp Univ Dr Negrin, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Res Unit, Barranco Ballena S-N,4th Floor South Wing, Las Palmas Gran Canaria 35019, Spain.; Villar, J (reprint author), St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr Biomed Sci, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM jesus.villar54@gmail.com FU Instituto de Salud Carlos III, Madrid, Spain [PI13/0119]; CIBER de Enfermedades Respiratorias [CB06/06/1088]; MAQUET-Getinge (Solna, Sweden); Asociacion Cientifica Pulmon y Ventilacion Mecanica, Las Palmas de Gran Canaria, Spain FX This trial is supported in part by the Instituto de Salud Carlos III, Madrid, Spain (PI13/0119), by the CIBER de Enfermedades Respiratorias (CB06/06/1088), by MAQUET-Getinge (Solna, Sweden), and by Asociacion Cientifica Pulmon y Ventilacion Mecanica, Las Palmas de Gran Canaria, Spain. The funders had no role in the content, decision to publish, or preparation of the manuscript. None of the clinical investigators enrolling patients have received any honorarium for participating in the study. NR 29 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD OCT 13 PY 2016 VL 17 AR 500 DI 10.1186/s13063-016-1625-5 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DY9DW UT WOS:000385434800006 PM 27737690 ER PT J AU Byrne, TN Stone, JH Pillai, SS Rapalino, O Deshpande, V AF Byrne, Thomas N. Stone, John H. Pillai, Shiv S. Rapalino, Otto Deshpande, Vikram TI Case 31-2016: A 53-Year-Old Man with Diplopia, Polydipsia, and Polyuria IgG4-related hypophysitis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LANGERHANS CELL HISTIOCYTOSIS; OF-THE-LITERATURE; AUTOIMMUNE HYPOPHYSITIS; SYSTEMIC-DISEASE; STALK LESIONS; PITUITARY; GRANULOMATOSIS; RITUXIMAB; MANIFESTATIONS; PANCREATITIS C1 [Byrne, Thomas N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Rheumatol, Boston, MA 02114 USA. [Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Byrne, Thomas N.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Stone, John H.] Harvard Med Sch, Dept Rheumatol, Boston, MA 02115 USA. [Rapalino, Otto] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Deshpande, Vikram] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. [Pillai, Shiv S.] Harvard Med Sch, Ragon Inst, Boston, MA 02115 USA. RP Byrne, TN (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Byrne, TN (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. FU Roche; Genentech; Xencor; Abide Pharmaceuticals; Pfizer; Affymetrix FX Dr. Stone reports receiving consulting fees and grant support from Roche, Genentech, and Xencor; Dr. Pillai, consulting fees from Genentech and grant support from Abide Pharmaceuticals and Pfizer; and Dr. Deshpande, consulting fees and grant support from Affymetrix. No other potential conflict of interest relevant to this article was reported. NR 42 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 BP 1469 EP 1480 DI 10.1056/NEJMcpc1610097 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400012 PM 27732818 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Treatment or Monitoring for Early Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID AGE C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA.; D'Amico, AV (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 5 Z9 5 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 BP 1482 EP 1483 DI 10.1056/NEJMe1610395 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400013 PM 27627134 ER PT J AU LaRocque, RC Ryan, ET AF LaRocque, Regina C. Ryan, Edward T. TI Medical Considerations before International Travel SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [LaRocque, Regina C.; Ryan, Edward T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM etryan@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2016 VL 375 IS 15 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DY5IH UT WOS:000385132400027 ER PT J AU Rahbari, NN Kedrin, D Incio, J Liu, H Ho, WW Nia, HT Edrich, CM Jung, K Daubriac, J Chen, I Heishi, T Martin, JD Huang, YH Maimon, N Reissfelder, C Weitz, J Boucher, Y Clark, JW Grodzinsky, AJ Duda, DG Jain, RK Fukumura, D AF Rahbari, Nuh N. Kedrin, Dmitriy Incio, Joao Liu, Hao Ho, William W. Nia, Hadi T. Edrich, Christina M. Jung, Keehoon Daubriac, Julien Chen, Ivy Heishi, Takahiro Martin, John D. Huang, Yuhui Maimon, Nir Reissfelder, Christoph Weitz, Jurgen Boucher, Yves Clark, Jeffrey W. Grodzinsky, Alan J. Duda, Dan G. Jain, Rakesh K. Fukumura, Dai TI Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases SO Science Translational Medicine LA English DT Article ID ANCHORAGE-INDEPENDENT GROWTH; PANCREATIC DUCTAL ADENOCARCINOMA; TUMOR-ASSOCIATED MACROPHAGES; INTERSTITIAL FLUID PRESSURE; MAMMARY-CARCINOMA CELLS; IN-VIVO; SOLID STRESS; HYALURONAN PRODUCTION; STROMAL HYALURONAN; GAUSSIA LUCIFERASE AB The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy. C1 [Rahbari, Nuh N.; Kedrin, Dmitriy; Incio, Joao; Liu, Hao; Ho, William W.; Nia, Hadi T.; Edrich, Christina M.; Jung, Keehoon; Daubriac, Julien; Chen, Ivy; Heishi, Takahiro; Martin, John D.; Huang, Yuhui; Maimon, Nir; Boucher, Yves; Duda, Dan G.; Jain, Rakesh K.; Fukumura, Dai] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Boston, MA 02114 USA. [Rahbari, Nuh N.; Kedrin, Dmitriy; Incio, Joao; Liu, Hao; Ho, William W.; Nia, Hadi T.; Edrich, Christina M.; Jung, Keehoon; Daubriac, Julien; Chen, Ivy; Heishi, Takahiro; Martin, John D.; Huang, Yuhui; Maimon, Nir; Boucher, Yves; Clark, Jeffrey W.; Duda, Dan G.; Jain, Rakesh K.; Fukumura, Dai] Harvard Med Sch, Boston, MA 02114 USA. [Rahbari, Nuh N.; Reissfelder, Christoph; Weitz, Jurgen] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Gen Thorac & Vasc Surg, D-01307 Dresden, Germany. [Kedrin, Dmitriy] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ho, William W.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chen, Ivy] Harvard Univ, Harvard Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Grodzinsky, Alan J.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Rahbari, Nuh N.] Mem Sloan Kettering Canc Ctr, Surg Oncol, New York, NY 10065 USA. [Huang, Yuhui] Soochow Univ, Cyrus Tang Hematol Ctr, Suzhou 215123, Jiangsu, Peoples R China. RP Jain, RK; Fukumura, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Boston, MA 02114 USA.; Jain, RK; Fukumura, D (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu; dai@steele.mgh.harvard.edu FU NIH [CA080124, T32DK007191, CA126642, CA197743, CA096915, CA139168, CA159258, CA098706, CA173518]; American Cancer Society [120733-RSG-11-073-01-TBG]; German Research Foundation (DFG); Foundation for Science and Technology (FCT, Portugal); Portuguese Human Potential Operational Program/European Social Fund (POPH/FSE) FX This study was supported, in part, by the NIH (CA080124 to R.K.J., D.F., D.G.D., and Y.B., T32DK007191 to D.K., CA126642 and CA197743 to R.K.J., CA096915 to D.F., CA139168 and CA159258 to D.G.D., and CA098706 and CA173518 to Y.B.), the American Cancer Society (grant 120733-RSG-11-073-01-TBG to D.G.D.), fellowship from the German Research Foundation (DFG) (to N.N.R.), fellowship from the Foundation for Science and Technology (FCT, Portugal), and the Portuguese Human Potential Operational Program/European Social Fund (POPH/FSE) funding program (to J.I.). NR 78 TC 2 Z9 2 U1 6 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 12 PY 2016 VL 8 IS 360 AR 360ra135 DI 10.1126/scitranslmed.aaf5219 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2UZ UT WOS:000389441800002 PM 27733559 ER PT J AU Raeesi, V Chou, LYT Chan, WCW AF Raeesi, Vahid Chou, Leo Y. T. Chan, Warren C. W. TI Tuning the Drug Loading and Release of DNA-Assembled Gold-Nanorod Superstructures SO ADVANCED MATERIALS LA English DT Article DE cancer; controlled drug release; DNA assembly; gold nanorods; core-satellite; nanotechnology; nanomedicine ID TUMOR TARGETING EFFICIENCY; NANOPARTICLE SUPERSTRUCTURES; DOXORUBICIN; DELIVERY; CANCER; DAUNOMYCIN; DESIGN; SIZE; CHEMOTHERAPY; PEGYLATION AB The use of DNA to assemble inorganic nanoparticles into superstructures is an emerging strategy to build non-toxic delivery vehicles for targeting diseases in the body. The impact of the core-satellite nanosystem design in mediating drug storage, drug release (via heat), and killing of HeLa cells in culture is investigated. C1 [Raeesi, Vahid; Chan, Warren C. W.] Univ Toronto, Dept Mat Sci & Engn, Toronto, ON M5S 3E1, Canada. [Raeesi, Vahid; Chou, Leo Y. T.; Chan, Warren C. W.] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5S 3G9, Canada. [Chou, Leo Y. T.] Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Chou, Leo Y. T.] Harvard Med Sch, Wyss Inst Biol Inspired Engn, 3 Blackfan Circle,CLSB 5th Floor, Boston, MA 02115 USA. [Chan, Warren C. W.] Univ Toronto, Dept Chem Engn, Toronto, ON M5S 3E5, Canada. [Chan, Warren C. W.] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada. RP Chan, WCW (reprint author), Univ Toronto, Dept Mat Sci & Engn, Toronto, ON M5S 3E1, Canada.; Chan, WCW (reprint author), Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5S 3G9, Canada.; Chan, WCW (reprint author), Univ Toronto, Dept Chem Engn, Toronto, ON M5S 3E5, Canada.; Chan, WCW (reprint author), Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada. EM warren.chan@utoronto.ca FU Canadian Institute of Health Research [MOP-130143, RMF-111623O]; Natural Sciences and Engineering Research Council (NSERC) [2015-06397]; Prostate Cancer Foundation [D2014-12]; Canadian Breast Cancer Foundation; NSERC FX The authors would like to acknowledge the Canadian Institute of Health Research (MOP-130143 and RMF-111623O), Natural Sciences and Engineering Research Council (NSERC, 2015-06397), and Prostate Cancer Foundation (D2014-12) for their financial support of the project. L.C. acknowledges the fellowship support from Canadian Breast Cancer Foundation and NSERC. NR 35 TC 5 Z9 5 U1 42 U2 42 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD OCT 12 PY 2016 VL 28 IS 38 BP 8511 EP 8518 DI 10.1002/adma.201600773 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DZ8EM UT WOS:000386103700023 PM 27501857 ER PT J AU Loley, C Alver, M Assimes, TL Bjonnes, A Goel, A Gustafsson, S Hernesniemi, J Hopewell, JC Kanoni, S Kleber, ME Lau, KW Lu, YC Lyytikainen, LP Nelson, CP Nikpay, M Qu, LM Salfati, E Scholz, M Tukiainen, T Willenborg, C Won, HH Zeng, LY Zhang, WH Anand, SS Beutner, F Bottinger, EP Clarke, R Dedoussis, G Do, R Esko, T Eskola, M Farrall, M Gauguier, D Giedraitis, V Granger, CB Hall, AS Hamsten, A Hazen, SL Huang, J Kahonen, M Kyriakou, T Laaksonen, R Lind, L Lindgren, C Magnusson, PKE Marouli, E Mihailov, E Morris, AP Nikus, K Pedersen, N Rallidis, L Salomaa, V Shah, SH Stewart, AFR Thompson, JR Zalloua, PA Chambers, JC Collins, R Ingelsson, E Iribarren, C Karhunen, PJ Kooner, JS Lehtimaki, T Loos, RJF Marz, W McPherson, R Metspalu, A Reilly, MP Ripatti, S Sanghera, DK Thiery, J Watkins, H Deloukas, P Kathiresan, S Samani, NJ Schunkert, H Erdmann, J Konig, IR AF Loley, Christina Alver, Maris Assimes, Themistocles L. Bjonnes, Andrew Goel, Anuj Gustafsson, Stefan Hernesniemi, Jussi Hopewell, Jemma C. Kanoni, Stavroula Kleber, Marcus E. Lau, King Wai Lu, Yingchang Lyytikainen, Leo-Pekka Nelson, Christopher P. Nikpay, Majid Qu, Liming Salfati, Elias Scholz, Markus Tukiainen, Taru Willenborg, Christina Won, Hong-Hee Zeng, Lingyao Zhang, Weihua Anand, Sonia S. Beutner, Frank Bottinger, Erwin P. Clarke, Robert Dedoussis, George Do, Ron Esko, Tonu Eskola, Markku Farrall, Martin Gauguier, Dominique Giedraitis, Vilmantas Granger, Christopher B. Hall, Alistair S. Hamsten, Anders Hazen, Stanley L. Huang, Jie Kahonen, Mika Kyriakou, Theodosios Laaksonen, Reijo Lind, Lars Lindgren, Cecilia Magnusson, Patrik K. E. Marouli, Eirini Mihailov, Evelin Morris, Andrew P. Nikus, Kjell Pedersen, Nancy Rallidis, Loukianos Salomaa, Veikko Shah, Svati H. Stewart, Alexandre F. R. Thompson, John R. Zalloua, Pierre A. Chambers, John C. Collins, Rory Ingelsson, Erik Iribarren, Carlos Karhunen, Pekka J. Kooner, Jaspal S. Lehtimaki, Terho Loos, Ruth J. F. Maerz, Winfried McPherson, Ruth Metspalu, Andres Reilly, Muredach P. Ripatti, Samuli Sanghera, Dharambir K. Thiery, Joachim Watkins, Hugh Deloukas, Panos Kathiresan, Sekar Samani, Nilesh J. Schunkert, Heribert Erdmann, Jeanette Koenig, Inke R. TI No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; INACTIVATION; SEX AB In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD. C1 [Loley, Christina; Koenig, Inke R.] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Campus Lubeck, Lubeck, Germany. [Loley, Christina; Willenborg, Christina; Erdmann, Jeanette; Koenig, Inke R.] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany. [Alver, Maris; Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Alver, Maris; Metspalu, Andres] Inst Mol & Cell Biol, Tartu, Estonia. [Assimes, Themistocles L.; Salfati, Elias] Stanford Univ, Sch Med Stanford, Dept Med, Div Cardiovasc Med, Stanford, CA USA. [Bjonnes, Andrew; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Goel, Anuj; Farrall, Martin; Kyriakou, Theodosios; Watkins, Hugh] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Goel, Anuj; Farrall, Martin; Kyriakou, Theodosios; Lindgren, Cecilia; Morris, Andrew P.; Ingelsson, Erik; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Hernesniemi, Jussi; Lyytikainen, Leo-Pekka; Laaksonen, Reijo; Karhunen, Pekka J.; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Hernesniemi, Jussi; Eskola, Markku; Nikus, Kjell] Heart Hosp, Dept Cariol, Tampere, Finland. [Hernesniemi, Jussi; Eskola, Markku; Nikus, Kjell] Univ Tampere, Sch Med, Tampere, Finland. [Hopewell, Jemma C.; Lau, King Wai; Clarke, Robert; Collins, Rory] Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford, England. [Kanoni, Stavroula; Marouli, Eirini; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany. [Lu, Yingchang; Bottinger, Erwin P.; Do, Ron; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lyytikainen, Leo-Pekka; Laaksonen, Reijo; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Nikpay, Majid; Stewart, Alexandre F. R.; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada. [Qu, Liming] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Scholz, Markus] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Scholz, Markus; Beutner, Frank; Thiery, Joachim] LIFE Res Ctr Civilizat Dis, Leipzig, Germany. [Tukiainen, Taru] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Tukiainen, Taru; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Willenborg, Christina; Erdmann, Jeanette] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Campus Lubeck, Lubeck, Germany. [Willenborg, Christina; Erdmann, Jeanette] Univ Heart Ctr Luebeck, Campus Lubeck, Lubeck, Germany. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, SAIHST, Seoul, South Korea. [Zeng, Lingyao] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany. [Zeng, Lingyao; Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany. [Zhang, Weihua; Schunkert, Heribert] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Chambers, John C.] Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England. [Anand, Sonia S.; Chambers, John C.; Kooner, Jaspal S.] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Beutner, Frank] Univ Leipzig, Heart Ctr Leipzig, Cardiol, Leipzig, Germany. [Dedoussis, George] Harokopio Univ Athens, Athens, Greece. [Do, Ron] Icahn Sch Med Mt Sinai, Ctr Stat Genet, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Zena & Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA. [Esko, Tonu; Kathiresan, Sekar] Harvard Med Sch, Dept Med, Boston, MA USA. [Gauguier, Dominique] INSERM, Ctr Rech Cordeliers, UMRS1138, Paris, France. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden. [Granger, Christopher B.; Shah, Svati H.] Duke Univ, Sch Med, Durham, NC USA. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Hamsten, Anders] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden. [Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44106 USA. [Huang, Jie] Boston VA Res Inst Inc, Boston, MA USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Laaksonen, Reijo] Zora Biosci, Espoo, Finland. [Lind, Lars] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden. [Lindgren, Cecilia] MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lindgren, Cecilia] Harvard Univ, Cambridge, MA 02138 USA. [Magnusson, Patrik K. E.; Pedersen, Nancy] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Rallidis, Loukianos] Univ Gen Hosp Attikon, Dept Cardiol 2, Athens, Greece. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Zalloua, Pierre A.] Lebanese Amer Univ, Sch Med, Beirut, Lebanon. [Zalloua, Pierre A.] Harvard Sch Publ Hlth, Boston, MA USA. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Iribarren, Carlos; Ripatti, Samuli] Kaiser Permanente, Div Res, Oakland, CA USA. [Karhunen, Pekka J.] Univ Tampere, Sch Med, Dept Forens Med, Tampere, Finland. [Kooner, Jaspal S.] Imperial Coll London, Cardiovasc Sci, Natl Heart & Lung Inst, London, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Maerz, Winfried] Synlab Serv GmbH, Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ripatti, Samuli] Univ Helsinki, Hjelt Inst, Helsinki, Finland. [Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Oklahoma Ctr Neurosci, Oklahoma City, OK USA. [Thiery, Joachim] Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Konig, IR (reprint author), Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Campus Lubeck, Lubeck, Germany.; Erdmann, J; Konig, IR (reprint author), DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.; Erdmann, J (reprint author), Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Campus Lubeck, Lubeck, Germany.; Erdmann, J (reprint author), Univ Heart Ctr Luebeck, Campus Lubeck, Lubeck, Germany. EM jeanette.erdmann@iieg.uni-luebeck.de; Inke.Koenig@imbs.uni-luebeck.de RI Deloukas, Panos/B-2922-2013; Assimes, Themistocles/D-9696-2015; Konig, Inke/A-4544-2009; Magnusson, Patrik/C-4458-2017 OI Deloukas, Panos/0000-0001-9251-070X; Assimes, Themistocles/0000-0003-2349-0009; FU German Federal Ministry of Education and Research (BMBF) [01ZX1313A-2014]; Reynold's Foundation; NHLBI grant [HL087647]; 6th Framework Program of the European Union [LSHM-CT-2006-037593]; NIH grants [HL095987, HL101621]; Estonian Research Council [IUT20-60]; Research Roadmap [3.2.0304.11-0312]; University Tartu [ARENG SP1GV]; EU FP6 award; Competitive Research Funding of the Tampere University Hospital [9M048, 9N035]; Finnish Cultural Foundation; Finnish Foundation for Cardiovascular Research; Emil Aaltonen Foundation, Finland; Tampere Tuberculosis Foundation; German Federal Ministry of Education and Research (BMBF); e:Med research and funding concept (e:AtheroSysMed) [01ZX1313A-2014]; Fondation Leducq (CADgenomics:Understanding CAD Genes) [12CVD02]; European Union Sixth Framework Programme FP6 (Cardiogenics) [FP6-LIFESCIHEALTH]; Seventh Framework Programme (CVgenes-at-target) [HEALTH-F2-2013-601456]; UK Medical Research Council (MRC); British Heart Foundation; Merck and Co; Roche Vitamins Ltd; British Heart Foundation [FS/14/55/30806, SP/04/002]; Wellcome Trust [07611, 084723/Z/08/Z, 090532/Z/09/Z]; EU's 7th Framework Programme [201668, 305739]; Tampere University Foundation; Tampere University Hospital Medical Funds [9M048, 9N035, X51001]; Emil Aaltonen Foundation; Finnish Foundation of Cardiovascular Research; Pirkanmaa Regional Fund of the Finnish Cultural Foundation; Yrjo Jahnsson Foundation; European Union; European Regional Development Fund (ERDF); Free State of Saxony; National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; Medical Research Council [G0601966, G0700931]; NIHR [RP-PG-0407-10371]; European Union FP7 (EpiMigrant) [European Union FP7 (EpiMigrant, 279143]; Action on Hearing [G51]; INTERREG IV Oberrhein Program (Project A28) European Regional Development Fund (ERDF); Wissenschaftsoffensive TMO; US National Heart, Lung, and Blood Institute [R01HL087676]; Andrea and Charles Bronfman Philanthropies; NHGRI [U01HG007417]; Canadian Institutes of Health Research [MOP-2380941, MOP82810, MOP77682]; Canada Foundation for Innovation [11966]; Heart & Stroke Foundation of Canada [NA6001, NA6650]; Knut and Alice Wallenberg Foundation; European Research Council (ERC Starting Grant); Swedish Diabetes Foundation [2013-024]; Swedish Research Council [2012-1397, M-2005-1112, 2009-2298]; Swedish Heart-Lung Foundation [20120197]; European Community Sixth Framework Program [LSHM-CT-2007-037273]; AstraZeneca; Torsten and Ragnar Soderberg Foundation; Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council; Foundation for Strategic Research; Stockholm County Council [560283]; NIH grants - National Institute of Diabetes and Digestive and Kidney Diseases [R01DK082766]; National Genome Research Institute [NOT-HG-11-009]; VPR Bridge grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA; Greek General Secretary of Research and Technology [PENED 2003]; Ministry for Higher Education; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; NIH grant [DK U01-066134]; NIDDK career development award [DK088942]; National Institute for Health Research; BHF grant [RG/14/5/30893]; BHF Centre of Research Excellence; Donovan Family Foundation; Fondation Leducq; MGH Research Scholar Award; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [251217, 285380]; Sigrid Juselius Foundation; European Community's Seventh Framework Programme through the BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project [261433]; Canadian Institute of Health Research and Natural Sciences and Engineering Research Council of Canada; American Heart Association [15POST23280019]; [P01HL076491]; [b2011036]; [R01 HL107816]; [WT098017] FX This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1313A-2014). The ADVANCE study was supported by a grant from the Reynold's Foundation and NHLBI grant HL087647. Sample collection in the Cardiogenics Consortium (http://www.cardiogenics.eu/web/) was funded by the 6th Framework Program of the European Union (LSHM-CT-2006-037593). We thank all the participants and clinicians involved in the recruitment process at Cambridge and Leicester (UK), Luebeck and Regensburg (Germany), and Paris (France). CATHGEN was supported by NIH grants HL095987 and HL101621. The Cleveland Clinic Gene Bank study was funded by P01HL076491 (to S.L.H). EGCUT was supported by Estonian Research Council grant no. IUT20-60 and Research Roadmap grant no. 3.2.0304.11-0312 and by University Tartu grant no. ARENG SP1GV. The FGENTCARD-Functional Genomic diagnostic tools for coronary artery disease project was funded by an EU FP6 award. We thank the patients for agreeing to participate in the study. We thank Sonia Youhanna, Nour Moukalled and Bariaa Khalil for their help with subject recruitment and data collection. The work of FINCAVAS was supported by the Competitive Research Funding of the Tampere University Hospital (Grant 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data. The GerMIFS studies were supported by grants from the German Federal Ministry of Education and Research (BMBF) within the framework of NGFN and NGFN-plus (Atherogenomics) and e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014), the Fondation Leducq (CADgenomics:Understanding CAD Genes, 12CVD02), and the European Union Sixth Framework Programme FP6 (under grant agreement FP6-LIFESCIHEALTH (Cardiogenics)) and the Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). The Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK Medical Research Council (MRC), British Heart Foundation, Merck and Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. Jemma C. Hopewell acknowledges support from the British Heart Foundation (FS/14/55/30806). HPS acknowledges the National Blood Service (NBS) donors and UK Twin study for using as population controls. A full list of the investigators who contributed to the generation of the NBS data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 07611. The UK Twin study was funded by the Wellcome Trust; European Community"s Seventh Framework Programme (FP7/2007-2013). The Helsinki Sudden Death Study (HSDS) was financially supported by EU's 7th Framework Programme (grant no. 201668 for AtheroRemo), the Tampere University Foundation, the Tampere University Hospital Medical Funds (grants X51001, 9M048 and 9N035 for Terho Lehtimaki, the Emil Aaltonen Foundation (Terho Lehtimaki, the Finnish Foundation of Cardiovascular Research (Terho Lehtimaki, Pekka J. Karhunen), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjo Jahnsson Foundation, and the Tampere Tuberculosis Foundation (Terho Lehtimaki).; LIFE-Heart is a part of the LIFE Leipzig Research Center for Civilization Diseases, Universitat Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), the NIHR (RP-PG-0407-10371), European Union FP7 (EpiMigrant, 279143) and Action on Hearing (G51). We thank the participants and research staff who made the study possible. LURIC was supported by the 7th Framework Program (integrated project AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the European Union and by the INTERREG IV Oberrhein Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO. We extend our appreciation to the participants of the LURIC study and thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. The MIGen study was funded by R01HL087676 from the US National Heart, Lung, and Blood Institute. The Mount Sinai IPM Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. It was in part supported by NHGRI U01HG007417. OHGS_A2, OHGS_B2, and OHGS_C2 were funded by Canadian Institutes of Health Research (# MOP-2380941 to R.M.), (# MOP82810, MOP77682 to R.R., A.F.S. & R.M.); Canada Foundation for Innovation (# 11966 to R.R., R.M. & A.F.S.; Heart & Stroke Foundation of Canada (# NA6001, # NA6650 to R.M). PIVUS was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). Research in SDS was partly supported by NIH grants-R01DK082766 funded by the National Institute of Diabetes and Digestive and Kidney Diseases and NOT-HG-11-009 funded by National Genome Research Institute, and VPR Bridge grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. Recruitment for THISEAS was partially funded by a research grant (PENED 2003) from the Greek General Secretary of Research and Technology; we thank all the dieticians and clinicians for their contribution to the project.; TwinGene was supported by grants from the Ministry for Higher Education, the Swedish Research Council (M-2005-1112 and 2009-2298), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH grant DK U01-066134, Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. ULSAM was supported by Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC Starting Grant), Swedish Diabetes Foundation (grant no. 2013-024), Swedish Research Council (grant no. 2012-1397), and Swedish Heart-Lung Foundation (20120197). We thank the SNP&SEQ Technology Platform in Uppsala (www. genotyping. se) for excellent genotyping. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2011036. Recruitment for the WTCCC study was funded by the British Heart Foundation and genotyping by the Wellcome Trust. Themistocles L. Assimes was supported by an NIDDK career development award DK088942. Panos Deloukas's work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research. Analysis was partly supported by BHF grant (to Panos Deloukas) RG/14/5/30893. Martin Farrall and Hugh Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z) and Martin Farrall, Hugh Watkins and Theodosios Kyriakou, the BHF Centre of Research Excellence. Anuj Goel, Hugh Watkins and Theodosios Kyriakou acknowledge European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) & and Anuj Goel, the Wellcome Trust Institutional strategic support fund. The UK Twin study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). PoBI samples from the Wellcome Trust funded People of the British Isles project. Sekar Kathiresan is supported by the Donovan Family Foundation, Fondation Leducq, MGH Research Scholar Award, and R01 HL107816. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, funded under grant WT098017. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Christopher P. Nelson and Nilesh J. Samani are funded by the British Heart Foundation and Nilesh J. Samani is a UK NIUHR Senior Investigator. Samuli Ripatti was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No. 213506 and 129680), Academy of Finland (Grant No. 251217 and 285380), the Finnish foundation for Cardiovascular Research, the Sigrid Juselius Foundation and the European Community's Seventh Framework Programme (FP7/2007-2013) through the BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) project, grant agreement 261433. Alexandre F. R.; Stewart is supported by operating grants from the Canadian Institute of Health Research and Natural Sciences and Engineering Research Council of Canada. Hong-Hee Won is supported by a postdoctoral award from the American Heart Association (15POST23280019). NR 29 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35278 DI 10.1038/srep35278 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3OT UT WOS:000385004200001 PM 27731410 ER PT J AU Mayr, FB Yende, S AF Mayr, Florian B. Yende, Sachin TI Understanding the complex host response in sepsis: is diabetes the key? SO CRITICAL CARE LA English DT Editorial Material ID MELLITUS C1 [Mayr, Florian B.; Yende, Sachin] Univ Pittsburgh, Dept Crit Care Med, CRISMA Ctr, Pittsburgh, PA 15260 USA. [Mayr, Florian B.; Yende, Sachin] Vet Affairs Pittsburgh Healthcare Syst, Univ Dr C,Room 2A128, Pittsburgh, PA 15240 USA. RP Mayr, FB (reprint author), Univ Pittsburgh, Dept Crit Care Med, CRISMA Ctr, Pittsburgh, PA 15260 USA.; Mayr, FB (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Univ Dr C,Room 2A128, Pittsburgh, PA 15240 USA. EM mayrfb@upmc.edu NR 7 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD OCT 12 PY 2016 VL 20 AR 321 DI 10.1186/s13054-016-1494-z PG 2 WC Critical Care Medicine SC General & Internal Medicine GA DY4AP UT WOS:000385041700001 PM 27729067 ER PT J AU Tang, SM Chan, RYT Lin, SB Rong, SS Lau, HHW Lau, WWY Yip, WWK Chen, LJ Ko, STC Yam, JCS AF Tang, Shu Min Chan, Rachel Y. T. Lin, Shi Bin Rong, Shi Song Lau, Henry H. W. Lau, Winnie W. Y. Yip, Wilson W. K. Chen, Li Jia Ko, Simon T. C. Yam, Jason C. S. TI Refractive Errors and Concomitant Strabismus: A Systematic Review and Meta-analysis SO SCIENTIFIC REPORTS LA English DT Article ID POPULATION-BASED SAMPLE; NON-HISPANIC WHITE; CHINESE CHILDREN; RISK-FACTORS; PREVALENCE; AMBLYOPIA; EYE; SINGAPORE; IMPACT; MYOPIA AB This systematic review and meta-analysis is to evaluate the risk of development of concomitant strabismus due to refractive errors. Eligible studies published from 1946 to April 1, 2016 were identified from MEDLINE and EMBASE that evaluated any kinds of refractive errors (myopia, hyperopia, astigmatism and anisometropia) as an independent factor for concomitant exotropia and concomitant esotropia. Totally 5065 published records were retrieved for screening, 157 of them eligible for detailed evaluation. Finally 7 population-based studies involving 23,541 study subjects met our criteria for meta-analysis. The combined OR showed that myopia was a risk factor for exotropia (OR: 5.23, P = 0.0001). We found hyperopia had a dose-related effect for esotropia (OR for a spherical equivalent [SE] of 2-3 diopters [D]: 10.16, P = 0.01; OR for an SE of 3-4D: 17.83, P < 0.0001; OR for an SE of 4-5D: 41.01, P < 0.0001; OR for an SE of >= 5D: 162.68, P < 0.0001). Sensitivity analysis indicated our results were robust. Results of this study confirmed myopia as a risk for concomitant exotropia and identified a dose-related effect for hyperopia as a risk of concomitant esotropia. C1 [Tang, Shu Min; Chan, Rachel Y. T.; Rong, Shi Song; Lau, Henry H. W.; Lau, Winnie W. Y.; Yip, Wilson W. K.; Chen, Li Jia; Yam, Jason C. S.] Chinese Univ Hong Kong, Dept Ophthalmol & Visual Sci, Hong Kong, Hong Kong, Peoples R China. [Lin, Shi Bin; Chen, Li Jia; Yam, Jason C. S.] Shantou Univ, Joint Shantou Int Eye Ctr, Shantou, Peoples R China. [Lin, Shi Bin; Chen, Li Jia; Yam, Jason C. S.] Chinese Univ Hong Kong, Shantou, Peoples R China. [Ko, Simon T. C.] Tung Wah Eastern Hosp, Dept Ophthalmol, Hong Kong, Hong Kong, Peoples R China. [Rong, Shi Song] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Yam, JCS (reprint author), Chinese Univ Hong Kong, Dept Ophthalmol & Visual Sci, Hong Kong, Hong Kong, Peoples R China.; Yam, JCS (reprint author), Shantou Univ, Joint Shantou Int Eye Ctr, Shantou, Peoples R China.; Yam, JCS (reprint author), Chinese Univ Hong Kong, Shantou, Peoples R China. EM yamcheuksing@cuhk.edu.hk RI Yam, Jason/I-5682-2014; Chen, Li Jia/I-5078-2014 OI Yam, Jason/0000-0002-2156-1486; Chen, Li Jia/0000-0003-3500-5840 FU General Research Fund [14111515]; Direct Grant of the Chinese University of Hong Kong [4054121] FX This study was supported by the General Research Fund 14111515; and the Direct Grant of the Chinese University of Hong Kong 4054121. We are indebted to Prof Calvin C.P. Pang for his critical review for the manuscript. NR 30 TC 0 Z9 0 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 12 PY 2016 VL 6 AR 35177 DI 10.1038/srep35177 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY3LV UT WOS:000384995100001 PM 27731389 ER PT J AU Charidimou, A Shoamanesh, A AF Charidimou, Andreas Shoamanesh, Ashkan CA Int META-MICROBLEEDS TI Clinical relevance of microbleeds in acute stroke thrombolysis Comprehensive meta-analysis SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; CEREBRAL MICROBLEEDS; INTRACEREBRAL HEMORRHAGE; INTRAVENOUS THROMBOLYSIS; BLEEDING RISK AB Objective: We performed a systematic review and meta-analysis to assess whether the presence of cerebral microbleeds (CMBs) on pretreatment MRI of patients with acute ischemic stroke treated with IV thrombolysis is associated with increased risk of symptomatic intracerebral hemorrhage (ICH) and poor functional outcome. Methods: We searched PubMed for relevant studies and calculated pooled odds ratios (OR) for symptomatic ICH and poor (i.e., modified Rankin Scale score.2) 3- to 6-month functional outcome using random effects models with DerSimonian-Laird weights among individuals with vs without CMBs. Results: Eight eligible studies including 2,601 stroke patients treated with IV thrombolysis were pooled in a meta-analysis. The cumulative CMBs prevalence was 24% (95% confidence interval [CI] 18%-30%). The pooled symptomatic ICH incidence was 5% (95% CI 4%-7%) among patients with CMBs and 3% (95% CI 2%-5%) in patients without CMBs. CMB presence was associated with higher risk of symptomatic ICH compared to patients without CMBs (OR 2.18; 95% CI 1.12-4.22; p = 0.021). Four studies (n = 1,665) reported data on 3-to 6-month poststroke functional outcome. The pooled incidence of poor functional outcome was 52% (95% CI 45%-59%) in patients with CMBs vs 41%(95% CI 35%-46%) in those without CMBs. Meta-analysis of these studies demonstrated OR for CMBs presence and adverse outcome to be 1.58 (95% CI 1.18-2.14; p = 0.002). Conclusions: CMBs are associated with greater symptomatic ICH risk and poor functional outcome in ischemic stroke patients undergoing thrombolytic therapy. In the absence of adjusted analyses and randomized evidence, this risk seems acceptable and should probably not discourage recanalization therapies in this patient population (Level B recommendation: nonrandomized Class IIa evidence). C1 [Charidimou, Andreas] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Charidimou, Andreas] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shoamanesh, Ashkan] McMaster Univ, Dept Med Neurol, Hamilton, ON, Canada. Populat Hlth Res Inst, Hamilton, ON, Canada. RP Charidimou, A (reprint author), Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA.; Charidimou, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk NR 26 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 11 PY 2016 VL 87 IS 15 BP 1534 EP 1541 DI 10.1212/WNL.0000000000003207 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EI1HU UT WOS:000392228600010 PM 27629086 ER PT J AU Messe, SR Khatri, P Reeves, MJ Smith, EE Saver, JL Bhatt, DL Grau-Sepulveda, MV Cox, M Peterson, ED Fonarow, GC Schwamm, LH AF Messe, Steven R. Khatri, Pooja Reeves, Mathew J. Smith, Eric E. Saver, Jeffrey L. Bhatt, Deepak L. Grau-Sepulveda, Maria V. Cox, Margueritte Peterson, Eric D. Fonarow, Gregg C. Schwamm, Lee H. TI Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry SO NEUROLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; HEALTH-CARE PROFESSIONALS; QUALITY-OF-CARE; GUIDELINES-STROKE; MEDICARE BENEFICIARIES; SEX-DIFFERENCES; TRIALS ARCHIVE; THROMBOLYSIS; ASSOCIATION; PROGRAM AB Objective: To determine patient and hospital characteristics associated with not providing IV tissue plasminogen activator (tPA) to eligible patients with acute ischemic stroke (AIS) in clinical practice. Methods: We performed a retrospective cohort study of patients with AIS arriving within 2 hours of onset to hospitals participating in Get With The Guidelines-Stroke without documented contraindications to IV tPA from April 2003 through December 2011, comparing those who received tPA to those who did not. Multivariable generalized estimating equation logistic regression modeling identified factors associated with not receiving tPA. Results: Of 61,698 eligible patients with AIS presenting within 2 hours of onset (median age 73 years, 51% female, 74% non-Hispanic white, median NIH Stroke Scale score 11, interquartile range 6-18), 15,282 (25%) were not treated with tPA within 3 hours. Failure to give tPA decreased over time from 55% in 2003 to 2005 to 18% in 2010 to 2011 (p < 0.0001). After adjustment for all covariates, including stroke severity, factors associated with failure to treat included older age, female sex, nonwhite race, diabetes mellitus, prior stroke, atrial fibrillation, prosthetic heart valve, NIH Stroke Scale score,5, arrival off-hours and not via emergency medical services, longer onset-to-arrival and door-to-CT times, earlier calendar year, and arrival at rural, nonteaching, non-stroke center hospitals located in the South or Midwest. Conclusions: Overall, about one-quarter of eligible patients with AIS presenting within 2 hours of stroke onset failed to receive tPA treatment. Thrombolysis has improved dramatically over time and is strongly associated with stroke center certification. Additionally, some groups, including older patients, milder strokes, women, and minorities, may be undertreated. C1 [Messe, Steven R.] Hosp Univ Penn, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Khatri, Pooja] Univ Cincinnati, Dept Neurol, Cincinnati, OH 45221 USA. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Med Sch, Boston, MA USA. [Grau-Sepulveda, Maria V.; Cox, Margueritte] Duke Univ, Duke Clin Res Ctr, Durham, NC USA. [Peterson, Eric D.] Duke Univ, Dept Med, Durham, NC USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Messe, SR (reprint author), Hosp Univ Penn, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM messe@mail.med.upenn.edu FU Pfizer, Inc (New York, NY); Merck-Schering Plough Partnership (North Wales, PA) FX The GWTG-Stroke program is supported, in part, by unrestricted educational grants to the American Heart Association by Pfizer, Inc (New York, NY) and the Merck-Schering Plough Partnership (North Wales, PA), which did not participate in the design, analysis, manuscript preparation, or approval. NR 41 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 11 PY 2016 VL 87 IS 15 BP 1565 EP 1574 DI 10.1212/WNL.0000000000003198 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EI1HU UT WOS:000392228600014 ER PT J AU Moussawi, K Gupta, A Reda, H AF Moussawi, Khaled Gupta, Anoopum Reda, Haatem TI Clinical Reasoning: A 20-year-old man with headache and double vision SO NEUROLOGY LA English DT Editorial Material ID LYME NEUROBORRELIOSIS; PSEUDOTUMOR CEREBRI; DIAGNOSIS; DISEASE C1 [Moussawi, Khaled; Gupta, Anoopum; Reda, Haatem] Harvard Med Sch, Boston, MA 02115 USA. [Moussawi, Khaled; Gupta, Anoopum; Reda, Haatem] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Moussawi, Khaled; Gupta, Anoopum] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Moussawi, Khaled] Natl Inst Drug Abuse, Baltimore, MD 21224 USA. [Moussawi, Khaled] Johns Hopkins Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Moussawi, K (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Moussawi, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Moussawi, K (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; Moussawi, K (reprint author), Natl Inst Drug Abuse, Baltimore, MD 21224 USA.; Moussawi, K (reprint author), Johns Hopkins Med, Dept Psychiat, Baltimore, MD 21205 USA. EM khaled.moussawi@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 11 PY 2016 VL 87 IS 15 BP E162 EP E167 DI 10.1212/WNL.0000000000003208 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA EI1HU UT WOS:000392228600001 PM 27765826 ER PT J AU Zhang, MF Wang, ZM Obazee, O Jia, JP Childs, EJ Hoskins, J Figlioli, G Mocci, E Collins, I Chung, CC Hautman, C Arslan, AA Beane-Freeman, L Bracci, PM Buring, J Duell, EJ Gallinger, S Giles, GG Goodman, GE Goodman, PJ Kamineni, A Kolonel, LN Kulke, MH Malats, N Olson, SH Sesso, HD Visvanathan, K White, E Zheng, W Abnet, CC Albanes, D Andreotti, G Brais, L Bueno-de-Mesquita, HB Basso, D Berndt, SI Boutron-Ruault, MC Bijlsma, MF Brenner, H Burdette, L Campa, D Caporaso, NE Capurso, G Cavestro, GM Cotterchio, M Costello, E Elena, J Boggi, U Gaziano, JM Gazouli, M Giovannucci, EL Goggins, M Gross, M Haiman, CA Hassan, M Helzlsouer, KJ Hu, N Hunter, DJ Iskierka-Jazdzewska, E Jenab, M Kaaks, R Key, TJ Khaw, KT Klein, EA Kogevinas, M Krogh, V Kupcinskas, J Kurtz, RC Landi, MT Landi, S Le Marchand, L Mambrini, A Mannisto, S Milne, RL Neale, RE Oberg, AL Panico, S Patel, AV Peeters, PHM Peters, U Pezzilli, R Porta, M Purdue, M Quiros, JR Riboli, E Rothman, N Scarpa, A Scelo, G Shu, XO Silverman, DT Soucek, P Strobel, O Sund, M Malecka-Panas, E Taylor, PR Tavano, F Travis, RC Thornquist, M Tjonneland, A Tobias, GS Trichopoulos, D Vashist, Y Vodicka, P Wactawski-Wende, J Wentzensen, N Yu, H Yu, K Zeleniuch-Jacquotte, A Kooperberg, C Risch, HA Jacobs, EJ Li, DH Fuchs, C Hoover, R Hartge, P Chanock, SJ Petersen, GM Stolzenberg-Solomon, RS Wolpin, BM Kraft, P Klein, AP Canzian, F Amundadottir, LT AF Zhang, Mingfeng Wang, Zhaoming Obazee, Ofure Jia, Jinping Childs, Erica J. Hoskins, Jason Figlioli, Gisella Mocci, Evelina Collins, Irene Chung, Charles C. Hautman, Christopher Arslan, Alan A. Beane-Freeman, Laura Bracci, Paige M. Buring, Julie Duell, Eric J. Gallinger, Steven Giles, Graham G. Goodman, Gary E. Goodman, Phyllis J. Kamineni, Aruna Kolonel, Laurence N. Kulke, Matthew H. Malats, Nuria Olson, Sara H. Sesso, Howard D. Visvanathan, Kala White, Emily Zheng, Wei Abnet, Christian C. Albanes, Demetrius Andreotti, Gabriella Brais, Lauren Bueno-de-Mesquita, H. Bas Basso, Daniela Berndt, Sonja I. Boutron-Ruault, Marie-Christine Bijlsma, Maarten F. Brenner, Hermann Burdette, Laurie Campa, Daniele Caporaso, Neil E. Capurso, Gabriele Cavestro, Giulia Martina Cotterchio, Michelle Costello, Eithne Elena, Joanne Boggi, Ugo Gaziano, J. Michael Gazouli, Maria Giovannucci, Edward L. Goggins, Michael Gross, Myron Haiman, Christopher A. Hassan, Manal Helzlsouer, Kathy J. Hu, Nan Hunter, David J. Iskierka-Jazdzewska, Elzbieta Jenab, Mazda Kaaks, Rudolf Key, Timothy J. Khaw, Kay-Tee Klein, Eric A. Kogevinas, Manolis Krogh, Vittorio Kupcinskas, Juozas Kurtz, Robert C. Landi, Maria T. Landi, Stefano Le Marchand, Loic Mambrini, Andrea Mannisto, Satu Milne, Roger L. Neale, Rachel E. Oberg, Ann L. Panico, Salvatore Patel, Alpa V. Peeters, Petra H. M. Peters, Ulrike Pezzilli, Raffaele Porta, Miquel Purdue, Mark Ramon Quiros, J. Riboli, Elio Rothman, Nathaniel Scarpa, Aldo Scelo, Ghislaine Shu, Xiao-Ou Silverman, Debra T. Soucek, Pavel Strobel, Oliver Sund, Malin Malecka-Panas, Ewa Taylor, Philip R. Tavano, Francesca Travis, Ruth C. Thornquist, Mark Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Vashist, Yogesh Vodicka, Pavel Wactawski-Wende, Jean Wentzensen, Nicolas Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Kooperberg, Charles Risch, Harvey A. Jacobs, Eric J. Li, Donghui Fuchs, Charles Hoover, Robert Hartge, Patricia Chanock, Stephen J. Petersen, Gloria M. Stolzenberg-Solomon, Rachael S. Wolpin, Brian M. Kraft, Peter Klein, Alison P. Canzian, Federico Amundadottir, Laufey T. TI Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21 SO ONCOTARGET LA English DT Article DE pancreatic cancer; GWAS; fine-mapping; imputation; NR5A2 ID GENOME-WIDE ASSOCIATION; URINARY-BLADDER CANCER; LONG-RANGE INTERACTION; RISK LOCI; GENOTYPE IMPUTATION; GENETIC SUSCEPTIBILITY; TERT-CLPTM1L LOCUS; COMMON VARIANT; BREAST-CANCER; COLON-CANCER AB Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology. C1 [Zhang, Mingfeng; Jia, Jinping; Hoskins, Jason; Collins, Irene; Hautman, Christopher; Amundadottir, Laufey T.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Chung, Charles C.; Beane-Freeman, Laura; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Berndt, Sonja I.; Burdette, Laurie; Caporaso, Neil E.; Hu, Nan; Landi, Maria T.; Purdue, Mark; Rothman, Nathaniel; Silverman, Debra T.; Taylor, Philip R.; Tobias, Geoffrey S.; Wentzensen, Nicolas; Yu, Kai; Hoover, Robert; Hartge, Patricia; Chanock, Stephen J.; Stolzenberg-Solomon, Rachael S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Chung, Charles C.; Burdette, Laurie] Leidos Biomed Res Inc, Canc Genom Res Lab, NCI, Div Canc Epidemiol & Genet,Frederick Natl Lab Can, Frederick, MD USA. [Obazee, Ofure; Figlioli, Gisella; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Childs, Erica J.; Mocci, Evelina; Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael; Giovannucci, Edward L.; Fuchs, Charles] Harvard Med Sch, Boston, MA USA. [Buring, Julie; Sesso, Howard D.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Duell, Eric J.] Catalan Inst Oncol ICO, Unit Nutr & Canc, Canc Epidemiol Res Program, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain. [Gallinger, Steven] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia. [Goodman, Gary E.; White, Emily; Peters, Ulrike; Thornquist, Mark; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, Ctr Stat, Southwest Oncol Grp, 1124 Columbia St, Seattle, WA 98104 USA. [Kamineni, Aruna] Grp Hlth Res Inst, Seattle, WA USA. [Kolonel, Laurence N.; Le Marchand, Loic; Yu, Herbert] Univ Hawaii, Canc Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA. [Kulke, Matthew H.; Brais, Lauren; Fuchs, Charles; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Malats, Nuria] CNIO Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Sesso, Howard D.; Giovannucci, Edward L.; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [White, Emily; Peters, Ulrike] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Div Epidemiol, Med Ctr, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.; Riboli, Elio] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [Basso, Daniela] Univ Hosp Padova, Dept Lab Med, Padua, Italy. [Boutron-Ruault, Marie-Christine] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] IGR, F-94805 Villejuif, France. [Bijlsma, Maarten F.] Univ Amsterdam, Acad Med Ctr, Lab Expt Oncol & Radiobiol, Amsterdam, Netherlands. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Campa, Daniele; Landi, Stefano] Univ Pisa, Dept Biol, Pisa, Italy. [Capurso, Gabriele] Sapienza Univ Rome, Digest & Liver Dis Unit, Rome, Italy. [Cavestro, Giulia Martina] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Gastroenterol & Gastrointestinal Endoscopy Unit, Milan, Italy. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Cotterchio, Michelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Costello, Eithne] Univ Liverpool, Natl Inst Hlth Res Liverpool Pancreas Biomed Res, Liverpool, Merseyside, England. [Elena, Joanne; Helzlsouer, Kathy J.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Boggi, Ugo] Univ Hosp Pisa, Dept Surg, Unit Expt Surg Pathol, Pisa, Italy. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Gazouli, Maria] Univ Athens, Sch Med, Dept Basic Med Sci, Biol Lab, Athens, Greece. [Giovannucci, Edward L.; Fuchs, Charles] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Pathol, Baltimore, MD USA. [Goggins, Michael; Hunter, David J.] Johns Hopkins Univ, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Med, Baltimore, MD USA. [Goggins, Michael] Sidney Kimmel Canc Ctr, Dept Oncol, Baltimore, MD USA. [Gross, Myron] Univ Minnesota, Lab Med & Pathol, Minneapolis, MN USA. [Haiman, Christopher A.] Univ Southern Calif, Prevent Med, Los Angeles, CA USA. [Hassan, Manal; Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Hunter, David J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Hunter, David J.] Harvard Sch Publ Hlth, Boston, MA USA. [Iskierka-Jazdzewska, Elzbieta] Med Univ Lodz, Dept Hematol, Lodz, Poland. [Jenab, Mazda; Scelo, Ghislaine] Int Agcy Res Canc, Lyon, France. [Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Key, Timothy J.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol Unit, Oxford OX1 2JD, England. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Ctr Recerca Epidemiol Ambiental CREAL, Madrid, Spain. [Kogevinas, Manolis; Porta, Miquel] Hosp del Mar, Inst Med Res IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Kupcinskas, Juozas] Lithuanian Univ Hlth Sci, Dept Gastroenterol, Kaunas, Lithuania. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Mambrini, Andrea] ASL1 Massa Carrara, Dept Oncol, Massa Carrara, Italy. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Neale, Rachel E.] QIMR Berghofer Med Res Inst, Dept Populat Hlth, Brisbane, Qld, Australia. [Oberg, Ann L.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurgia, Naples, Italy. [Patel, Alpa V.; Jacobs, Eric J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Pezzilli, Raffaele] St Orsola Malpighi Hosp, Dept Digest Dis & Internal Med, Pancreas Unit, Bologna, Italy. [Porta, Miquel] Univ Autonoma Barcelona, Sch Med, Barcelona, Spain. [Porta, Miquel] CIBER Epidemiol Salud Publ CIBERESP, Madrid, Spain. [Ramon Quiros, J.] Publ Hlth & Participat Directorate, Asturias, Spain. [Scarpa, Aldo] Univ & Hosp Trust Verona, ARC NET Ctr Appl Res Canc, Verona, Italy. [Soucek, Pavel] Charles Univ Prague, Fac Med Pilsen, Biomed Ctr, Lab Pharmacogen, Plzen, Czech Republic. [Strobel, Oliver] Univ Heidelberg Hosp, Dept Gen Surg, Heidelberg, Germany. [Sund, Malin] Umea Univ, Dept Surg & Peroperat Sci, Umea, Sweden. [Malecka-Panas, Ewa] Med Univ Lodz, Dept Digest Tract Dis, Lodz, Poland. [Tavano, Francesca] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Soffe, Div Gastroenterol, San Giovanni Rotondo, Italy. [Tavano, Francesca] IRCCS Sci Inst & Reg Gen Hosp Casa Sollievo Soffe, Res Lab, San Giovanni Rotondo, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Vashist, Yogesh] Univ Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, Hamburg, Germany. [Vodicka, Pavel] Acad Sci Czech Republic, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic. [Wactawski-Wende, Jean] Univ Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Petersen, Gloria M.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Kraft, Peter] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Klein, Alison P.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Amundadottir, LT (reprint author), NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM amundadottirl@mail.nih.gov RI Abnet, Christian/C-4111-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; Kogevinas, Manolis/C-3918-2017; Porta, Miquel/B-5787-2008; Beane Freeman, Laura/C-4468-2015; OI Malats, Nuria/0000-0003-2538-3784; Abnet, Christian/0000-0002-3008-7843; Brenner, Hermann/0000-0002-6129-1572; Porta, Miquel/0000-0003-1684-7428; Beane Freeman, Laura/0000-0003-1294-4124; Hoskins, Jason/0000-0001-6944-1996; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute FX The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. NR 78 TC 0 Z9 0 U1 9 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 11 PY 2016 VL 7 IS 41 BP 66328 EP 66343 DI 10.18632/oncotarget.11041 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UO UT WOS:000387446200004 PM 27579533 ER PT J AU Han, YM Kim, KJ Jeong, M Park, JM Go, EJ Kang, JX Hong, SP Hahm, KB AF Han, Young-Min Kim, Kyung-Jo Jeong, Migyeung Park, Jong-Min Go, Eun-Jin Kang, Jing X. Hong, Sung Pyo Hahm, Ki Baik TI Suppressed Helicobacter pylori-associated gastric tumorigenesis in Fat-1 transgenic mice producing endogenous omega-3 polyunsaturated fatty acids SO ONCOTARGET LA English DT Article DE Fat-1 transgenic mice; COX-2; 15-PGDH; omega-3 PUFAs; anti-proliferation ID RANDOMIZED CONTROLLED-TRIAL; EPIDERMAL-GROWTH-FACTOR; 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE; CANCER CHEMOPREVENTION; CARCINOGENESIS; INFLAMMATION; PREVENTION; OMEGA-3-FATTY-ACIDS; ERADICATION; EXPRESSION AB Dietary approaches to preventing Helicobacter pylori (H. pylori)-associated gastric carcinogenesis are widely accepted because surrounding break-up mechanisms are mandatory for cancer prevention, however, eradication alone has been proven to be insufficient. Among these dietary interventions, omega-3-polyunsaturated-fatty acids (omega-3 PUFAs) are often the first candidate selected. However, there was no trial of fatty acids in preventing H. pylori-associated carcinogenesis and inconclusive results have been reported, likely based on inconsistent dietary administration. In this study, we developed an H. pylori initiated-, high salt diet promoted-gastric tumorigenesis model and conducted a comparison between wild-type (WT) and Fat-1-transgenic (TG)-mice. Gross and pathological lesions in mouse stomachs were evaluated at 16, 24, 32, and 45 weeks after H. pylori infection, and the underlying molecular changes to explain the cancer preventive effects were investigated. Significant changes in: i) ameliorated gastric inflammations at 16 weeks of H. pylori infection, ii) decreased angiogenic growth factors at 24 weeks, iii) attenuated atrophic gastritis and tumorigenesis at 32 weeks, and iv) decreased gastric cancer at 45 weeks were all noted in Fat-1-TG-mice compared to WT-mice. While an increase in the expression of Cyclooxygenase (COX)-2, and reduced expression of the tumor suppressive 15-PGDH were observed in WT-mice throughout the experimental periods, the expression of Hydroxyprostaglandin dehydrogenase (15-PGDH) was preserved in Fat-1-TG-mice. Using a comparative protein array, attenuated expressions of proteins implicated in proliferation and inflammation were observed in Fat-1-TG-mice compared to WT-mice. Conclusively, long-term administration of omega-3 PUFAs can suppress H. pylori-induced gastric tumorigenesis through a dampening of inflammation and reduced proliferation in accordance with afforded rejuvenation. C1 [Han, Young-Min; Jeong, Migyeung; Park, Jong-Min; Go, Eun-Jin; Hahm, Ki Baik] CHA Univ, CHA Canc Inst, CHA Canc Prevent Res Ctr, Seoul, South Korea. [Kim, Kyung-Jo] Univ Ulsan, Seoul Asan Med Ctr, Dept Gastroenterol, Seoul, South Korea. [Kang, Jing X.] Harvard Med Sch, Massachusetts Gen Hosp, Lab Lipid Med & Technol, Boston, MA USA. [Hong, Sung Pyo; Hahm, Ki Baik] CHA Bundang Med Ctr, Dept Gastroenterol, Seongnam, South Korea. RP Hahm, KB (reprint author), CHA Univ, CHA Canc Inst, CHA Canc Prevent Res Ctr, Seoul, South Korea.; Hahm, KB (reprint author), CHA Bundang Med Ctr, Dept Gastroenterol, Seongnam, South Korea. EM hahmkb@cha.ac.kr FU Basic Science Research Program through National Research Foundation of Korea (NRF) - Ministry of Education [2014R1A1A2058732]; Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through High Value-added Food Technology Development Program; Japanese Society for Promotion of Science; Ministry of Agriculture, Food and Rural Affairs (MAFRA) [116015-03-1-CG000] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2058732 to JM Park), by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through High Value-added Food Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (116015-03-1-CG000), and also by Japanese Society for Promotion of Science (to T Azuma). NR 61 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 11 PY 2016 VL 7 IS 41 BP 66606 EP 66622 DI 10.18632/oncotarget.11261 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EB5UO UT WOS:000387446200023 PM 27528223 ER PT J AU Fuchs, CS Tabernero, J Tomasek, J Chau, I Melichar, B Safran, H Tehfe, MA Filip, D Topuzov, E Schlittler, L Udrea, AA Campbell, W Brincat, S Emig, M Melemed, SA Hozak, RR Ferry, D Caldwell, CW Ajani, JA AF Fuchs, Charles S. Tabernero, Josep Tomasek, Jiri Chau, Ian Melichar, Bohuslav Safran, Howard Tehfe, Mustapha A. Filip, Dumitru Topuzov, Eldar Schlittler, Luis Udrea, Anghel Adrian Campbell, William Brincat, Stephen Emig, Michael Melemed, Symantha A. Hozak, Rebecca R. Ferry, David Caldwell, C. William Ajani, Jaffer A. TI Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab SO BRITISH JOURNAL OF CANCER LA English DT Article DE ramucirumab; gastric carcinoma; gastroesophageal carcinoma; biomarkers; VEGFR2; antibody; angiogenesis; REGARD ID VEGF-C EXPRESSION; GROWTH-FACTOR; PROGNOSTIC-SIGNIFICANCE; MICROVESSEL DENSITY; PHASE-3 TRIAL; DOUBLE-BLIND; HER2 STATUS; CANCER; SURVIVAL; ADENOCARCINOMA AB Background: Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma. Methods: A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had >= 1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3. Results: None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI = 0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI = 0.38, 1.22) and low (HR = 0.73, 95% CI = 0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression. Conclusions: REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited. C1 [Fuchs, Charles S.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. [Tabernero, Josep] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Barcelona 08035, Spain. [Tabernero, Josep] Univ Autonoma Barcelona, Inst Oncol VHIO, Barcelona 08035, Spain. [Tomasek, Jiri] Masaryk Univ, Fac Med, Masaryk Mem Canc Inst, Brno 65653, Czech Republic. [Chau, Ian] Royal Marsden Hosp, Downs Rd, Sutton SM2 5PT, Surrey, England. [Melichar, Bohuslav] Univ Palackeho, Lekarska Fak, Onkol klin, IP Pavlova 6, Olomouc 77900, Czech Republic. [Melichar, Bohuslav] Fak Nemocnice, IP Pavlova 6, Olomouc 77900, Czech Republic. [Safran, Howard] Brown Univ, Oncol Res Grp, 164 Summit Ave,Fain 3, Providence, RI 02906 USA. [Tehfe, Mustapha A.] Ctr Hosp Montreal, 1560 Sherbrooke East St, Montreal, PQ H2L 4M1, Canada. [Filip, Dumitru] Spitalul Judetean Urgenta, Str George Cosbuc 31, Baia Mare 430031, Romania. [Topuzov, Eldar] Northwest State Med Univ, Minist Healthcare Russian Federat, State Budgetary Educ Inst Higher Profess Educ, St Petersburg, Russia. [Schlittler, Luis] Hosp Cida Passo Fundo, Rua Tiradentes,295 Ctr, BR-99010260 Passo Fundo, Brazil. [Udrea, Anghel Adrian] Medisprof SRL, P-Ta 1 Mai 3, Cluj Napoca 400058, Romania. [Campbell, William] Hosp Herrera Llerandi, 6 Ave, Guatemala City, Guatemala. [Brincat, Stephen] Sir Anthony Mamo Oncol Ctr, Msida, Malta. [Emig, Michael] Lilly Deutschland GmbH, Werner Reimers Str 2, D-61352 Bad Homburg, Germany. [Melemed, Symantha A.; Hozak, Rebecca R.; Caldwell, C. William] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Ferry, David] Eli Lilly & Co, 440 Route 22 East, Bridgewater, NJ 08807 USA. [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 426, Houston, TX 77030 USA. RP Fuchs, CS (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. EM Charles_Fuchs@dfci.harvard.edu FU Eli Lilly and Company FX We thank the patients, investigators, and institutions involved in this study, especially those who provided samples for these analyses. In addition, Kathy Guarnery is acknowledged for assistance with figure development, Tuan Nguyen for additional statistical support, Anastasia Perkowski for editorial support, and Mary Dugan Wood for writing assistance. This research was financially supported by Eli Lilly and Company. NR 35 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 11 PY 2016 VL 115 IS 8 BP 974 EP 982 DI 10.1038/bjc.2016.293 PG 9 WC Oncology SC Oncology GA EA3BZ UT WOS:000386474800012 PM 27623234 ER PT J AU Pokorney, SD Shrader, P Thomas, L Fonarow, GC Kowey, PR Singer, DE Ansell, J Gersh, BJ Mahaffey, KW Hylek, EM Go, AS Piccini, JP Peterson, ED AF Pokorney, Sean D. Shrader, Peter Thomas, Laine Fonarow, Gregg C. Kowey, Peter R. Singer, Daniel E. Ansell, Jack Gersh, Bernard J. Mahaffey, Kenneth W. Hylek, Elaine M. Go, Alan S. Piccini, Jonathan P. Peterson, Eric D. CA Outcomes Registry Better Informed TI Influence of Kidney Function Estimation Methods on Eligibility for Edoxaban Population Impact of the US Food and Drug Administration's Approach for Its Product Labeling SO CIRCULATION LA English DT Letter DE anticoagulation; atrial fibrillation; renal function ID GLOMERULAR-FILTRATION-RATE C1 [Pokorney, Sean D.; Piccini, Jonathan P.; Peterson, Eric D.] Duke Univ, Med Ctr, Div Cardiol, DUMC 3845, Durham, NC 27710 USA. [Pokorney, Sean D.; Shrader, Peter; Thomas, Laine; Piccini, Jonathan P.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90024 USA. [Kowey, Peter R.] Lankenau Inst Med Res, Wynnewood, PA USA. [Singer, Daniel E.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Ansell, Jack] Hofstra North Shore Long Isl Sch Med, Hempstead, NY USA. [Gersh, Bernard J.] Mayo Clin, Coll Med, Rochester, MN USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Hylek, Elaine M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Go, Alan S.] Kaiser Permanente, Oakland, CA USA. RP Pokorney, SD (reprint author), Duke Univ, Med Ctr, Div Cardiol, DUMC 3845, Durham, NC 27710 USA. EM sean.pokorney@duke.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 11 PY 2016 VL 134 IS 15 BP 1122 EP 1124 DI 10.1161/CIRCULATIONAHA.116.024333 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DZ9UK UT WOS:000386225100013 PM 27753615 ER PT J AU Dotimas, JR Lee, AW Schmider, AB Carroll, SH Shah, A Bilen, J Elliott, KR Myers, RB Soberman, RJ Yoshioka, J Lee, RT AF Dotimas, James R. Lee, Austin W. Schmider, Angela B. Carroll, Shannon H. Shah, Anu Bilen, Julide Elliott, Kayla R. Myers, Ronald B. Soberman, Roy J. Yoshioka, Jun Lee, Richard T. TI Diabetes regulates fructose absorption through thioredoxin-interacting protein SO ELIFE LA English DT Article ID INTESTINAL GLUCOSE-ABSORPTION; BRUSH-BORDER MEMBRANE; FATTY LIVER-DISEASE; TRANSPORTER GLUT5; SUGAR ABSORPTION; UP-REGULATION; APICAL GLUT2; BETA-CELL; P38 MAPK; TXNIP AB Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake. C1 [Dotimas, James R.; Lee, Austin W.; Carroll, Shannon H.; Shah, Anu; Bilen, Julide; Elliott, Kayla R.; Myers, Ronald B.; Yoshioka, Jun; Lee, Richard T.] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Dotimas, James R.; Lee, Austin W.; Carroll, Shannon H.; Shah, Anu; Bilen, Julide; Elliott, Kayla R.; Myers, Ronald B.; Yoshioka, Jun; Lee, Richard T.] Brigham & Womens Hosp, Dept Med, Cambridge, MA 02139 USA. [Dotimas, James R.; Lee, Austin W.; Carroll, Shannon H.; Shah, Anu; Bilen, Julide; Elliott, Kayla R.; Myers, Ronald B.; Yoshioka, Jun; Lee, Richard T.] Harvard Med Sch, Cambridge, MA 02138 USA. [Schmider, Angela B.; Soberman, Roy J.] Massachusetts Gen Hosp, Dept Med, Nephrol Div, Charlestown, MA USA. [Soberman, Roy J.] Massachusetts Gen Hosp, Mol Imaging Core, Charlestown, MA USA. RP Lee, RT (reprint author), Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Lee, RT (reprint author), Brigham & Womens Hosp, Dept Med, Cambridge, MA 02139 USA.; Lee, RT (reprint author), Harvard Med Sch, Cambridge, MA 02138 USA. EM Richard_Lee@harvard.edu FU National Institutes of Health [AG040019, HL117986, 1R01AR065538, S10RR027931, K01DK089145, DK107396, 1R01CA193520, R01DK062472] FX National Institutes of Health AG040019 Richard T Lee; National Institutes of Health HL117986 Richard T Lee; National Institutes of Health 1R01AR065538 Roy J Soberman; National Institutes of Health S10RR027931 Roy J Soberman; National Institutes of Health K01DK089145 Angela B Schmider; National Institutes of Health DK107396 Richard T Lee; National Institutes of Health 1R01CA193520 Roy J Soberman; National Institutes of Health R01DK062472 Roy J Soberman NR 43 TC 2 Z9 2 U1 7 U2 7 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 11 PY 2016 VL 5 AR e18313 DI 10.7554/eLife.18313 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DZ7MJ UT WOS:000386049700001 ER PT J AU Narang, A Sinha, SS Rajagopalan, B Ijioma, NN Jayaram, N Kithcart, AP Tanguturi, VK Cullen, MW AF Narang, Akhil Sinha, Shashank S. Rajagopalan, Bharath Ijioma, Nkechinyere N. Jayaram, Natalie Kithcart, Aaron P. Tanguturi, Varsha K. Cullen, Michael W. TI The Supply and Demand of the Cardiovascular Workforce Striking the Right Balance SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular care team; demographics; fellowship; prevention; training pathway ID COLLEGE-OF-CARDIOLOGY; GRADUATE MEDICAL-EDUCATION; AFFORDABLE CARE ACT; TEAM-BASED CARE; HEALTH-CARE; PRESIDENTS PAGE; PRIMARY PREVENTION; MYOCARDIAL-INFARCTION; UNITED-STATES; TASK-FORCE AB As the burden of cardiovascular disease in the United States continues to increase, uncertainty remains on how well-equipped the cardiovascular workforce is to meet the challenges that lie ahead. In a time when health care is rapidly shifting, numerous factors affect the supply and demand of the cardiovascular workforce. This Council Commentary critically examines several factors that influence the cardiovascular workforce. These include current workforce demo-graphics and projections, evolving health care and practice environments, and the increasing burden of cardiovascular disease. Finally, we propose 3 strategies to optimize the workforce. These focus on cardiovascular disease prevention, the effective utilization of the cardiovascular care team, and alterations to the training pathway for cardiologists. (C) 2016 by the American College of Cardiology Foundation. C1 [Narang, Akhil] Univ Chicago, Cardiol Sect, Chicago, IL USA. [Sinha, Shashank S.] Univ Michigan, Div Cardiovasc Med, Samuel & Jean Frankel Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Rajagopalan, Bharath] Univ Buffalo, Div Cardiovasc Med, Buffalo, NY USA. [Ijioma, Nkechinyere N.; Cullen, Michael W.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA. [Jayaram, Natalie] Childrens Mercy Hosp & Clin, Div Cardiol, Kansas City, MO USA. [Kithcart, Aaron P.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Tanguturi, Varsha K.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Narang, A (reprint author), Univ Chicago Med, Cardiol Sect, Dept Internal Med, 5841 South Maryland Ave,MC 6080, Chicago, IL 60637 USA. EM Akhil.Narang@uchospitals.edu FU NHLBI NIH HHS [T32 HL007381, T32 HL007853] NR 60 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 11 PY 2016 VL 68 IS 15 BP 1680 EP 1689 DI 10.1016/j.jacc.2016.06.070 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5ZD UT WOS:000385940100011 PM 27712782 ER PT J AU Bebell, LM AF Bebell, Lisa M. TI Cough It Up A Health Care Paradox SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Bebell, Lisa M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bebell, Lisa M.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Bebell, LM (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Bebell, LM (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. EM lbebell@mgh.harvard.edu FU FIC NIH HHS [R25 TW009337]; NIAID NIH HHS [T32 AI007433] NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 11 PY 2016 VL 316 IS 14 BP 1449 EP 1450 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DY1TC UT WOS:000384876300014 PM 27727387 ER PT J AU Fedorenko, E Scott, TL Brunner, P Coon, WG Pritchett, B Schalk, G Kanwisher, N AF Fedorenko, Evelina Scott, Terri L. Brunner, Peter Coon, William G. Pritchett, Brianna Schalk, Gerwin Kanwisher, Nancy TI Neural correlate of the construction of sentence meaning SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE language; ECoG; compositionality; syntax; semantics ID ANTERIOR TEMPORAL-LOBE; LANGUAGE COMPREHENSION; DISCOURSE COMPREHENSION; SYNTACTIC ANOMALIES; SENSORIMOTOR CORTEX; CORTICAL DYNAMICS; SITUATION MODELS; GAMMA ACTIVITY; BROCAS AREA; HUMAN BRAIN AB The neural processes that underlie your ability to read and understand this sentence are unknown. Sentence comprehension occurs very rapidly, and can only be understood at a mechanistic level by discovering the precise sequence of underlying computational and neural events. However, we have no continuous and online neural measure of sentence processing with high spatial and temporal resolution. Here we report just such a measure: intracranial recordings from the surface of the human brain show that neural activity, indexed by gamma-power, increases monotonically over the course of a sentence as people read it. This steady increase in activity is absent when people read and remember nonword-lists, despite the higher cognitive demand entailed, ruling out accounts in terms of generic attention, working memory, and cognitive load. Response increases are lower for sentence structure without meaning ("Jabberwocky" sentences) and word meaning without sentence structure (word-lists), showing that this effect is not explained by responses to syntax or word meaning alone. Instead, the full effect is found only for sentences, implicating compositional processes of sentence understanding, a striking and unique feature of human language not shared with animal communication systems. This work opens up new avenues for investigating the sequence of neural events that underlie the construction of linguistic meaning. C1 [Fedorenko, Evelina] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Fedorenko, Evelina] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Scott, Terri L.] Boston Univ, Dept Speech Language & Hearing Sci, Boston, MA 02215 USA. [Brunner, Peter; Coon, William G.; Schalk, Gerwin] New York State Dept Hlth, Wadsworth Ctr, Natl Ctr Adapt Neurotechnol, Albany, NY 12208 USA. [Brunner, Peter; Schalk, Gerwin] Albany Med Coll, Dept Neurol, Albany, NY 12208 USA. [Coon, William G.; Schalk, Gerwin] SUNY Albany, Dept Biomed Sci, Albany, NY 12222 USA. [Pritchett, Brianna; Kanwisher, Nancy] MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA. RP Fedorenko, E (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA.; Fedorenko, E (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Kanwisher, N (reprint author), MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA. EM evelina.fedorenko@mgh.harvard.edu; ngk@mit.edu OI Scott, Terri/0000-0001-9205-8581; Schalk, Gerwin/0000-0003-3443-9487 FU NIH [EB00856, EB006356, EB018783]; US Army Research Office [W911NF-08-1-0216, W911NF-12-1-0109, W911NF-14-1-0440]; Fondazione Neurone; National Institute of Child Health and Human Development [HD-057522] FX We thank Ted Gibson, Charles Jennings, Roger Levy, Kyle Mahowald, Steve Piantadosi, and Nathaniel Smith for providing helpful comments on this work; Eyal Dechter for help with setting up the experiment; Steve Piantadosi and Kyle Mahowald for providing some word-level features extracted from corpora; and Zuzanna Balewski and Ted Gibson for help with collecting norming data on Mechanical Turk. This research was supported by the NIH (Grants EB00856, EB006356, and EB018783), the US Army Research Office (Grants W911NF-08-1-0216, W911NF-12-1-0109, W911NF-14-1-0440), and Fondazione Neurone. E.F. was supported by National Institute of Child Health and Human Development Award HD-057522. NR 84 TC 1 Z9 1 U1 9 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 11 PY 2016 VL 113 IS 41 BP E6256 EP E6262 DI 10.1073/pnas.1612132113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1XE UT WOS:000384886900031 PM 27671642 ER PT J AU Xu, YZ Chen, JY Wang, HG Zheng, H Feng, D Zhang, AQ Leng, JJ Duan, WD Yang, ZY Chen, MY Shi, XJ Cai, SW Ji, WB Jiang, K Zhang, WZ Chen, YL Gu, WQ Dong, JH Lu, SC AF Xu, Yinzhe Chen, Jiye Wang, Hongguang Zheng, Hui Feng, Dan Zhang, Aiqun Leng, Jianjun Duan, Weidong Yang, Zhanyu Chen, Mingyi Shi, Xianjie Cai, Shouwang Ji, Wenbin Jiang, Kai Zhang, Wenzhi Chen, Yongliang Gu, Wanqing Dong, Jiahong Lu, Shichun TI Perioperative and long-term outcomes of liver resection for hepatitis B virus-related hepatocellular carcinoma without versus with hepatic inflow occlusion: study protocol for a prospective randomized controlled trial SO TRIALS LA English DT Article DE Hepatocellular carcinoma; Liver resection; Vascular occlusion; Randomized controlled trial; Ischemia-reperfusion injury; Inflammatory response; Survival ID PARTIAL-HEPATECTOMY; VASCULAR CONTROL; BLOOD-LOSS; INTERMITTENT; STRATEGIES; MANAGEMENT; BURDEN; INJURY; ASIA AB Background: The high prevalence of hepatitis B virus (HBV) imposes a huge burden of hepatocellular carcinoma (HCC) in Asia. Surgical resection remains an important therapeutic strategy for HCC. Hepatic inflow occlusion, known as the Pringle maneuver, is the most commonly used method of reducing blood loss during liver parenchymal transection. A major issue with this maneuver is ischemia-reperfusion injury to the remnant liver, and the hemodynamic disturbance it induces in the tumor-bearing liver raises an oncological concern. Given the technical advances in living donor liver transplantation, vascular occlusion in liver resection can be avoided in experienced hands. The aim of this study is to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with hepatic inflow occlusion. Methods/design: This study will include eligible patients with HBV-related HCC elected for liver resection. Fifty-seven patients will be enrolled in each randomization arm to detect a 20 % difference in the serum level of total bilirubin on postoperative day 5 (80 % power and alpha = 0.05). The secondary endpoints include procedural parameters, perioperative liver function and inflammatory response, postoperative morbidity and mortality, and long-term outcomes. Patients will be followed for up to 5 years. Data will be statistically analyzed on an intention-to-treat basis. Discussion: This prospective randomized controlled trial is designed to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with vascular occlusion. The clinical implications of these outcomes may change current surgical practice and fill the oncological gaps therein. C1 [Xu, Yinzhe; Chen, Jiye; Wang, Hongguang; Zhang, Aiqun; Leng, Jianjun; Duan, Weidong; Yang, Zhanyu; Chen, Mingyi; Shi, Xianjie; Cai, Shouwang; Ji, Wenbin; Jiang, Kai; Zhang, Wenzhi; Chen, Yongliang; Gu, Wanqing; Dong, Jiahong; Lu, Shichun] Chinese Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, 28 Fuxing Rd, Beijing 100853, Peoples R China. [Xu, Yinzhe] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Transplantat, 55 Fruit St, Boston, MA 02114 USA. [Zheng, Hui] Harvard Med Sch, Massachusetts Gen Hosp, Biostat Ctr, 50 Staniford St, Boston, MA 02114 USA. [Feng, Dan] Chinese Peoples Liberat Army Gen Hosp, Inst Hosp Management, Div Stand Operat Management, 28 Fuxing Rd, Beijing 100853, Peoples R China. RP Lu, SC (reprint author), Chinese Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, 28 Fuxing Rd, Beijing 100853, Peoples R China. EM lsc620213@aliyun.com FU National Key Technology Research & Development Program of China [2012BAI06B01]; Major National Science and Technology Project for Infectious Diseases of China [2012ZX10002-017]; Beijing Natural Science Foundation [7144244] FX This work will be supported by the National Key Technology Research & Development Program of China (2012BAI06B01), the Major National Science and Technology Project for Infectious Diseases of China (2012ZX10002-017), and the Beijing Natural Science Foundation (7144244). NR 40 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD OCT 11 PY 2016 VL 17 AR 492 DI 10.1186/s13063-016-1621-9 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DY1IR UT WOS:000384848600003 PM 27724929 ER PT J AU Vatansever, F Hamblin, MR AF Vatansever, Fatma Hamblin, Michael R. TI Surface-initiated ring-opening metathesis polymerization (SI-ROMP) to attach a tethered organic corona onto CdSe/ZnS core/shell quantum dots SO JOURNAL OF NANOPARTICLE RESEARCH LA English DT Article DE Tunable fluorophores; Nanomaterials; Quantum dot; Surface functionalization; Surface-initiated ring-opening metathesis polymerization; Grubbs catalyst; Nanomedicine ID SEMICONDUCTOR NANOCRYSTALS; TOP-DOWN; NANOPARTICLES; NANOTECHNOLOGY; NANOSCALE; CLUSTERS; THERAPY; BRUSHES; GROWTH; TRANSITIONS AB Core-shell CdSe/ZnS quantum dots (QDs) are useful as tunable photostable fluorophores for multiple applications in industry, biology, and medicine. However, to achieve the optimum optical properties, the surface of the QDs must be passivated to remove charged sites that might bind extraneous substances and allow aggregation. Here we describe a method of growing an organic polymer corona onto the QD surface using the bottom-up approach of surface-initiated ring-opening metathesis polymerization (SI-ROMP) with Grubbs catalyst. CdSe/ZnS QDs were first coated with mercaptopropionic acid by displacing the original trioctylphosphine oxide layer, and then reacted with 7-octenyl dimethyl chlorosilane. The resulting octenyl double bonds allowed the attachment of ruthenium alkylidene groups as a catalyst. A subsequent metathesis reaction with strained bicyclic monomers (norbornene-dicarbonyl chloride (NDC), and a mixture of NDC and norbornenylethylisobutyl-polyhedral oligomeric silsesquioxane (norbornoPOSS)) allowed the construction of tethered organic homo-polymer or co-polymer layers onto the QD. Compounds were characterized by FT-IR, H-1-NMR, X-ray photoelectron spectroscopy, differential scanning calorimetry, and transmission electron microscopy. Atomic force microscopy showed that the coated QDs were separate and non-aggregated with a range of diameter of 48-53 nm. C1 [Vatansever, Fatma; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Vatansever, Fatma; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Boston, MA 02139 USA. RP Vatansever, F; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. EM vatansever.fatma@mgh.harvard.edu; hamblin@helix.mgh.harvard.edu FU US NIH [R01AI050875] FX MRH was supported by the US NIH grant R01AI050875. NR 72 TC 0 Z9 0 U1 13 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1388-0764 EI 1572-896X J9 J NANOPART RES JI J. Nanopart. Res. PD OCT 10 PY 2016 VL 18 IS 10 AR 302 DI 10.1007/s11051-016-3328-y PG 16 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA ED6KZ UT WOS:000388965800005 ER PT J AU Rossmann, MP Zhou, Y Zon, LI AF Rossmann, Marlies P. Zhou, Yi Zon, Leonard I. TI Development: For cloche the Bell Tolls SO CURRENT BIOLOGY LA English DT Editorial Material ID ZEBRAFISH GENE CLOCHE; EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTOR; HEMOGENIC ENDOTHELIUM; MOUSE EMBRYO; DIFFERENTIATION; BLOOD; SPECIFICATION; ACTS; HEMATOPOIESIS AB A recent publication identifies npas4l as the gene defective in the well-known cloche mutant that lacks most endothelial as well as hematopoietic cells. This work poses intriguing questions as to the genetic and molecular nature of the origin of hemato-vascular lineages during early embryogenesis. C1 [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Childrens Hosp, Howard Hughes Med Inst, Stem Cell Program, Boston, MA 02115 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Harvard Med Sch, Boston, MA 02115 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Rossmann, Marlies P.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Zon, LI (reprint author), Childrens Hosp, Howard Hughes Med Inst, Stem Cell Program, Boston, MA 02115 USA.; Zon, LI (reprint author), Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA.; Zon, LI (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Zon, LI (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Zon, LI (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Zon, LI (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Zon, LI (reprint author), Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM zon@enders.tch.harvard.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD OCT 10 PY 2016 VL 26 IS 19 BP R890 EP R892 DI 10.1016/j.cub.2016.08.009 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DZ2SF UT WOS:000385690800010 PM 27728792 ER PT J AU Higuma, T Soeda, T Yamada, M Yokota, T Yokoyama, H Izumiyama, K Nishizaki, F Minami, Y Xing, L Yamamoto, E Lee, H Okumura, K Jang, IK AF Higuma, Takumi Soeda, Tsunenari Yamada, Masahiro Yokota, Takashi Yokoyama, Hiroaki Izumiyama, Kei Nishizaki, Fumie Minami, Yoshiyasu Xing, Lei Yamamoto, Erika Lee, Hang Okumura, Ken Jang, Ik-Kyung TI Does Residual Thrombus After Aspiration Thrombectomy Affect the Outcome of Primary PCI in Patients With ST-Segment Elevation Myocardial Infarction? An Optical Coherence Tomography Study SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE intracoronary thrombus; optical coherence tomography; percutaneous coronary intervention; ST-segment elevation myocardial infarction ID PERCUTANEOUS CORONARY INTERVENTION; NO-REFLOW PHENOMENON; INTRAVASCULAR ULTRASOUND; ANGIOGRAPHIC ASSESSMENT; MANUAL THROMBECTOMY; PRIMARY ANGIOPLASTY; CALCIFIED NODULE; RANDOMIZED-TRIAL; PLAQUE EROSION; BLUSH GRADE AB OBJECTIVES The aim of this study was to evaluate if residual thrombus burden after aspiration thrombectomy affects the outcomes of primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Recent studies failed to show clinical benefit of aspiration thrombectomy in STEMI patients. This might be due to insufficient removal of thrombus at the culprit lesion. METHODS A total of 109 STEMI patients who underwent aspiration thrombectomy followed by stenting within 24 h from symptom onset were included. Optical coherence tomography was performed after thrombectomy to measure residual thrombus burden. Patients were divided into tertiles based on the amount of residual thrombus and the outcomes were compared. RESULTS Myocardial no reflow, defined as TIMI (Thrombolysis In Myocardial Infarction) flow grade of <= 2 and/or myocardial blush grade of <= 1 after stenting, was more observed frequently in patients in the highest tertile compared with those in the lowest tertile (44.4% vs. 16.7%; p = 0.001). Patients in the highest tertile also had greater myocardial damage measured by creatine kinase MB compared with those in the lowest tertile (p = 0.002). CONCLUSIONS STEMI patients with greater residual thrombus burden after aspiration thrombectomy had worse microvascular dysfunction and greater myocardial damage compared with those with smaller residual thrombus burden. (C) 2016 by the American College of Cardiology Foundation. C1 [Higuma, Takumi; Yamada, Masahiro; Yokota, Takashi; Yokoyama, Hiroaki; Izumiyama, Kei; Nishizaki, Fumie; Okumura, Ken] Hirosaki Univ, Grad Sch Med, Dept Cardiol, Hirosaki, Aomori, Japan. [Higuma, Takumi; Soeda, Tsunenari; Minami, Yoshiyasu; Xing, Lei; Yamamoto, Erika; Jang, Ik-Kyung] Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. [Higuma, Takumi; Soeda, Tsunenari; Minami, Yoshiyasu; Xing, Lei; Yamamoto, Erika; Lee, Hang; Jang, Ik-Kyung] Harvard Med Sch, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@mgh.harvard.edu NR 26 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD OCT 10 PY 2016 VL 9 IS 19 BP 2002 EP 2011 DI 10.1016/j.jcin.2016.06.050 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ3AF UT WOS:000385714600007 PM 27712735 ER PT J AU Seisen, T Sun, M Leow, JJ Preston, MA Cole, AP Gelpi-Hammerschmidt, F Hanna, N Meyer, CP Kibel, AS Lipsitz, SR Nguyen, PL Bellmunt, J Choueiri, TK Trinh, QD AF Seisen, Thomas Sun, Maxine Leow, Jeffrey J. Preston, Mark A. Cole, Alexander P. Gelpi-Hammerschmidt, Francisco Hanna, Nawar Meyer, Christian P. Kibel, Adam S. Lipsitz, Stuart R. Nguyen, Paul L. Bellmunt, Joaquim Choueiri, Toni K. Quoc-Dien Trinh TI Efficacy of High-Intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder: A Propensity Score-Weighted Analysis From the National Cancer Data Base SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; CYTOREDUCTIVE NEPHRECTOMY; POSTCHEMOTHERAPY SURGERY; RANDOMIZED-TRIAL; SURVIVAL; CHEMOTHERAPY; METHOTREXATE; RADIOTHERAPY; VINBLASTINE; DOXORUBICIN AB PurposeEvidence from studies of other malignancies has indicated that aggressive local treatment (LT), even in the presence of metastatic disease, is beneficial. Against a backdrop of stagnant mortality rates for metastatic urothelial carcinoma of the bladder (mUCB) at presentation, we hypothesized that high-intensity LT of primary tumor burden, defined as the receipt of radical cystectomy or 50 Gy of radiation therapy delivered to the bladder, affects overall survival (OS).Patients and MethodsWe identified 3,753 patients within the National Cancer Data Base who received multiagent systemic chemotherapy combined with high-intensity versus conservative LT for primary mUCB. Patients who received no LT, transurethral resection of the bladder tumor alone, or < 50 Gy of radiation therapy delivered to the bladder were included in the conservative LT group. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox regression analyses were used to compare OS of patients who received high-intensity versus conservative LT.ResultsOverall, 297 (7.91%) and 3,456 (92.09%) patients with mUCB received high-intensity and conservative LT, respectively. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer in the high-intensity LT group than in the conservative LT group (14.92 [interquartile range, 9.82 to 30.72] v 9.95 [interquartile range, 5.29 to 17.08] months, respectively; P < .001). Furthermore, in IPTW-adjusted Cox regression analysis, high-intensity LT was associated with a significant OS benefit (hazard ratio, 0.56; 95% CI, 0.48 to 0.65; P < .001).ConclusionWe report an OS benefit for individuals with mUCB treated with high-intensity versus conservative LT. Although the findings are subject to the usual biases related to the observational study design, these preliminary data warrant further consideration in randomized controlled trials, particularly given the poor prognosis associated with mUCB. C1 [Seisen, Thomas; Sun, Maxine; Leow, Jeffrey J.; Preston, Mark A.; Cole, Alexander P.; Gelpi-Hammerschmidt, Francisco; Hanna, Nawar; Meyer, Christian P.; Kibel, Adam S.; Lipsitz, Stuart R.; Nguyen, Paul L.; Quoc-Dien Trinh] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bellmunt, Joaquim; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Brigham & Womens Hosp, Div Urol Surg, Ctr Surg & Publ Hlth, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM qtrinh@bwh.harvard.edu FU Vattikuti Urology Institute FX Supported by an unrestricted educational grant from the Vattikuti Urology Institute. NR 33 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3529 EP + DI 10.1200/JCO.2016.66.7352 PG 12 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400008 ER PT J AU Ganzel, C Manola, J Douer, D Rowe, JM Fernandez, HF Paietta, EM Litzow, MR Lee, JW Luger, SM Lazarus, HM Cripe, LD Tallman, MS AF Ganzel, Chezi Manola, Judith Douer, Dan Rowe, Jacob M. Fernandez, Hugo F. Paietta, Elisabeth M. Litzow, Mark R. Lee, Ju-Whei Luger, Selina M. Lazarus, Hillard M. Cripe, Larry D. Tallman, Martin S. TI Extramedullary Disease in Adult Acute Myeloid Leukemia Is Common but Lacks Independent Significance: Analysis of Patients in ECOG-ACRIN Cancer Research Group Trials, 1980-2008 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; ACUTE NONLYMPHOCYTIC LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; ACUTE MYELOGENOUS LEUKEMIA; COLONY-STIMULATING FACTOR; POSTREMISSION THERAPY; 1ST REMISSION; RISK-FACTORS; INVOLVEMENT; INDUCTION AB PurposeExtramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD.MethodsPatients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results.ResultsOf the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites.The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD (P = .005), skin involvement (P = .002), spleen (P < .001), and liver (P < .001), but not CNS (P = .34), nodal involvement (P = .94), and gingival hypertrophy (P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic.ConclusionThis large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD. C1 [Ganzel, Chezi; Rowe, Jacob M.] Shaare Zedek Med Ctr, Jerusalem, Israel. [Ganzel, Chezi; Douer, Dan; Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Paietta, Elisabeth M.] Montefiore Med Ctr, New York, NY USA. [Manola, Judith; Lee, Ju-Whei] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fernandez, Hugo F.] H Lee Moffitt Canc Inst, Tampa, FL USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Luger, Selina M.] Univ Penn, Philadelphia, PA 19104 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Cripe, Larry D.] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. RP Ganzel, C (reprint author), Shaare Zedek Med Ctr, Dept Hematol, Byte 12, IL-91031 Jerusalem, Israel. EM ganzelc@szmc.org.il FU National Cancer Institute of the National Institutes of Health [CA180820, CA21115, CA180794, CA23318, CA66636, CA17145, CA49883, CA73590, CA13650, CA15488, CA14548, CA14958, CA180791, CA189859, CA180853, CA180790, CA180795] FX Supported by Grants No. CA180820, CA21115, CA180794, CA23318, CA66636, CA17145, CA49883, CA73590, CA13650, CA15488, CA14548, CA14958, CA180791, CA189859, CA180853, CA180790, and CA180795 from the National Cancer Institute of the National Institutes of Health. NR 30 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3544 EP + DI 10.1200/JCO.2016.67.5892 PG 12 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400010 PM 27573652 ER PT J AU Naing, A Papadopoulos, KP Autio, KA Ott, PA Patel, MR Wong, DJ Falchook, GS Pant, S Whiteside, M Rasco, DR Mumm, JB Chan, IH Bendell, JC Bauer, TM Colen, RR Hong, DS Van Vlasselaer, P Tannir, NM Oft, M Infante, JR AF Naing, Aung Papadopoulos, Kyriakos P. Autio, Karen A. Ott, Patrick A. Patel, Manish R. Wong, Deborah J. Falchook, Gerald S. Pant, Shubham Whiteside, Melinda Rasco, Drew R. Mumm, John B. Chan, Ivan H. Bendell, Johanna C. Bauer, Todd M. Colen, Rivka R. Hong, David S. Van Vlasselaer, Peter Tannir, Nizar M. Oft, Martin Infante, Jeffrey R. TI Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CD8(+) T-CELLS; IL-10; INFLAMMATION; NIVOLUMAB; CANCER; IPILIMUMAB; MELANOMA; RECEPTOR; THERAPY AB PurposeInterleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010.Patients and MethodsPatients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 g/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points.ResultsIn the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 g/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months.ConclusionAM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies. C1 [Naing, Aung; Colen, Rivka R.; Hong, David S.; Tannir, Nizar M.] MD Anderson Canc Ctr, Houston, TX USA. [Papadopoulos, Kyriakos P.; Rasco, Drew R.] START Ctr Canc Care, San Antonio, TX USA. [Autio, Karen A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Ott, Patrick A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Patel, Manish R.] Florida Canc Specialists, Sarah Cannon Res Inst, Sarasota, FL USA. [Wong, Deborah J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Whiteside, Melinda; Mumm, John B.; Chan, Ivan H.; Van Vlasselaer, Peter; Oft, Martin] ARMO BioSci, Redwood City, CA USA. [Falchook, Gerald S.] HealthONE, Sarah Cannon Res Inst, Denver, CO USA. [Pant, Shubham] Univ Oklahoma, Oklahoma City, OK USA. [Bendell, Johanna C.; Bauer, Todd M.; Infante, Jeffrey R.] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA. RP Infante, JR (reprint author), Sarah Cannon Res Inst, 250 25th Ave North,Suite 200, Nashville, TN 37203 USA. EM jinfante@tnonc.com FU ARMO BioSciences FX Supported by ARMO BioSciences, which provided funding, data collection, medical writing, and editorial assistance. NR 23 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3562 EP + DI 10.1200/JCO.2016.68.1106 PG 11 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400012 ER PT J AU Demetri, GD AF Demetri, George D. TI Trabectedin in Soft Tissue Sarcoma: Have We Hit the Bull's-eye? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID METASTATIC LIPOSARCOMA; LEIOMYOSARCOMA; EFFICACY; FAILURE; SAFETY; TRIAL C1 [Demetri, George D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Demetri, George D.] Harvard Med Sch, Boston, MA 02115 USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Demetri, GD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3583 EP + DI 10.1200/JCO.2016.68.3029 PG 2 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400020 ER PT J AU Mittakanti, HR Thomas, IC Shelton, JB Makarov, DV Skolarus, TA Cooperberg, MR Chung, BI Sonn, GA Brooks, JD Leppert, JT AF Mittakanti, Harsha R. Thomas, I-Chun Shelton, Jeremy B. Makarov, Danil V. Skolarus, Ted A. Cooperberg, Matthew R. Chung, Benjamin I. Sonn, Geoffrey A. Brooks, James D. Leppert, John T. TI Accuracy of Prostate-Specific Antigen Values in Prostate Cancer Registries SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Mittakanti, Harsha R.; Thomas, I-Chun; Chung, Benjamin I.; Sonn, Geoffrey A.; Brooks, James D.; Leppert, John T.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Shelton, Jeremy B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Shelton, Jeremy B.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Makarov, Danil V.] Vet Adm New York Harbor Healthcare Syst, New York, NY USA. [Makarov, Danil V.] NYU, Langone Med Ctr, New York, NY USA. [Skolarus, Ted A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Skolarus, Ted A.] Vet Adm Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Cooperberg, Matthew R.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Cooperberg, Matthew R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Leppert, John T.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. RP Mittakanti, HR (reprint author), Stanford Univ, Sch Med, Stanford, CA 94305 USA. OI Makarov, Danil/0000-0002-0565-9272 NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2016 VL 34 IS 29 BP 3586 EP + DI 10.1200/JCO.2016.68.9216 PG 4 WC Oncology SC Oncology GA DZ4TJ UT WOS:000385852400024 ER PT J AU Nordenfelt, P Elliott, HL Springer, TA AF Nordenfelt, Pontus Elliott, Hunter L. Springer, Timothy A. TI Coordinated integrin activation by actin-dependent force during T-cell migration SO NATURE COMMUNICATIONS LA English DT Article ID LEUKOCYTE INTEGRIN; ADHESION RECEPTORS; FILAMIN BINDING; ALPHA-SUBUNITS; FOCAL ADHESION; BETA-SUBUNIT; F-ACTIN; LFA-1; TALIN; EXPRESSION AB For a cell to move forward it must convert chemical energy into mechanical propulsion. Force produced by actin polymerization can generate traction across the plasma membrane by transmission through integrins to their ligands. However, the role this force plays in integrin activation is unknown. Here we show that integrin activity and cytoskeletal dynamics are reciprocally linked, where actin-dependent force itself appears to regulate integrin activity. We generated fluorescent tension-sensing constructs of integrin alpha L beta 2 (LFA-1) to visualize intramolecular tension during cell migration. Using quantitative imaging of migrating T cells, we correlate tension in the alpha L or beta 2 subunit with cell and actin dynamics. We find that actin engagement produces tension within the beta 2 subunit to induce and stabilize an active integrin conformational state and that this requires intact talin and kindlin motifs. This supports a general mechanism where localized actin polymerization can coordinate activation of the complex machinery required for cell migration. C1 [Nordenfelt, Pontus; Springer, Timothy A.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 3 Blackfan Circle, Boston, MA 02115 USA. [Nordenfelt, Pontus; Springer, Timothy A.] Childrens Hosp Boston, Program Cellular & Mol Med, 3 Blackfan Circle, Boston, MA 02115 USA. [Nordenfelt, Pontus; Elliott, Hunter L.] Harvard Med Sch, Image & Data Anal Core, 240 Longwood Ave, Boston, MA 02115 USA. [Nordenfelt, Pontus] Lund Univ, Fac Med, Div Infect Med, Dept Clin Sci,BMC, B14,Solvegatan 19, S-22362 Lund, Sweden. RP Nordenfelt, P; Springer, TA (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 3 Blackfan Circle, Boston, MA 02115 USA.; Nordenfelt, P; Springer, TA (reprint author), Childrens Hosp Boston, Program Cellular & Mol Med, 3 Blackfan Circle, Boston, MA 02115 USA.; Nordenfelt, P (reprint author), Harvard Med Sch, Image & Data Anal Core, 240 Longwood Ave, Boston, MA 02115 USA.; Nordenfelt, P (reprint author), Lund Univ, Fac Med, Div Infect Med, Dept Clin Sci,BMC, B14,Solvegatan 19, S-22362 Lund, Sweden. EM nordenfelt@crystal.harvard.edu; timothy.springer@childrens.harvard.edu OI Nordenfelt, Pontus/0000-0002-9481-9951 FU NIH [CA031798, 1S10RR026549-01]; Swedish Research Council [VR 524-2011-891]; Swedish Society for Medical Research; Image and Data Analysis Core at Harvard Medical School; Swedish Society of Medicine [SLS-173751, SLS-323411]; Blanceflor Foundation; Crafoord Foundation; Knut & Alice Wallenberg Foundation FX This work was supported by NIH Grant CA031798 (TAS). P.N. was funded by fellowships from the Swedish Research Council (VR 524-2011-891), Swedish Society for Medical Research, the Image and Data Analysis Core at Harvard Medical School, scholarships from the Swedish Society of Medicine (SLS-173751; SLS-323411) and the Blanceflor Foundation, as well as funding from the Crafoord Foundation and Knut & Alice Wallenberg Foundation. We thank Dr Brenton Hoffman for providing raw data on force-FRET efficiency relationship. We thank Dr Peter Horwath for providing the source code for CellTracker. We acknowledge the Nikon Imaging Center at Harvard Medical School for excellent help and advice on microscope instrumentation and NIH 1S10RR026549-01 for shared instrumentation funding. NR 60 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 10 PY 2016 VL 7 AR 13119 DI 10.1038/ncomms13119 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0SH UT WOS:000385549500001 PM 27721490 ER PT J AU Pollack, CE Ross, ME Armstrong, K Branas, CC Rhodes, KV Bekelman, JE Wentz, A Stillson, C Radhakrishnan, A Oyeniran, E Grande, D AF Pollack, Craig Evan Ross, Michelle E. Armstrong, Katrina Branas, Charles C. Rhodes, Karin V. Bekelman, Justin E. Wentz, Alicia Stillson, Christian Radhakrishnan, Archana Oyeniran, Enny Grande, David TI Using a Mystery-Caller Approach to Examine Access to Prostate Cancer Care in Philadelphia SO PLOS ONE LA English DT Article AB Purpose Prior work suggests that access to health care may influence the diagnosis and treatment of prostate cancer. Mystery-caller methods have been used previously to measure access to care for health services such as primary care, where patients' self-initiate requests for care. We used a mystery-caller survey for specialized prostate cancer care to assess dimensions of access to prostate cancer care. Materials and Methods We created an inventory of urology and radiation oncology practices in southeastern Pennsylvania. Using a 'mystery caller' approach, a research assistant posing as a medical office scheduler in a primary care office, attempted to make a new patient appointment on behalf of a referred patient. Linear regression was used to determine the association between time to next available appointment with practice and census tract characteristics. Results We successfully obtained information on new patient appointments from 198 practices out of the 223 in the region (88.8%). Radiation oncology practices were more likely to accept Medicaid compared to urology practices (91.3% vs 36.4%) and had shorter mean wait times for new patient appointments (9.0 vs 12.8 days). We did not observe significant differences in wait times according to census tract characteristics including neighborhood socioeconomic status and the proportion of male African American residents. Conclusions Mystery-caller methods that reflect real-world referral processes from primary care offices can be used to measure access to specialized cancer care. We observed significant differences in wait times and insurance acceptance between radiation oncology and urology practices. C1 [Pollack, Craig Evan; Radhakrishnan, Archana] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. [Pollack, Craig Evan; Radhakrishnan, Archana] Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Ross, Michelle E.; Branas, Charles C.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Armstrong, Katrina] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rhodes, Karin V.] Northwell Hlth Hofstra Med Sch, Off Populat Hlth Management, Great Neck, NY USA. [Bekelman, Justin E.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Wentz, Alicia] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Stillson, Christian; Grande, David] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Oyeniran, Enny] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Grande, David] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Pollack, CE (reprint author), Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA.; Pollack, CE (reprint author), Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM Cpollac2@jhmi.edu FU National Institute on Minority Health and Health Disparities [P60MD006900]; National Cancer Institute (NCI); Office of Behavioral and Social Sciences [K07CA151910] FX Funding for this study was provided by the National Institute on Minority Health and Health Disparities (P60MD006900) and Dr. Craig Evan Pollack's (CP) salary is supported by the National Cancer Institute (NCI) and Office of Behavioral and Social Sciences (K07CA151910). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 7 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2016 VL 11 IS 10 AR e0164411 DI 10.1371/journal.pone.0164411 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CF UT WOS:000385504100057 PM 27723780 ER PT J AU Weber, D Long, J Leonard, MB Zemel, B Baker, JF AF Weber, David Long, Jin Leonard, Mary B. Zemel, Babette Baker, Joshua F. TI Development of Novel Methods to Define Deficits in Appendicular Lean Mass Relative to Fat Mass SO PLOS ONE LA English DT Article ID MUSCLE MASS; RHEUMATOID-ARTHRITIS; ALTERNATIVE DEFINITIONS; FUNCTIONAL IMPAIRMENT; PHYSICAL PERFORMANCE; SARCOPENIC OBESITY; REFERENCE VALUES; HEALTH; DISABILITY; STRENGTH AB Background Recent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity. Methods Whole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m(2)) and fat mass index (FMI, kg/m(2)). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMI(FMI)) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z- Score <-1.0. Correlations with physical function were assessed in an at-risk population. Results Positive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z- score on ALMI Z- score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [ Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z- scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not. Conclusions Adjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data. C1 [Weber, David] Univ Rochester, Golisano Childrens Hosp, Div Endocrinol & Diabet, Rochester, NY 14627 USA. [Long, Jin; Zemel, Babette] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Long, Jin; Leonard, Mary B.] Stanford Univ, Dept Pediat & Med, Stanford, CA 94305 USA. [Baker, Joshua F.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Baker, Joshua F.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Baker, Joshua F.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Baker, JF (reprint author), Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA.; Baker, JF (reprint author), Univ Penn, Sch Med, Philadelphia, PA 19104 USA.; Baker, JF (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. EM bakerjo@uphs.upenn.edu FU Veterans Affairs Clinical Science Research and Development Career Development Award [IK2 CX000955]; NIH [K24 DK076808, K12 HD068373]; University of Pennsylvania Clinical and Translational Research Center [UL1 RR024134] FX Dr. Baker is supported by a Veterans Affairs Clinical Science Research and Development Career Development Award (IK2 CX000955). This work was also supported by NIH grants K24 DK076808 (MBL), K12 HD068373 (DRW) and the University of Pennsylvania Clinical and Translational Research Center (UL1 RR024134). NR 26 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2016 VL 11 IS 10 AR e0164385 DI 10.1371/journal.pone.0164385 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0CF UT WOS:000385504100053 PM 27723820 ER PT J AU Habtezion, A Edderkaoui, M Pandol, SJ AF Habtezion, Aida Edderkaoui, Mouad Pandol, Stephen J. TI Macrophages and pancreatic ductal adenocarcinoma SO CANCER LETTERS LA English DT Review DE Macrophages; Tumor associated macrophages; Pancreas cancer; Pancreatic ductal adenocarcinoma ID TUMOR-ASSOCIATED MACROPHAGES; PRE-METASTATIC NICHE; BONE-MARROW; INTRAEPITHELIAL NEOPLASIA; INFILTRATING MACROPHAGES; PREMETASTATIC NICHE; CHEMOKINE RECEPTOR; MALIGNANT-TUMORS; CANCER EXOSOMES; GROWTH-FACTORS AB Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Habtezion, Aida] Stanford Univ, Div Gastroenterol & Hepatol, Sch Med, Stanford, CA 94305 USA. [Edderkaoui, Mouad; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Healthcare Syst, Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA USA. [Edderkaoui, Mouad; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Healthcare Syst, Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA USA. [Edderkaoui, Mouad; Pandol, Stephen J.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Habtezion, A (reprint author), Stanford Univ, Div Gastroenterol & Hepatol, Sch Med, Stanford, CA 94305 USA. EM aidah@stanford.edu FU National Pancreas Foundation; Department of Veterans Affairs; NIH [DK092421, P01CA163200, P50 AA11999, K01AA019996] FX This work was supported in part by the National Pancreas Foundation Grant, Department of Veterans Affairs, NIH DK092421, NIH P01CA163200 and NIH P50 AA11999, and NIH K01AA019996. NR 92 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD OCT 10 PY 2016 VL 381 IS 1 BP 211 EP 216 DI 10.1016/j.canlet.2015.11.049 PG 6 WC Oncology SC Oncology GA DW8WG UT WOS:000383935600024 PM 26708507 ER PT J AU Wang, HD Naghavi, M Allen, C Barber, RM Bhutta, ZA Carter, A Casey, DC Charlson, FJ Chen, AZ Coates, MM Coggeshall, M Dandona, L Dicker, DJ Erskine, HE Ferrari, AJ Fitzmaurice, C Foreman, K Forouzanfar, MH Fraser, MS Pullman, N Gething, PW Goldberg, EM Graetz, N Haagsma, JA Hay, SI Huynh, C Johnson, C Kassebaum, NJ Kinfu, Y Kulikoff, XR Kutz, M Kyu, HH Larson, HJ Leung, J Liang, XF Lim, SS Lind, M Lozano, R Marquez, N Mensah, GA Mikesell, J Mokdad, AH Mooney, MD Nguyen, G Nsoesie, E Pigott, DM Pinho, C Roth, GA Salomon, JA Sandar, L Silpakit, N Sligar, A Sorensen, RJD Stanaway, J Steiner, C Teeple, S Thomas, BA Troeger, C VanderZanden, A Vollset, SE Wanga, V Whiteford, HA Wolock, T Zoeckler, L Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abera, SF Abreu, DMX Abu-Raddad, LJ Abyu, GY Achoki, T Adelekan, AL Ademi, Z Adou, AK Adsuar, JC Afanvi, KA Afshin, A Agardh, EE Agarwal, A Agrawal, A Kiadaliri, AA Ajala, ON Akanda, AS Akinyemi, RO Akinyemiju, TF Akseer, N Al Lami, FH Alabed, S Al-Aly, Z Alam, K Alam, NKM Alasfoor, D Aldhahri, SF Aldridge, RW Alegretti, MA Aleman, AV Alemu, ZA Alexander, LT Alhabib, S Ali, R Alkerwi, A Alla, F Allebeck, P Al-Raddadi, R Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amegah, AK Ameh, EA Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, B Anderson, GM Antonio, CAT Aregay, AF Arnlov, J Arsenijevic, VSA Al Artaman Asayesh, H Asghar, RJ Atique, S Avokpaho, EFGA Awasthi, A Azzopardi, P Bacha, U Badawi, A Bahit, MC Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, A Basu, S Bayou, YT Bazargan-Hejazi, S Beardsley, J Bedi, N Beghi, E Belay, HA Bell, B Bell, ML Bello, AK Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhalla, A Biadgilign, S Bikbov, B Bin Abdulhak, AA Biroscak, BJ Biryukov, S Bjertness, E Blore, JD Blosser, CD Bohensky, MA Borschmann, R Bose, D Bourne, RRA Brainin, M Brayne, CEG Brazinova, A Breitborde, NJK Brenner, H Brewer, JD Brown, A Brown, J Brugha, TS Buckle, GC Butt, ZA Calabria, B Campos-Novato, IR Campuzano, JC Carapetis, JR Cardenas, R Carpenter, D Carrero, JJ Castaneda-Oquela, CA Rivas, JC Catala-Lopez, F Cavalleri, F Cercy, K Cerda, J Chen, WQ Chew, A Chiang, PPC Chibalabala, M Chibueze, CE Chimed-Ochir, O Chisumpa, VH Choi, JYJ Chowdhury, R Christensen, H Christopher, DJ Ciobanu, LG Cirillo, M Cohen, AJ Colistro, V Colomar, M Colquhoun, SM Cooper, C Cooper, LT Cortinovis, M Cowie, BC Crump, JA Damsere-Derry, J Danawi, H Dandona, R Daoud, F Darby, SC Dargan, PI das Neves, J Davey, G Davis, AC Davitoiu, DV de Castro, EF de Jager, P De Leo, D Degenhardt, L Dellavalle, RP Deribe, K Deribew, A Dharmaratne, SD Dhillon, PK Diaz-Torne, C Ding, EL dos Santos, KPB Dossou, E Driscoll, TR Duan, LL Dubey, M Bartholow, B Ellenbogen, RG Lycke, C Elyazar, I Endries, AY Ermakov, SP Eshrati, B Esteghamati, A Estep, K Faghmous, IDA Fahimi, S Jose, E Farid, TA Farinha, CSES Faro, A Farvid, MS Farzadfar, F Feigin, VL Fereshtehnejad, SM Fernandes, JG Fernandes, JC Fischer, F Fitchett, JRA Flaxman, A Foigt, N Fowkes, FGR Franca, EB Franklin, RC Friedman, J Frostad, J Hirst, T Futran, ND Gall, SL Gambashidze, K Gamkrelidze, A Ganguly, P Gankpe, FG Gebre, T Gebrehiwot, TT Gebremedhin, AT Gebru, AA Geleijnse, JM Gessner, BD Ghoshal, AG Gibney, KB Gillum, RF Gilmour, S Giref, AZ Giroud, M Gishu, MD Giussani, G Glaser, E Godwin, WW Gomez-Dantes, H Gona, P Goodridge, A Gopalani, SV Gosselin, RA Gotay, CC Goto, A Gouda, HN Greaves, F Gugnani, HC Gupta, R Gupta, R Gupta, V Gutierrez, RA Hafezi-Nejad, N Haile, D Hailu, AD Hailu, GB Halasa, YA Hamadeh, RR Hamidi, S Hancock, J Handal, AJ Hankey, GJ Hao, YT Harb, HL Harikrishnan, S Haro, JM Havmoeller, R Heckbert, SR Heredia-Pi, IB Heydarpour, P Hilderink, HBM Hoek, HW Hogg, RS Horino, M Horita, N Hosgood, HD Hotez, PJ Hoy, DG Hsairi, M Htet, AS Htike, MMT Hu, GQ Huang, C Huang, H Huiart, L Husseini, A Huybrechts, I Huynh, G Iburg, KM Innos, K Inoue, M Iyer, VJ Jacobs, TA Jacobsen, KH Jahanmehr, N Jakovljevic, MB James, P Javanbakht, M Jayaraman, SP Jayatilleke, AU Jeemon, P Jensen, PN Jha, V Jiang, G Jiang, Y Jibat, T Jimenez-Corona, A Jonas, JB Joshi, TK Kabir, Z Karnak, R Kan, HD Kant, S Karch, A Karema, CK Karimkhani, C Karletsos, D Karthikeyan, G Kasaeian, A Katibeh, M Kaul, A Kawakami, N Kayibanda, JF Keiyoro, PN Kemmer, L Kemp, AH Kengne, AP Keren, A Kereselidze, M Kesavachandran, CN Khader, YS Khalil, IA Khan, AR Khan, EA Khang, YH Khera, S Khoja, TAM Kieling, C Kim, D Kim, YJ Kissela, BM Kissoon, N Knibbs, LD Knudsen, AK Kokubo, Y Kolte, D Kopec, JA Kosen, S Koul, PA Koyanagi, A Krog, NH Defo, BK Bicer, BK Kudom, AA Kuipers, EJ Kulkarni, VS Kumar, GA Kwan, GF Lal, A Lal, DK Lalloo, R Lam, H Lam, JO Langan, SM Lansingh, VC Larsson, A Laryea, DO Latif, AA Lawrynowicz, 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Berhane, Adugnaw Bernabe, Eduardo Betsu, Balem Demtsu Beyene, Addisu Shunu Bhala, Neeraj Bhalla, Ashish Biadgilign, Sibhatu Bikbov, Boris Bin Abdulhak, Aref A. Biroscak, Brian J. Biryukov, Stan Bjertness, Espen Blore, Jed D. Blosser, Christopher D. Bohensky, Megan A. Borschmann, Rohan Bose, Dipan Bourne, Rupert R. A. Brainin, Michael Brayne, Carol E. G. Brazinova, Alexandra Breitborde, Nicholas J. K. Brenner, Hermann Brewer, Jerry D. Brown, Alexandria Brown, Jonathan Brugha, Traolach S. Buckle, Geoffrey Colin Butt, Zahid A. Calabria, Bianca Campos-Novato, Ismael Ricardo Campuzano, Julio Cesar Carapetis, Jonathan R. Cardenas, Rosario Carpenter, David Carrero, Juan Jesus Castaneda-Oquela, Carlos A. Rivas, Jacqueline Castillo Catala-Lopez, Ferran Cavalleri, Fiorella Cercy, Kelly Cerda, Jorge Chen, Wanqing Chew, Adrienne Chiang, Peggy Pei -Chia Chibalabala, Mirriam Chibueze, Chioma Ezinne Chimed-Ochir, Odgerel Chisumpa, Vesper Hichilombwe Choi, Jee-Young Jasmine Chowdhury, Rajiv Christensen, Hanne Christopher, Devasahayam Jesudas Ciobanu, Liliana G. Cirillo, Massimo Cohen, Aaron J. Colistro, Valentina Colomar, Mercedes Colquhoun, Samantha M. Cooper, Cyrus Cooper, Leslie Trumbull Cortinovis, Monica Cowie, Benjamin C. Crump, John A. Damsere-Derry, James Danawi, Hadi Dandona, Rakhi Daoud, Farah Darby, Sarah C. Dargan, Paul I. das Neves, Jose Davey, Gail Davis, Adrian C. Davitoiu, Dragos V. de Castro, E. Filipa de Jager, Pieter De Leo, Diego Degenhardt, Louisa Dellavalle, Robert P. Deribe, Kebede Deribew, Amare Dharmaratne, Samath D. Dhillon, Preet K. Diaz-Torne, Cesar Ding, Eric L. dos Santos, Kadine Priscila Bender Dossou, Edem Driscoll, Tim R. Duan, Leilei Dubey, Manisha Bartholow, Bruce Ellenbogen, Richard G. Lycke, Christian Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Eshrati, Babak Esteghamati, Alireza Estep, Kara Faghmous, Imad D. A. Fahimi, Saman Jose, Emerito Farid, Talha A. Sa Farinha, Carla Sofia e Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Feigin, Valery L. Fereshtehnejad, Seyed-Mohammad Fernandes, Jefferson G. Fernandes, Joao C. Fischer, Florian Fitchett, Joseph R. A. Flaxman, Abraham Foigt, Nataliya Fowkes, F. Gerry R. Franca, Elisabeth Barboza Franklin, Richard C. Friedman, Joseph Frostad, Joseph Hirst, Thomas Futran, Neal D. Gall, Seana L. Gambashidze, Ketevan Gamkrelidze, Amiran Ganguly, Parthasarathi Gankpe, Fortune Gbetoho Gebre, Teshome Gebrehiwot, Tsegaye Tsewelde Gebremedhin, Amanuel Tesfay Gebru, Alemseged Aregay Geleijnse, Johanna M. Gessner, Bradford D. Ghoshal, Aloke Gopal Gibney, Katherine B. Gillum, Richard F. Gilmour, Stuart Giref, Ababi Zergaw Giroud, Maurice Gishu, Melkamu Dedefo Giussani, Giorgia Glaser, Elizabeth Godwin, William W. Gomez-Dantes, Hector Gona, Philimon Goodridge, Amador Gopalani, Sameer Vali Gosselin, Richard A. Gotay, Carolyn C. Goto, Atsushi Gouda, Hebe N. Greaves, Felix Gugnani, Harish Chander Gupta, Rahul Gupta, Rajeev Gupta, Vipin Gutierrez, Reyna A. Hafezi-Nejad, Nima Haile, Demewoz Hailu, Alemayehu Desalegne Hailu, Gessessew Bugssa Halasa, Yara A. Hamadeh, Randah Ribhi Hamidi, Samer Hancock, Jamie Handal, Alexis J. Hankey, Graeme J. Hao, Yuantao Harb, Hilda L. Harikrishnan, Sivadasanpillai Haro, Josep Maria Havmoeller, Rasmus Heckbert, Susan R. Heredia-Pi, Ileana Beatriz Heydarpour, Pouria Hilderink, Henk B. M. Hoek, Hans W. Hogg, Robert S. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hotez, Peter J. Hoy, Damian G. Hsairi, Mohamed Htet, Aung Soe Than Htike, Maung Maung Hu, Guoqing Huang, Cheng Huang, Hsiang Huiart, Laetitia Husseini, Abdullatif Huybrechts, Inge Huynh, Grace Iburg, Kim Moesgaard Innos, Kaire Inoue, Manami Iyer, Veena J. Jacobs, Troy A. Jacobsen, Kathryn H. Jahanmehr, Nader Jakovljevic, Mihajlo B. James, Peter Javanbakht, Mehdi Jayaraman, Sudha P. Jayatilleke, Achala Upendra Jeemon, Panniyammakal Jensen, Paul N. Jha, Vivekanand Jiang, Guohong Jiang, Ying Jibat, Tariku Jimenez-Corona, Aida Jonas, Jost B. Joshi, Tushar Kant Kabir, Zubair Karnak, Ritul Kan, Haidong Kant, Surya Karch, Andre Karema, Corine Kakizi Karimkhani, Chante Karletsos, Dimitris Karthikeyan, Ganesan Kasaeian, Amir Katibeh, Marzieh Kaul, Anil Kawakami, Norito Kayibanda, Jeanne Francoise Keiyoro, Peter Njenga Kemmer, Laura Kemp, Andrew Haddon Kengne, Andre Pascal Keren, Andre Kereselidze, Maia Kesavachandran, Chandrasekharan Nair Khader, Yousef Saleh Khalil, Ibrahim A. Khan, Abdur Rahman Khan, Ejaz Ahmad Khang, Young-Ho Khera, Sahil Muthafer Khoja, Tawfik Ahmed Kieling, Christian Kim, Daniel Kim, Yun Jin Kissela, Brett M. Kissoon, Niranjan Knibbs, Luke D. Knudsen, Ann Kristin Kokubo, Yoshihiro Kolte, Dhaval Kopec, Jacek A. Kosen, Soewarta Koul, Parvaiz A. Koyanagi, Ai Krog, Norun Hjertager Defo, Barthelemy Kuate Bicer, Burcu Kucuk Kudom, Andreas A. Kuipers, Ernst J. Kulkarni, Veena S. Kumar, G. Anil Kwan, Gene F. Lal, Aparna Lal, Dharmesh Kumar Lalloo, Ratilal Lam, Hilton Lam, Jennifer O. Langan, Sinead M. Lansingh, Van C. Larsson, Anders Laryea, Dennis Odai Latif, Asma Abdul Lawrynowicz, Alicia Elena Beatriz Leigh, James Levi, Miriam Li, Yongmei Lindsay, M. Patrice Lipshultz, Steven E. Liu, Patrick Y. Liu, Shiwei Liu, Yang Lo, Loon-Tzian Logroscino, Giancarlo Lotufo, Paulo A. Lucas, Robyn M. Lunevicius, Raimundas Lyons, Ronan A. Ma, Stefan Pedro Machado, Vasco Manuel Mackay, Mark T. MacLachlan, Jennifer H. Abd El Razek, Hassan Magdy Abd El Razek, Mohammed Magdy Majdan, Marek Majeed, Azeem Malekzadeh, Reza Ayele Manamo, Wondimu Ayele Mandisarisa, John Mangalam, Srikanth Mapoma, Chabila C. Marcenes, Wagner Margolis, David Joel Martin, Gerard Robert Martinez-Raga, Jose Marzan, Melvin Barrientos Masiye, Felix Mason-Jones, Amanda J. Massano, Joao Matzopoulos, Richard Mayosi, Bongani M. McGarvey, Stephen Theodore McGrath, John J. Mckee, Martin McMahon, Brian J. Meaney, Peter A. Mehari, Alem Mehndiratta, Man Mohan Mena-Rodriguez, Fabiola Mekonnen, Alemayehu B. Melaku, Yohannes Adama Memiah, Peter Memish, Ziad A. Mendoza, Walter Meretoja, Atte Meretoja, Tuomo J. Mhimbira, Francis Apolinary Micha, Renata Miller, Ted R. Mirarefin, Mojde Misganaw, Awoke Mock, Charles N. Abdulmuhsin Mohammad, Karzan Mohammadi, Alireza Mohammed, Shafiu Mohan, Viswanathan Mola, Glen Liddell D. Monasta, Lorenzo Montanez Hernandez, Julio Cesar Montero, Pablo Montico, Marcella Montine, Thomas J. Moradi-Lakeh, Maziar Morawska, Lidia Morgan, Katherine Mori, Rintaro Mozaffarian, Dariush Mueller, Ulrich Satyanarayana Murthy, Gudlavalleti Venkata Murthy, Srinivas Musa, Kamarul Imran Nachega, Jean B. Nagel, Gabriele Naidoo, Kovin S. Naik, Nitish Naldi, Luigi Nangia, Vinay Nash, Denis Nejjari, Chakib Neupane, Subas Newton, Charles R. Newton, John N. Ng, Marie Ngalesoni, Frida Namnyak Ngirabega, Jean de Dieu Quyen Le Nguyen Nisar, Muhammad Imran Nkamedjie Pete, Patrick Martial Nomura, Marika Norheim, Ole F. Norman, Paul E. Norrving, Bo Nyakarahuka, Luke Ogbo, Felix Akpojene Ohkubo, Takayoshi Ojelabi, Foluke Adetola Olivares, Pedro R. Olusanya, Bolajoko Olubukunola Olusanya, Jacob Olusegun Opio, John Nelson Oren, Eyal Ortiz, Alberto Osman, Majdi Ota, Erika Ozdemir, Raziye Pa, Mahesh Pandian, Jeyaraj D. Pant, Puspa Raj Papachristou, Christina Park, Eun-Kee Park, Jae-Hyun Parry, Charles D. Parsaeian, Mahboubeh Caicedo, Angel J. Paternina Patten, Scott B. Patton, George C. Paul, Vinod K. Pearce, Neil Pedro, Joao Mario Stokic, Ljiljana Pejin Pereira, David M. Perico, Norberto Pesudovs, Konrad Petzold, Max Phillips, Michael Robert Piel, Frederic B. Pillay, Julian David Plass, Dietrich Platts-Mills, James A. Polinder, Suzanne Pope, C. Arden Popova, Svetlana Poulton, Richie G. Pourmalek, Farshad Prabhakaran, Dorairaj Qorbani, Mostafa Quame-Amaglo, Justice Quistberg, D. Alex Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Rajesh Kumar Rajavi, Zhale Rajsic, Sasa Raju, Murugesan Rakovac, Ivo Rana, Saleem M. Ranabhat, Chhabi L. Rangaswamy, Thara Rao, Puja Rao, Sowmya R. Refaat, Amany H. Rehm, Jurgen Reitsma, Marissa B. Remuzzi, Giuseppe Resnikofff, Serge Ribeiro, Antonio L. Ricci, Stefano Blancas, Maria Jesus Rios Roberts, Bayard Roca, Anna Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Rothenbacher, Dietrich Roy, Ambuj Roy, Nawal K. Ruhago, George Mugambage Sagar, Rajesh Saha, Sukanta Sahathevan, Ramesh Saleh, Muhammad Muhammad Sanabria, Juan R. Sanchez-Nino, Maria Dolores Sanchez-Riera, Lidia Santos, Itamar S. Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schaub, Michael P. Schmidt, Maria Ines Schneider, Ione J. C. Schottker, Ben Schutte, Aletta E. Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shackelford, Katya A. Shaddick, Gavin Shaheen, Amira Shahraz, Saeid Shaikh, Masood Ali Shakh-Nazarova, Marina Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Shen, Ziyan Shepard, Donald S. Sheth, Kevin N. Shetty, Balakrishna P. Shi, Peilin Shibuya, Kenji Shin, Min-Jeong Shiri, Rahman Shiue, Ivy Shrime, Mark G. Sigfusdottir, Inga Dora Silberberg, Donald H. Silva, Diego Augusto Santos Silveira, Dayane Gabriele Alves Silverberg, Jonathan I. Simard, Edgar P. Singh, Abhishek Singh, Gitanjali M. Singh, Jasvinder A. 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Undurraga, Eduardo A. Uthman, Olalekan A. Van Dingenen, Rita Van Donkelaar, Aaron Vasankari, Tommi Vasconcelos, Ana Maria Nogales Venketasubramanian, Narayanaswamy Vidavalur, Ramesh Vijayakumar, Lakshmi Villalpando, Salvador Violante, Francesco S. Vlassov, Vasiliy Victorovich Wagner, Joseph A. Wagner, Gregory R. Wallin, Mitchell T. Wang, Linhong Watkins, David A. Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny White, Richard A. Wijeratne, Tissa Wilkinson, James D. Williams, Hywel C. Wiysonge, Charles Shey Woldeyohannes, Solomon Meseret Wolfe, Charles D. A. Won, Sungho Wong, John Q. Woolf, Anthony D. Xavier, Denis Xiao, Qingyang Xu, Gelin Yakob, Bereket Yalew, Ayalnesh Zemene Yan, Lijing L. Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yebyo, Henock Gebremedhin Yip, Paul Yirsaw, Biruck Desalegn Yonemoto, Naohiro Yonga, Gerald Younis, Mustafa Z. Yu, Shicheng Zaidi, Zoubida Zaki, Maysaa El Sayed Zannad, Faiez Zavala, Diego E. Zeeb, Hajo Zeleke, Berihun M. Zhang, Hao Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Vos, Theo Lopez, Alan D. Murray, Christopher J. L. CA GBD 015 Mortality and Causes Death TI Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID ROAD TRAFFIC INJURIES; ECONOMIC-DEVELOPMENT; UNITED-STATES; EPIDEMIOLOGIC TRANSITION; DEVELOPMENT ASSISTANCE; INTEGRATED APPROACH; CIVIL REGISTRATION; ALZHEIMERS-DISEASE; VITAL-STATISTICS; VERBAL AUTOPSY AB Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Wang, Haidong; Naghavi, Mohsen; Allen, Christine; Barber, Ryan M.; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Zian; Coates, Matthew M.; Coggeshall, Megan; Dandona, Lalit; Dicker, Daniel J.; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Foreman, Kyle; Forouzanfar, Mohammad H.; Fraser, Maya S.; Goldberg, Ellen M.; Graetz, Nicholas; Huynh, Chantal; Johnson, Catherine; Kassebaum, Nicholas J.; Kulikoff, Xie Rachel; Kutz, Michael; Kyu, Hmwe H.; Larson, Heidi J.; Leung, Janni; Lim, Stephen S.; Lind, Margaret; Lozano, Rafael; Marquez, Neal; Mikesell, Joe; Mokdad, Ali H.; Mooney, Meghan D.; Nguyen, Grant; Nsoesie, Elaine; Pigott, David M.; Pinho, Christine; Roth, Gregory A.; Sandar, Logan; Silpakit, Naris; Sligar, Amber; Sorensen, Reed J. D.; Stanaway, Jeffrey; Steiner, Caitlyn; Teeple, Stephanie; Thomas, Bernadette A.; Troeger, Christopher; VanderZanden, Amelia; Vollset, Stein Emil; Wanga, Valentine; Whiteford, Harvey A.; Wolock, Timothy; Zoeckler, Leo; Achoki, Tom; Afshin, Ashkan; Alexander, Lily T.; Anderson, Gregory M.; Biryukov, Stan; Blore, Jed D.; Brown, Alexandria; Brown, Jonathan; Cercy, Kelly; Chew, Adrienne; Cohen, Aaron J.; Daoud, Farah; Dossou, Edem; Estep, Kara; Flaxman, Abraham; Friedman, Joseph; Frostad, Joseph; Futran, Neal D.; Godwin, William W.; Hancock, Jamie; Kasaeian, Amir; Kemmer, Laura; Khalil, Ibrahim A.; Lindsay, M. Patrice; Liu, Patrick Y.; Masiye, Felix; Mirarefin, Mojde; Misganaw, Awoke; Moradi-Lakeh, Maziar; Morgan, Katherine; Ng, Marie; Quame-Amaglo, Justice; Rao, Puja; Reitsma, Marissa B.; Shackelford, Katya A.; Sur, Patrick; Wagner, Joseph A.; Vos, Theo; Lopez, Alan D.; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA USA. 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[Takahashi, Ken] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Chisumpa, Vesper Hichilombwe; Mapoma, Chabila C.; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Choi, Jee-Young Jasmine] Seoul Natl Univ Med Lib, Seoul, South Korea. [Chowdhury, Rajiv] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christopher, Devasahayam Jesudas] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Cirillo, Massimo] Univ Salerno, Baronissi, Italy. [Cohen, Aaron J.] Hlth Effects Inst, Boston, MA USA. [Colistro, Valentina] Minist Salud Publ, Montevideo, Uruguay. [Colomar, Mercedes] UNICEM, Montevideo, Uruguay. [Cooper, Cyrus] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Cooper, Cyrus] Univ Southampton, NIHR Biomed Res Ctr, Southampton, Hants, England. [Cooper, Cyrus] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. [Cooper, Leslie Trumbull] Mayo Clin, Jacksonville, FL 32224 USA. [Cortinovis, Monica; Giussani, Giorgia] Mario Negri Inst Pharmacol Res, Milan, Italy. [Cowie, Benjamin C.] WHO, Collaborating Ctr Viral Hepatitis, Victorian Infect Dis Reference Lab Melbourne, Melbourne, Vic, Australia. [Crump, John A.] Dunedin Sch Med, Ctr Int Hlth, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damsere-Derry, James] Bldg & Rd Res Inst, Kumasi, Ghana. [Danawi, Hadi; Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [das Neves, Jose] Univ Porto, Inst Invest & Inovacao Saude I3S, Oporto, Portugal. [das Neves, Jose] Univ Porto, INEB, Oporto, Portugal. [Massano, Joao] Univ Porto, Fac Med, Oporto, Portugal. [Pedro, Joao Mario] Univ Porto, EPIUnit, Oporto, Portugal. [Davey, Gail] Wellcome Trust Brighton & Sussex, Ctr Global Hlth Res, Brighton, E Sussex, England. [Davis, Adrian C.; Greaves, Felix; Newton, John N.] Publ Hlth England, London, England. [Davitoiu, Dragos V.] Univ Med Pharm Bucharest, Bucharest, Romania. [de Castro, E. Filipa] Natl Inst Publ Hlth, Mexico City, DF, Mexico. [de Jager, Pieter] Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [de Jager, Pieter] Natl Inst Occupat Hlth, Natl Hlth Lab Serv, Johannesburg, South Africa. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO USA. [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Dharmaratne, Samath D.] Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Ganguly, Parthasarathi; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Diaz-Torne, Cesar] Hosp Santa Creu i Sant Pau, Barcelona, Spain. [dos Santos, Kadine Priscila Bender] Univ Estado Santa Catarina, Florianopolis, SC, Brazil. [Dubey, Manisha; Rahman, Mohammad Hifz Ur; Singh, Abhishek] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Bell, Brent] Univ N Carolina, Chapel Hill, NC USA. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Russian Federat, Fed Res Inst Hlth Org & Informat, Minist Hlth, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Farzadfar, Farshad; Kasaeian, Amir; Parsaeian, Mahboubeh] Univ Tehran Med Sci, Non Communicable Dis Res Ctr, Endocrinol & Metab Populat Sci Inst, Tehran, Iran. [Heydarpour, Pouria] Univ Tehran Med Sci, Multiple Sclerosis Res Ctr, Neuroscience Inst, Tehran, Iran. [Kasaeian, Amir] Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Univ Tehran Med Sci, Dept Epidemiol & Biostat, Sch Publ Hlth, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Tehran, Iran. [Kuipers, Ernst J.] Dept Hlth, Manila, Philippines. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Sa Farinha, Carla Sofia e] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sa Farinha, Carla Sofia e] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Harvard MGH Ctr Genom, Mongan Inst Hlth Policy, Vulnerable Populat, Boston, MA 02114 USA. [Feigin, Valery L.] Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Ao, Braden J. Te] Auckland Univ Technol, Auckland, New Zealand. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Sci Educ, Sao Paulo, Brazil. [Fernandes, Joao C.] Queen Mary Univ London, Ctr Expt Med & Rheumatol, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Shiue, Ivy] Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Futran, Neal D.] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Piel, Frederic B.] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Greaves, Felix; Majeed, Azeem] Imperial Coll London, London, England. [Gall, Seana L.] Univ Tasmania, Hobart, Tas, Australia. [Gambashidze, Ketevan; Gamkrelidze, Amiran; Kereselidze, Maia; Shakh-Nazarova, Marina] Natl Ctr Dis Control & Publ Hlth, Tbilisi, Rep of Georgia. [Ganguly, Parthasarathi; Iyer, Veena J.] Indian Inst Publ Hlth Gandhinagar, Ahmadabad, Gujarat, India. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Gebre, Teshome] Task Force Global Hlth, Decatur, GA USA. [Gebremedhin, Amanuel Tesfay] Ludwig Maximilians Univ Munchen, Munich, Germany. [Gebru, Alemseged Aregay; Hailu, Alemayehu Desalegne] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Ghoshal, Aloke Gopal] Natl Allergy Asthma Bronchitis Inst, Kolkata, India. [Gibney, Katherine B.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Gillum, Richard F.; Mehari, Alem] Howard Univ, Coll Med, Washington, DC 20059 USA. [Gilmour, Stuart; Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Glaser, Elizabeth] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Halasa, Yara A.; Shepard, Donald S.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Gona, Philimon] Univ Massachusetts, Boston, MA USA. [Goodridge, Amador] Inst Invest Cient & Serv Alta Tecnol INDICASAT AI, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Gotay, Carolyn C.; Kissoon, Niranjan; Kopec, Jacek A.; Murthy, Srinivas; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Goto, Atsushi] Ctr Publ Hlth Sci, Div Epidemiol, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gugnani, Harish Chander] Dept St James Sch Med, Dept Microbiol, The Quarter, Anguilla, England. [Gugnani, Harish Chander] Dept St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla, England. [Gupta, Rajeev] West Virginia Bur Publ Hlth, Charleston, WV USA. [Gupta, Rajeev] Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Dept Anthropol, Delhi, India. [Gutierrez, Reyna A.] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Fremantle, WA, Australia. [Norman, Paul E.] Univ Western Australia, Fremantle, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Haro, Josep Maria] Parc Sanitari Sant Joan Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Hilderink, Henk B. M.] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hogg, Robert S.] Simon Fraser Univ, Burnaby, BC, Canada. [Hogg, Robert S.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Than Htike, Maung Maung] Minist Hlth, Nay Pyi Taw, Myanmar. [Hu, Guoqing] Cent S Univ, Dept Epidemiol & Hlth Stat, Sch Publ Hlth, Changsha, Hunan, Peoples R China. [Huang, Cheng] George Washington Univ, Washington, DC USA. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Huiart, Laetitia] CHU Reunion, St Denis, France. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Israel. [Huybrechts, Inge] IARC, Lyon, France. [Huybrechts, Inge] Univ Ghent, Ghent, Belgium. [Huynh, Grace] Inst Dis Modeling, Bellevue, WA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Jacobs, Troy A.] USAID Global Hlth Bur, MCH Div, HIDN, Washington, DC USA. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA USA. [Jahanmehr, Nader] Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran. [Katibeh, Marzieh] Shahid Beheshti Univ Med Sci, Ophthalm Epidemiol Res Ctr, Tehran, Iran. [Rajavi, Zhale; Yaseri, Mehdi] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayaraman, Sudha P.] Virginia Commonwealth Univ, Dept Surg, Richmond, VA USA. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jeemon, Panniyammakal; Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Tianjin, Peoples R China. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Gen Directorate Epidemiol, Minist Hlth, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Joshi, Tushar Kant] Ctr Occupat & Environm Hlth, New Delhi, India. [Kabir, Zubair] Natl Univ Ireland Univ Coll Cork, Cork, Ireland. [Karnak, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Zhongshan Hosp, Lucknow, Uttar Pradesh, India. [Shen, Ziyan; Zhang, Hao] Zhongshan Hosp, Dept Nephrol, Lucknow, Uttar Pradesh, India. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Kant, Surya] King Georges Med Univ, Lucknow, Uttar Pradesh, India. [Karch, Andre] Epidemiol & Stat Methods Res Grp, Helmholtz Ctr Infect Res, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Karletsos, Dimitris] Univ Pompeu Fabra, Ctr Res Hlth & Econ, Barcelona, Spain. [Karthikeyan, Ganesan; Naik, Nitish; Paul, Vinod K.; Roy, Ambuj; Sagar, Rajesh; Satpathy, Maheswar; Tandon, Nikhil] All India Inst Med Sci, New Delhi, India. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kayibanda, Jeanne Francoise] Inst Rech Ihopital Monttfort, Ottawa, ON, Canada. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Parry, Charles D.] Alcohol Tobacco & Other Drug Res Unit, Cape Town, South Africa. [Kengne, Andre Pascal; Matzopoulos, Richard; Wiysonge, Charles Shey] South African Med Res Council, Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.; Watkins, David A.] Univ Cape Town, Cape Town, South Africa. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khera, Sahil; Tavakkoli, Mohammad] New York Med Coll, Valhalla, NY USA. [Muthafer Khoja, Tawfik Ahmed] Execut Board Hlth Ministers Council Cooperat Coun, Riyadh, Saudi Arabia. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Kim, Yun Jin] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kim, Yun Jin] Southern Univ Coll, Skudai, Malaysia. [Kissela, Brett M.] Univ Cincinnati, Cincinnati, OH USA. [Kokubo, Yoshihiro] Natl Cerebral Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Brown Univ, Div Cardiol, Providence, RI 02912 USA. [McGarvey, Stephen Theodore] Brown Univ, Providence, RI 02912 USA. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment, Hlth Policy & Human, Jakarta, Indonesia. [Koul, Parvaiz A.] Sher Kashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari Sant Joan Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog & Publ Hlth, Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Kulkarni, Veena S.] Arkansas State Univ, State Univ, AR USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA USA. [Rao, Sowmya R.] Boston Univ, Dept Surg, Sch Med, Boston, MA USA. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Nachega, Jean B.] Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Lansingh, Van C.] Help Me See Inc, New York, NY USA. [Lansingh, Van C.] Inst Mexicano Oftalmol, Queretaro, Mexico. [Laryea, Dennis Odai] Komfo Anokye Teaching Hosp, Kumasi, Ghana. [Latif, Asma Abdul] WomenUniv, Lahore Coll, Dept Zool, Lahore, Pakistan. [Lawrynowicz, Alicia Elena Beatriz] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Argentina. [Levi, Miriam] Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy. [Liu, Yang] San Francisco VA Med Ctr, San Francisco, CA USA. [Lindsay, M. Patrice] Heart & Stroke Fdn Canada, Ottawa, ON, Canada. [Lipshultz, Steven E.; Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Lipshultz, Steven E.] Childrens Hosp Michigan, Detroit, MI USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Liu, Yang; Phillips, Michael Robert; Xiao, Qingyang] Emory Univ, Atlanta, GA 30322 USA. [Lo, Loon-Tzian] UnionHlth Associates LLC, St Louis, MO USA. [Lo, Loon-Tzian] Alton Mental Hlth Ctr, Alton, IL USA. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lunevicius, Raimundas] Aintree Univ Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Ma, Stefan] Minist Hlth Singapore, Singapore, Singapore. [Ma, Stefan] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Pedro Machado, Vasco Manuel] Dept Publ Hlth, No Region Hlth Adm, Oporto, Portugal. [Mackay, Mark T.; Weintraub, Robert G.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Abd El Razek, Hassan Magdy] Mansoura Fac Med, Mansoura, Egypt. [Abd El Razek, Mohammed Magdy] Aswan Univ Hosp, Aswan Fac Med, Aswan, Egypt. [Mandisarisa, John] JSI Res & Training, Harare, Zimbabwe. [Mangalam, Srikanth] Tech Stand & Safety Author, Toronto, ON, Canada. [Marcenes, Wagner] Kings Coll London, Div Populat & Patient Hlth, Inst Dent, London, England. [Meaney, Peter A.] Univ Penn, Perelman Sch Med, Philadelphia, PA USA. [Margolis, David Joel; Silberberg, Donald H.] Univ Penn, Philadelphia, PA USA. [Martin, Gerard Robert] Childrens Natl Hlth Syst, Washington, DC USA. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Valencia, Spain. [Marzan, Melvin Barrientos] Univ E Ramon Magsaysay Mem Med Ctr, Quezon City, Philippines. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Massano, Joao] ULS Matosinhos, Hosp Pedro Hispano, Matosinhos, Portugal. [McMahon, Brian J.] Alaska Native Tribal Hlth Consortium, Anchorage, AK USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Woldeyohannes, Solomon Meseret] Univ Gondar, Dept Epidemiol & Biostat, Inst Publ Hlth, Gondar, Ethiopia. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare; Zeleke, Berihun M.] Univ Gondar, Gondar, Ethiopia. [Memiah, Peter] Univ Florida, Pensacola, FL USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Breast Surg Unit, Ctr Comprehens Canc, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Micha, Renata; Mozaffarian, Dariush] Friedman Sch Nutr Sci & Policy, Boston, MA USA. [Shi, Peilin; Singh, Gitanjali M.] Tufts Univ, Boston, MA 02111 USA. [Miller, Ted R.] Pacific Inst Res Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Abdulmuhsin Mohammad, Karzan] Univ Salahaddin, Erbil, Iraq. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Mohan, Viswanathan] Madras Diabet Res Fdn, Chennai, Tamil Nadu, India. [Mohan, Viswanathan] Dr Mohans Diabet Special Ctr, Chennai, Tamil Nadu, India. [Mola, Glen Liddell D.] Univ Papua New Guinea, Boroko, Papua N Guinea. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Prevent Med & Publ Hlth Res Ctr, Gastrointestinal & Liver Dis Res Ctr, Dept Community Med, Brisbane, Qld, Australia. [Morawska, Lidia] Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia. [Werdecker, Andrea] Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Satyanarayana Murthy, Gudlavalleti Venkata] Indian Inst Publ Hlth, Gurgaon, India. [Dhillon, Preet K.; Ganguly, Parthasarathi; Lal, Dharmesh Kumar; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Musa, Kamarul Imran] Univ Sci Malaysia, Sch Med Sci, Kubang Kerian, Malaysia. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Caicedo, Angel J. Paternina] Univ Pittsburgh, Publ Hlth Dynam Lab, Pittsburgh, PA USA. [Parry, Charles D.] Univ Stellenbosch, Dept Psychiat, Cape Town, South Africa. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nagel, Gabriele; Rothenbacher, Dietrich] Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany. [Naidoo, Kovin S.; Sartorius, Benn] Univ KwaZulu Natal, Durban, South Africa. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Inst Implementat Sci Populat Hlth, Sch Publ Hlth, New York, NY USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. 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EM cjlm@uw.edu RI Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Nagel, Gabriele/C-3635-2012; Patton, George/B-5246-2013; Brenner, Hermann/B-4627-2017; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Tonelli, Marcello/B-3028-2009; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Musa, Kamarul Imran/N-3198-2015; Pereira, David/M-9286-2013; OI Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Nagel, Gabriele/0000-0001-6185-8535; Patton, George/0000-0001-5039-8326; Brenner, Hermann/0000-0002-6129-1572; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Hoek, Hans/0000-0001-6353-5465; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Jacobsen, Kathryn/0000-0002-4198-6246; Biroscak, Brian/0000-0002-1323-9358; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Massano, Joao/0000-0002-5791-7149; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Husseini, Abdullatif/0000-0001-8767-5956; Taylor, Hugh/0000-0002-9437-784X; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Musa, Kamarul Imran/0000-0002-3708-0628; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. 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Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abraham, B Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Ackerman, IN Adebiyi, AO Ademi, Z Adou, AK Afanvi, KA Agardh, EE Agarwal, A Kiadaliri, AA Ahmadieh, H Ajala, ON Akinyemi, RO Akseer, N Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Alegretti, MA Alemu, ZA Alexander, LT Alhabib, S Ali, R Alkerwi, A Alla, F Allebeck, P Al-Raddadi, R Alsharif, U Altirkawi, KA Alvis-Guzman, N Amare, AT Amberbir, A Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, GM Anderson, B Antonio, CAT Aregay, AF Arnlov, J Al Artaman Asayesh, H Assadi, R Atique, S Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, A Bazargan-Hejazi, S Bell, B Bell, ML Bennett, DA Bensenor, IM Benzian, H Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhatt, S Biadgilign, S Bienhofff, K Bikbov, B Biryukov, S Bisanzio, D Bjertness, E Blore, J Borschmann, R Boufous, 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Qorbani, Mostafa Rabiee, Rynaz H. S. Radfar, Amir Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Rajesh Kumar Rajsic, Sasa Ram, Usha Rao, Puja Refaat, Amany H. Reitsma, Marissa B. Remuzzi, Giuseppe Resnikofff, Serge Reynolds, Alex Ribeiro, Antonio L. Rios Blancas, Maria Jesus Rolm, Hirbo Shore Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Roth, Gregory A. Rothenbacher, Dietrich Roy, Ambuj Sagar, Rajesh Sahathevan, Ramesh Sanabria, Juan R. Dolores Sanchez-Nino, Maria Santos, Itamar S. Santos, Joao Vasco Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schaub, Michael P. Schmidt, Maria Ines Schneider, Ione J. C. Schottker, Ben Schwebel, David C. Scott, James G. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shackelford, Katya A. Shaheen, Amira Shaikh, Masood Ali Sharma, Rajesh Sharma, Upasana Shen, Jiabin Shepard, Donald S. Sheth, Kevin N. Shibuya, Kenji Shin, Min-Jeong Shiri, Rahman Shiue, Ivy Shrime, Mark G. Sigfusdottir, Inga Dora Silva, Diego Augusto Santos Alves Silveira, Dayane Gabriele Singh, Abhishek Singh, Jasvinder A. Singh, Om Prakash Singh, Prashant Kumar Sivonda, Anna Skirbekk, Vegard Skogen, Jens Christoffer Sligar, Amber Silwa, Karen Soljak, Michael Soreide, Kjetil Soriano, Joan B. Sposato, Luciano A. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Steel, Nicholas Stein, Dan J. Steiner, Timothy J. Steinke, Sabine Stovner, Lars Stroumpoulis, Konstantinos Sunguya, Bruno F. Sur, Patrick Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Takala, Jukka S. Landon, Nikhil Tanne, David Tavakkoli, Mohammad Taye, Bineyam Taylor, Hugh R. Te Ao, Braden J. Tedla, Bemnet Amare Terkawi, Abdullah Sulieman Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tobe-Gai, Ruoyan Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Tran, Bach Xuan Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Gool, Coen H. Varakin, Yuri Y. Vasankari, Tommi Venketasubramanian, Narayanaswamy Verma, Raj Kumar Violante, Francesco S. Vladimirov, Sergey K. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Wagner, Gregory R. Waller, Stephen G. Wang, Linhong Watkins, David A. Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny White, Richard A. Williams, Hywel C. Wiysonge, Charles Shey Wolfe, Charles D. A. Won, Sungho Woodbrook, Rachel Wubshet, Mamo Xavier, Denis Xu, Gelin Yadav, Ajit Kumar Yan, Lijing L. Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yebyo, Henock Gebremedhin Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zeeb, Hajo Zhou, Maigeng Zodpey, Sanjay Zuhlke, Liesl Joanna Murray, Christopher J. L. CA GBD 2015 Dis Injury Incidence TI Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID EBOLA HEMORRHAGIC-FEVER; SELF-RATED HEALTH; ALZHEIMERS-DISEASE; MENTAL-HEALTH; PLASMODIUM-FALCIPARUM; ANCHORING VIGNETTES; UNITED-STATES; VIRUS DISEASE; HIV INCIDENCE; DEMENTIA AB Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd. C1 [Vos, Theo; Allen, Christine; Arora, Megha; Barber, Ryan M.; Brown, Alexandria; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Z.; Coggeshall, Megan; Cornaby, Leslie; Dandona, Lalit; Dicker, Daniel J.; Dilegge, Tina; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Fleming, Tom; Forouzanfar, Mohammad H.; Fullman, Nancy; Goldberg, Ellen M.; Graetz, Nicholas; Haagsma, Juanita A.; Johnson, Catherine O.; Kassebaum, Nicholas J.; Kawashima, Toana; Kemmer, Laura; Khalil, Ibrahim A.; Kyu, Hmwe H.; Leung, Janni; Lim, Stephen S.; Lopez, Alan D.; Marczak, Laurie; Mokdad, Ali H.; Naghavi, Mohsen; Nguyen, Grant; Nsoesie, Elaine; Olsen, Helen; Pigott, David M.; Pinho, Christine; Rankin, Zane; Reinig, Nikolas; Sandar, Logan; Smith, Alison; Stanaway, Jeffrey; Steiner, Caitlyn; Teeple, Stephanie; Thomas, Bernadette A.; Troeger, Christopher; Wagner, Joseph A.; Wang, Haidong; Wanga, Valentine; Whiteford, Harvey A.; Zoeckler, Leo; Alexander, Lily T.; Anderson, Gregory M.; Bienhofff, Kelly; Biryukov, Stan; Blore, Jed; Brown, Jonathan; Coates, Matthew M.; Daoud, Farah; Estep, Kara; Foreman, Kyle; Fox, Jordan; Friedman, Joseph; Frostad, Joseph; Godwin, William W.; Hancock, Jamie; Huynh, Chantal; Iannarone, Marissa; Kim, Cho-il; Kutz, Michael; Masiye, Felix; Mirarefin, Mojde; Mooney, Meghan D.; Moradi-Lakeh, Maziar; Mullany, Erin; Mumford, John Everett; Rao, Puja; Reitsma, Marissa B.; Reynolds, Alex; Roth, Gregory A.; Shackelford, Katya A.; Sivonda, Anna; Sligar, Amber; Sur, Patrick; Vollset, Stein Emil; Woodbrook, Rachel; Zhou, Maigeng; Murray, Christopher J. 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[Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Maria Haro, Josep] Parc Sanitari Sant Joan de Deu CIBERSAM, St Boi De Llobregat, Barcelona, Spain. [Maria Haro, Josep] Univ Barcelona, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Hoek, Hans W.] Columbia Univ, New York, NY USA. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Grad Sch Med, Dept Pulmonol, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Inoue, Manami] Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Jeemon, Panniyammakal; Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Jiang, Ying] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Hlth Dev, Kitakyushu, Fukuoka, Japan. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Minist Hlth, Gen Directorate Epidemiol, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kalkonde, Yogeshwar] Soc Educ Act & Res Community Hlth, Gadchiroli, India. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equ Hlth Care, Kigali, Rwanda. Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khera, Sahil] New York Med Coll, Valhalla, NY 10595 USA. [Khoja, Tawfik Ahmed Muthafer] Execut Board Hlth Ministers Council Cooperat Coun, Riyadh, Saudi Arabia. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Kim, Cho-il] Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kim, Yun Jin] Southern Univ Coll, Skudai, Malaysia. [Knudsen, Ann Kristin; Vollset, Stein Emil] Ctr Dis Burden, Oslo, Norway. [Skogen, Jens Christoffer] Dept Hlth Promot, Oslo, Norway. [Savic, Miloje] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Div Cardiol, Providence, RI USA. [McGarvey, Stephen Theodore] Brown Univ, Providence, RI 02912 USA. 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[Lallukka, Tea] Fac Med, Dept Publ Hlth, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.; Nachega, Jean B.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Langan, Sinead M.; McKee, Martin] London Sch Hyg & Trop Med, London, England. [Lavados, Pablo M.] Univ Desarrollo, Serv Neurol, Clin Alemana, Santiago, Chile. [Leasher, Janet L.] Nova Southeastern Univ, Coll Optometry, Ft Lauderdale, FL 33314 USA. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Levi, Miriam] Tuscany Reg Ctr Occupat Injuries & Dis, Florence, Italy. San Francisco VA Med Ctr, San Francisco, CA USA. [Liang, Juan] Sichuan Univ, West China Univ Hosp 2, Natl Off Maternal & Child Hlth Surveillance, Chengdu, Peoples R China. [Liu, Yang; Phillips, Michael Robert] Emory Univ, Atlanta, GA 30322 USA. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Fitzroy, Vic, Australia. [Lloyd, Belinda K.] Eastern Hlth, Melbourne, Vic, Australia. [Lo, Warren D.] Nationwide Childrens Hosp, Columbus, OH USA. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Looker, Katharine J.] Univ Bristol, Bristol, Avon, England. [Lunevicius, Raimundas] Aintree Univ Hosp NHS Fdn Trust, Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Mackay, Mark T.; Weintraub, Robert G.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Abd El Razek, Mohammed Magdy] Aswan Univ Hosp, Aswan Fac Med, Aswan, Egypt. [Mahdavi, Mandi] Social Secur Org, Res Inst, Tehran, Iran. [Mahdavi, Mandi] Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. [Marcenes, Wagner] Kings Coll London, Inst Dent, Div Populat & Patient Hlth, London, England. [Meaney, Peter A.] Perelman Sch Med, Philadelphia, PA USA. [Margolis, David Joel] Univ Penn, Philadelphia, PA 19104 USA. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Moncada, Valencia, Spain. [Massano, Joao] Hosp Pedro Hispano ULS Matosinhos, Matosinhos, Portugal. [McMahon, Brian J.] Alaska Native Tribal Hlth Consortium, Anchorage, AK USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mehari, Alem] Howard Univ, Coll Med, Washington, DC USA. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare] Univ Gondar, Gondar, Ethiopia. [Memiah, Peter] Univ West Florida, Pensacola, FL 32514 USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Ctr Comprehens Canc, Breast Surg Unit, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Prevent Med & Publ Hlth Res Ctr, Gastrointestinal & Liver Dis Res Ctr, Dept Community Med, Tehran, Iran. [Morawska, Lidia] Queensland Univ Technol, Int Lab Air Qual & Hlth, Brisbane, Qld, Australia. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Werdecker, Andrea] Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich O.; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Paternina Caicedo, Angel J.] Univ Pittsburgh, Publ Hlth Dynam Lab, Pittsburgh, PA USA. [Murdoch, Michele E.] West Herts Hosp NHS Trust, Watford, Hereford, England. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nagel, Gabriele; Rothenbacher, Dietrich] Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res Bangladesh Icddr B, Dhaka, Bangladesh. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Ospedal Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Quyen Le Nguyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Nkamedjie Pete, Patrick Martial] Inst Res Socioecon Dev & Commun, Yaounde, Cameroon. Hosp Univ Bellvitge, Lhospitalet De Llobregat, Spain. [Nunes, Bruno P.] Univ Fed Pelotas, Pelotas, Brazil. [Ogbo, Felix Akpojene] Univ Western Sydney, Ctr Hlth Res, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Ohkubo, Takayoshi] Teikyo Univ, Sch Med, Tokyo, Japan. [Olivares, Pedro R.] Univ Autonoma Chile, Talca, Chile. [Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun] Ctr Hlth Start Initiat, Lagos, Nigeria. [Ortiz, Alberto] IIS Fdn Jimenez Diaz UAM, Madrid, Spain. [Osman, Majdi] YBank, Cambridge, MA USA. [Ota, Erika] St Lukes Int Univ, Tokyo, Japan. [Mahesh, P. A.] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Eun-Kee] Kosin Univ, Coll Med, Dept Med Humanities & Social Med, Busan, South Korea. [de Azeredo Passos, Valeria Maria] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Paternina Caicedo, Angel J.] Univ Cartagena, Cartagena, Colombia. [Patten, Scott B.] Dept Community Hlth Sci, Calgary, AB, Canada. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Pereira, David M.] Univ Porto, Fac Farm, Dept Quim, REQUIMTE LAQV,Lab Farmacognosia, Oporto, Portugal. [Perez-Padilla, Rogelio] Natl Inst Resp Dis, Mexico City, DF, Mexico. [Pesudovs, Konrad] Flinders Univ Adelaide, Adelaide, SA, Australia. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] German Environm Agcy, Exposure Assessment & Environm Hlth Indicators, Berlin, Germany. [Terkawi, Abdullah Sulieman] Dept Anesthesiol, Charlottesville, VA USA. [Platts-Mills, James A.] Univ Virginia, Charlottesville, VA USA. [Pond, Constance D.] Univ Newcastle, Callaghan, NSW, Australia. [Prasad, Noela M.] Fred Hollows Fdn, Sydney, NSW, Australia. [Prasad, Noela M.] Ctr Eye Res Australia, Melbourne, Vic, Australia. [Qorbani, Mostafa] Alborz Univ Med Sci, Sch Med, Dept Community Med, Karaj, Iran. [Radfar, Amir] A T Still Univ, Kirksville, MO USA. [Rafay, Anwar] Contech Sch Publ Hlth, Lahore, Pakistan. [Rahman, Sajjad Ur] BRAC, Res & Evaluat Div, Dhaka, Bangladesh. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] Univ Hlth Sci Med Informat & Technol, ERAWEB Program, Hall in Triol, Austria. [Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Refaat, Amany H.] Suez Canal Univ, Ismailia, Egypt. [Remuzzi, Giuseppe] Univ Milan, Dept Biomed & Clin Sci L Sacco, Milan, Italy. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Rojas-Rueda, David] ISGlobal Inst Salud Global Barcelona, Barcelona, Spain. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Roy, Ambuj; Sagar, Rajesh; Satpathy, Maheswar] All India Inst Med Sci, New Delhi, India. [Sahathevan, Ramesh] Ballarat Hlth Serv, Ballarat, Vic, Australia. [Sahathevan, Ramesh] Univ Kebangsaan Malaysia, Med Ctr, Kuala Lumpur, Malaysia. [Sanabria, Juan R.] Marshall Univ, J Edwards Sch Med, Huntington, WV USA. [Sanabria, Juan R.] Case Western Reserve Univ, Cleveland, OH USA. [Dolores Sanchez-Nino, Maria] IIS Fdn Jimenez Diaz, Madrid, Spain. [Sarmiento-Suarez, Rodrigo] Univ Ciencias Aplicadas & Ambientales, Bogota, Colombia. [Sartorius, Benn] Univ KwaZulu Natal, Durban, South Africa. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schaub, Michael P.] Swiss Res Inst Publ Hlth & Addict, Zurich, Switzerland. [Yebyo, Henock Gebremedhin] Univ Zurich, Zurich, Switzerland. [Schneider, Ione J. C.; Silva, Diego Augusto Santos] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schottker, Ben] German Canc Res Ctr, Heidelberg, Germany. [Schottker, Ben] FOM Univ, Inst Hlth Care & Social Sci, Essen, Germany. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shaheen, Amira] An Najah Univ, Dept Publ Hlth, Nablus, Israel. [Sharma, Rajesh] Indian Inst Technol Ropar, Rupnagar, India. [Sharma, Upasana] ICMR Natl Inst Epidemiol, Chennai, Tamil Nadu, India. [Shen, Jiabin] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Shin, Min-Jeong] Korea Univ, Grad Sch, Dept Publ Hlth Sci, Seoul, South Korea. [Yoon, Seok-Jun] Korea Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Shiue, Ivy] Northumbria Univ, Fac Hlth & Life Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Alves Silveira, Dayane Gabriele] Univ Brasilia, Brasilia, DF, Brazil. [Singh, Om Prakash] Banaras Hindu Univ, Inst Med Sci, Dept Med, Varanasi, Uttar Pradesh, India. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skogen, Jens Christoffer] Alcohol & Drug Res Western Norway, Stavanger, Norway. [Soreide, Kjetil] Stavanger Univ Hosp, Stavanger, Norway. Hatter Inst Cardiovasc Res Africa, Fac Hlth Sci, Cape Town, South Africa. [Stein, Dan J.] Dept Psychiat, Cape Town, South Africa. [Watkins, David A.] Univ Cape Town, Cape Town, South Africa. [Soriano, Joan B.] Univ Autonoma Madrid, Catedra UAM Linde, Hosp Univ de la Princesa, Inst Invest, Palma de Mallorca, Spain. [Sposato, Luciano A.] Western Univ, Dept Clin Neurol Sci, London, ON, Canada. [Sreeramareddy, Chandrashekhar T.] Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia. [Stathopoulou, Vasiliki] Attikon Univ Hosp, Athens, Greece. [Steel, Nicholas] Univ East Anglia, Norwich, Norfolk, England. [Stein, Dan J.] South African Med Res Council Unit Anxiety & Stre, Cape Town, South Africa. [Steiner, Timothy J.; Stovner, Lars] Norwegian Univ Sci & Technol, Dept Neurosci, Trondheim, Norway. [Steinke, Sabine] Univ Hosp Muenster, Dept Dermatol, Munster, Nrw, Germany. [Stovner, Lars] St Olavs Hosp, Norwegian Advisory Unit Headache, Trondheim, Norway. [Stroumpoulis, Konstantinos] Alexandra Gen Hosp Athens, Athens, Greece. [Stroumpoulis, Konstantinos] Ctr Hosp Publ Cotentin, Cherbourg, France. [Sunguya, Bruno F.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Swaminathan, Soumya] Indian Council Med Res, New Delhi, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Law & Soc, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Sociol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Publ Hlth, Irvine, CA USA. [Tabares-Seisdedos, Rafael] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst, Valencia, Spain. [Tabares-Seisdedos, Rafael] CIBERSAM, Valencia, Spain. [Takala, Jukka S.] Minist Manpower, WSH Inst, Singapore, Singapore. [Takala, Jukka S.] Tampere Univ Technol, Tampere, Finland. [Tanne, David] Chaim Sheba Med Ctr, Tel Hashomer, Israel. 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[Dimbuene, Zacharie Tsala] Univ Kinshasa, Fac Econ & Management, Dept Populat Sci & Dev, Kinshasa, Congo. [Dimbuene, Zacharie Tsala] African Populat & Hlth Res Ctr, Nairobi, Kenya. [Tsilimbaris, Miltiadis] Univ Crete, Dept Med, Iraklion, Greece. [Tyrovolas, Stefanos] Univ Barcelona, CIBERSAM, Fundacio St Joan de Deu, Parc Sanitari St Joan de Deu, Barcelona, Spain. [Ukwaja, Kingsley N.] Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria. [Uneke, Chigozie Jesse] Ebonyi State Univ, Abakaliki, Nigeria. [Uthman, Olalekan A.] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [van Gool, Coen H.] Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. [Vasankari, Tommi] UKK Inst Hlth Promot Res, Tampere, Finland. [Venketasubramanian, Narayanaswamy] Raffles Hosp, Raffles Neurosci Ctr, Singapore, Singapore. [Violante, Francesco S.] Univ Bologna, Bologna, Italy. [Vladimirov, Sergey K.] Fed Res Inst Hlth Org & Informat, Moscow, Russia. 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[Yu, Chuanhua] Wuhan Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Wuhan, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan, Peoples R China. [Zaidi, Zoubida] Univ Hosp, Setif, Algeria. [Zaki, Maysaa El Sayed] Mansoura Univ, Fac Med, Mansoura, Egypt. [Zeeb, Hajo] Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Zuhlke, Liesl Joanna] Red Cross War Mem Childrens Hosp, Cape Town, South Africa. RP Vos, T (reprint author), Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM tvos@uw.edu RI Tonelli, Marcello/B-3028-2009; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Scott, James/D-5900-2012; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Kravchenko, Michael/B-2596-2012; Nagel, Gabriele/C-3635-2012; Patton, George/B-5246-2013; Varakin, Yuriy/C-8634-2012; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; OI Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Leung, Ricky/0000-0002-2852-6771; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Scott, James/0000-0002-0744-0688; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Kravchenko, Michael/0000-0001-5187-5518; Nagel, Gabriele/0000-0001-6185-8535; Patton, George/0000-0001-5039-8326; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Taylor, Hugh/0000-0002-9437-784X; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Massano, Joao/0000-0002-5791-7149; Piel, Frederic B./0000-0001-8131-7728 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 71 TC 12 Z9 12 U1 85 U2 85 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1545 EP 1602 PG 58 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000008 ER PT J AU Kassebaum, NJ Arora, M Barber, RM Bhutta, ZA Carter, A Casey, DC Charlson, FJ Coates, MM Coggeshall, M Cornaby, L Dandona, L Dicker, DJ Erskine, HE Ferrari, AJ Fitzmaurice, C Foreman, K Forouzanfar, MH Fullman, N Gething, PW Goldberg, EM Graetz, N Haagsma, JA Johnson, C Kemmer, L Khalil, IA Kinfu, Y Kutz, MJ Kyu, HH Leung, J Liang, XF Lim, SS Lim, SS Lozano, R Mensah, GA Mikesell, J Mokdad, AH Mooney, MD Naghavi, M Nguyen, G Nsoesie, E Pigott, DM Pinho, C Rankin, Z Reinig, N Salomon, JA Sandar, L Smith, A Sorensen, RJD Stanaway, J Steiner, C Teeple, S Thomas, BA Troeger, C VanderZanden, A Wagner, JA Wanga, V Whiteford, HA Zhou, M Zoeckler, L Abajobir, AA Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abraham, B Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Achoki, T Ackerman, IN Adebiyi, AO Adedeji, IA Adsuar, JC Afanvi, KA Afshin, A Agardh, EE Agarwal, A Kumar, S Ahmed, MB Kiadaliri, AA Ahmadieh, H Akseer, N Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Alegretti, MA Aleman, AV Alemu, ZA Alexander, LT Raghib, A Alkerwi, A Alla, F Allebeck, P Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Amini, H Ammar, W Amrock, SM Anderson, GM Anderson, BO Antonio, CAT Anwari, P Arnlov, J Arsenijevic, VSA Artaman, A Asayesh, H Asghar, RJ Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Balakrishnan, K Banerjee, A Barac, A Barker-Collo, SL Barnighausen, T Barregard, L Barrero, LH Basu, S Bayou, TA Beardsley, J Bedi, N Beghi, E Bell, B Bell, ML Benjet, C Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhansali, A Bhatt, S Biadgilign, S Bienhofff, K Bikbov, B Bin Abdulhak, AA 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Radfar, Amir Rafay, Anwar Rahimi, Kazem Rahimi-Movaghar, Vafa Rahman, Mahfuzar Rahman, Mohammad Hifz Ur Rahman, Sajjad Ur Rai, Dheeraj Rai, Rajesh Kumar Rajsic, Sasa Raju, Murugesan Ram, Usha Ranganathan, Kavitha Refaat, Amany H. Reitsma, Marissa B. Remuzzi, Giuseppe Resnikoff, Serge Reynolds, Alex Ribeiro, Antonio L. Ricci, Stefano Roba, Hirbo Shore Rojas-Rueda, David Ronfani, Luca Roshandel, Gholamreza Roth, Gregory A. Roy, Ambuj Sackey, Ben Benasco Sagar, Rajesh Sanabria, Juan R. Dolores Sanchez-Nino, Maria Santos, Itamar S. Santos, Joao Vasco Sarmiento-Suarez, Rodrigo Sartorius, Benn Satpathy, Maheswar Savic, Miloje Sawhney, Monika Schmidt, Maria Ines Schneider, Ione J. C. Schutte, Aletta E. Schwebel, David C. Seedat, Soraya Sepanlou, Sadaf G. Servan-Mori, Edson E. Shahraz, Saeid Shaikh, Masood Ali Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Sheth, Kevin N. Shibuya, Kenji Shigematsu, Mika Shin, Min-Jeong Shin, Rahman Sigfusdottir, Inga Dora Santos Silva, Diego Augusto Silverberg, Jonathan I. Simard, Edgar P. Singh, Abhishek Singh, Jasvinder A. Singh, Prashant Kumar Skirbekk, Vegard Skogen, Jens Christoffer Soljak, Michael Soreide, Kjetil Sorensen, Reed J. D. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Steel, Nicholas Stein, Dan J. Stein, Murray B. Steiner, Timothy J. Stovner, Lars Jacob Stranges, Saverio Stroumpoulis, Konstantinos Sunguya, Bruno F. Sur, Patrick J. Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Landon, Nikhil Tanne, David Tavakkoli, Mohammad Taye, Bineyam Taylor, Hugh R. Ao, Braden J. Te Tegegne, Teketo Kassaw Tekle, Dejen Yemane Terkawi, Abdullah Sulieman Tessema, Gizachew Assefa Thakur, J. S. Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tobe-Gai, Ruoyan Tonelli, Marcello Topor-Madry, Roman Topouzis, Fotis Tran, Bach Xuan Dimbuene, Zacharie Tsala Tsilimbaris, Miltiadis Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Gool, Coen H. van Os, Jim Vasankari, Tommi Vasconcelos, Ana Maria Nogales Venketasubramanian, Narayanaswamy Violante, Francesco S. Vlassov, Vasiliy Victorovich Vollset, Stein Emil Wagner, Gregory R. Wallin, Mitchell T. Wang, Linhong Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea WestermaM, Ronny Wijeratne, Tissa Wilkinson, James D. Williams, Hywel C. Wiysonge, Charles Shey Woldeyohannes, Solomon Meseret Wolfe, Charles D. A. Won, Sungho Xu, Gelin Yadav, Ajit Kumar Yakob, Bereket Yan, Lijing L. Yan, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zeeb, Hajo Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Zeeb, Hajo Zodpey, Sanjay Zonies, David Zuhlke, Liesl Joanna Vos, Theo Lopez, Alan D. Murray, Christopher J. L. CA GBD 2015 DALY & HALE TI Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID SUSTAINABLE DEVELOPMENT GOALS; UNITED-STATES; 187 COUNTRIES; BACK-PAIN; COMPRESSION; TRENDS; RECOMMENDATIONS; PREVALENCE; MORBIDITY; MORTALITY AB Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Copyright (C) The Author(s). Published by Elsevier Ltd. 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[Crump, John A.] Univ Otago, Ctr Int Hlth, Dunedin Sch Med, Dunedin, New Zealand. [Derrett, Sarah] Univ Otago, Injury Prevent Res Unit, Dept Prevent & Social Med, Dunedin Sch Med, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damasceno, Albertino] Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [Das Neves, Jose] Univ Porto, Inst Invest Inovacao Sande I3S, Oporto, Portugal. [Das Neves, Jose] Univ Porto, INEB Inst Engn Biomed, Oporto, Portugal. [Pedro, Joao Mario] Univ Porto, EPI Unit Inst Publ Hlth, Oporto, Portugal. [Santos, Joao Vasco] Univ Porto, Oporto, Portugal. [Davey, Gail] Wellcome Trust Brighton Sussex Ctr Global Hlth Re, Brighton, E Sussex, England. [Davis, Adrian C.; Newton, John N.; Steel, Nicholas] Publ Hlth England, London, England. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Des Jarlais, Don C.] Mt Sinai Beth Israel, New York, NY USA. [Des Jarlais, Don C.] Icahn Sch Med Mt Sinai, New York, NY USA. [Dharmaratne, Samath D.] Univ Peradeniya, Dept Community Med, Fac Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Doyle, Kerrie E.] RMIT Univ, Bundoora, Vic, Australia. [Dubey, Manisha; Rahman, Mahfuzar; Ram, Usha; Singh, Abhishek; Yadav, Ajit Kumar] Int Inst Populat Sci, Mumbai, Maharashtra, India. [Duncan, Bruce Bartholow; Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Duncan, Bruce Bartholow] Univ N Carolina, Chapel Hill, NC USA. [Ebrahimi, Hedyeh; Esteghamati, Alireza; Farzadfar, Farshad; Hafezi-Nejad, Nima; Kasaeian, Amir; Parsaeian, Mahboubeh; Pishgar, Farhad; Sheikhbahaei, Sara] Endocrinol & Metab Populat Sci Inst, Non Communicable Dis Res Ctr, Tehran, Iran. [Ebrahimi, Hedyeh] Shariati Hosp, Digest Dis Res Inst, Liver & Pancreaticobiliary Dis Res Ctr, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Digest Dis Res Inst, Tehran, Iran. [Hassanvand, Mohammad Sadegh] Inst Environm Res, Ctr Air Pollut Res, Tehran, Iran. [Heydarpour, Pouria] Multiple Sclerosis Res Ctr Neurosci Inst, Tehran, Iran. [Kasaeian, Amir] Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Pishgar, Farhad] Urooncol Res Ctr, Tehran, Iran. [Rahimi-Movaghar, Vafa] Sina Trauma & Surg Res Ctr, Tehran, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Tehran, Iran. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Russian Federat, Fed Res Inst Hlth Org & Informat, Minist Hlth, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Sa Farinha, Carla Sofia e] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sa Farinha, Carla Sofia e] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom, Vulnerable Populat & Hlth Disparities, Boston, MA USA. [Feigin, Valery L.] Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Ao, Braden J. Te] Auckland Univ Technol, Auckland, New Zealand. [Fernandes, Jefferson G.] Inst Educ & Sci, German Hosp Oswaldo Cruz, Sao Paulo, Brazil. [Fernandes, Joao C.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med Dent, Ctr Expt Med Rheumatol, London, England. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Garcia-Basteiro, Alberto L.] Manh Hlth Res Ctr, Manhica, Mozambique. [Garcia-Basteiro, Alberto L.] Barcelona Inst Global Hlth, Barcelona, Spain. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gibney, Katherine B.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. [Gibney, Katherine B.] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Gillum, Richard F.; Mehari, Alem] Howard Univ, Coll Med, Washington, DC USA. [Ginawi, Ibrahim Abdelmageem Mohamed] Univ Hail, Coll Med, Hail, Saudi Arabia. [Hailu, Alemayehu Desalegne] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku] Univ Addis Ababa, Addis Ababa, Ethiopia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Roba, Hirbo Shore] Haramaya Univ, Coll Hlth & Med Sci, Dawa, Ethiopia. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Gona, Philimon] Univ Massachusetts, Boston, MA USA. [Goodridge, Amador] Inst Invest Cient Serv Alta Tecnol, INDICASAT AIP, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Gotay, Carolyn C.; Kissoon, Niranjan; Kopec, Jacek A.; Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Goto, Atsushi] Div Epidemiol, Ctr Publ Hlth Sci, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gupta, Rahul] West Virginia Bur Publ Hlth, Charleston, WV USA. [Gupta, Rajeev] Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Dept Anthropol, Delhi, India. [Knudsen, Ann Kristin; Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Hailu, Alemayehu Desalegne; Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Hailu, Gessessew Bugssa] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Halasa, Yara A.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Hamadeh] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Haro, Josep Maria] Parc Sanitari Sant Joan Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Hay, Roderick J.] Int Fdn Dermatol, London, England. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sch Med, Dept Med Mycol & Parasitol, Sari, Iran. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Skirbekk, Vegard] Columbia Univ, New York, NY USA. [Hoffman, Daniel J.] Rutgers State Univ, New Brunswick, NJ USA. [Horino, Masako] Nevada Div Publ & Behav Hlth, Dept Hlth & Human Serv, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Dept Pulmonol, Grad Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY USA. [Hoy, Damian G.] Publ Hlth Div, Pacific Community, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA USA. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jeemon, Panniyammakal] Ctr Chron Dis Control, New Delhi, India. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Tianjin, Peoples R China. [Jiang, Ying] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Hlth Dev, Kitakyushu, Fukuoka, Japan. [Jimenez-Corona, Aida] Inst Ophthalmol Conde Valencia, Dept Ocular Epidemiol & Visual Hlth, Mexico City, DF, Mexico. [Jimenez-Corona, Aida] Gen Directorate Epidemiol, Minist Hlth, Mexico City, DF, Mexico. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kajungu, Dan K.] Sante Stat Analyt Res Inst, Kampala, Uganda. [Kajungu, Dan K.] Mildmay Uganda, Kampala, Uganda. [Kalkonde, Yogeshwar] Action & Res Community Hlth, Soc Educ, Gadchiroli, India. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Zhongshan Hosp, Dept Pulm Med, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Kandel, Amit] SUNY Buffalo, Buffalo, NY USA. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Hannover, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Lyons, Ronan A.] Farr Inst, Swansea, W Glam, Wales. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Kengne, Andre Pascal; Matzopoulos, Richard; Wiysonge, Charles Shey] South African Med Res Council, Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.] Univ Cape Town, Cape Town, South Africa. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khoja, Tawfik Ahmed Muthafer] Execut Board Hlth Minist Council Cooperat Council, Riyadh, Saudi Arabia. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Kim, Cho-il] Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA USA. [Kim, Yun Jin] Southern Univ Coll, Skudai, Malaysia. [Knudsen, Ann Kristin; Vollset, Stein Emil] Ctr Dis Burden, Oslo, Norway. [Skogen, Jens Christoffer] Norwegian Inst Publ Hlth, Dept Hlth Promot, Oslo, Norway. [Savic, Miloje; Skirbekk, Vegard] Norwegian Inst Publ Hlth, Oslo, Norway. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kolte, Dhaval] Brown Univ, Div Cardiol, Providence, RI USA. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari Sant Joan Deu CIBERSAM, Res Dev Unit, Barcelona, Spain. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Kuchenbecker, Ricardo S.] Univ Fed Rio Grande do Sul, Grad Studies Epidemiol, Porto Alegre, RS, Brazil. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kuipers, Ernst J.] Univ Med Ctr Rotterdam, Erasmus MC, Rotterdam, Netherlands. [Lallukka, Tea; Shin, Rahman] Work Org, Work Disabil Prevent, Finnish Inst Occupat Hlth, Helsinki, Finland. [Lallukka, Tea] Univ Helsinki, Dept Publ Hlth, Fac Med, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Latif, Asma Abdul] Lahore Coll Women Univ, Dept Zool, Lahore, Pakistan. [Lavados, Pablo M.] Univ Desarrollo, Clin Alemana, Serv Neurol, Santiago, Chile. [Lawrynowicz, Alicia Elena Beatriz] Inst Nacl Epidemiol Dr Juan H Jara, Mar Del Plata, Argentina. [Leasher, Janet L.] Nova SE Univ, Coll Optometry, Ft Lauderdale, Ft Lauderdale, FL USA. [Leung, Ricky] SUNY Albany, Albany, NY USA. [Li, Yichong] San Francisco VA Med Ctr, San Francisco, CA USA. [Lipshultz, Steven E.; Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Lipshultz, Steven E.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. [Liu, Yang; Phillips, Michael Robert] Emory Univ, Atlanta, GA USA. [Lloyd, Belinda K.] Turning Point, Eastern Hlth, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Looker, Katharine J.; Rai, Dheeraj] Univ Bristol, Bristol, Avon, England. [Lunevicius, Raimundas] Aintree Univ, Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [El Razek, Hassan Magdy Abd] Mansoura Fac Med, Mansoura, Egypt. Social Secur Org Res Inst, Tehran, Iran. [Mckee, Martin] Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. [Malta, Deborah Carvalho] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Marcenes, Wagner] Kings Coll London, Div Populat & Patient Hlth, Inst Dent, London, England. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] CEU Cardenal Herrera Univ, Valencia, Spain. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Mckee, Martin; Murthy, Gudlavalleti Venkata Satyanarayana] London Sch Hyg Trop Med, London, England. [Meaney, Peter A.] Univ Penn, Perelman Sch Med, Philadelphia, PA USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Memiah, Peter] Univ Florida, Pensacola, FL USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Breast Surg Unit, Ctr Comprehens Canc, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mills, Edward J.] Univ Ottawa, Ottawa, ON, Canada. [Mirrakhimov, Erkin M.] Kyrgyz State Med Acad, Bishkek, Kyrgyzstan. [Mirrakhimov, Erkin M.] Natl Ctr Cardiol & Internal Dis, Bishkek, Kyrgyzstan. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Mohammadi, Alireza] Baqiyatallah Univ Med Sci, Neurosci Res Ctr, Tehran, Iran. [Mohammed, Shafiu] Ahmadu Bello Univ, Hlth Syst & Policy Res Unit, Zaria, Nigeria. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Prevent Med & Publ Hlth Res Ctr, Tehran, Iran. [Werdecker, Andrea] Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich O.; WestermaM, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Murdoch, Michele E.] West Herts Hosp NHS Trust, Watford, England. [Murthy, Gudlavalleti Venkata Satyanarayana] Indian Inst Publ Hlth, Gurgaon, India. [Dhillon, Preet K.; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Nachega, Jean B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Nachega, Jean B.; Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Nachega, Jean B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Tran, Bach Xuan] Johns Hopkins Univ, Baltimore, MD USA. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Naldi, Luigi; Remuzzi, Giuseppe] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Le Nguyen, Quyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Pete, Patrick Martial Nkamedjie] Inst Res, Socioecon Dev & Commun, Yaounde, Cameroon. [Nolla, Joan M.] Hosp Univ Bellvitge, Lhospitalet De Llobregat, Spain. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Obermeyer, Carla Makhlouf] Amer Univ Beirut, Ctr Res Populat & Hlth, Fac Hlth Sci, Beirut, Lebanon. [Ogbo, Felix Akpojene] Univ Western Sydney, Ctr Hlth Res, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Sch Med, Dept Prevent Med, Seoul, South Korea. [Oladimeji, Olanrewaju] Human Sci Res Council, Durban, South Africa. [Oladimeji, Olanrewaju; Sartorius, Benn] Univ KwaZulu Natal, Durban, South Africa. [Olivares, Pedro R.] Univ Autonoma Chile, Talca, Chile. [Olusanya, Bolajoko Olubukunola; Olusanya, Jacob Olusegun] Ctr Healthy Start Initiat, Lagos, Nigeria. [Oren, Eyal] Univ Arizona, Tucson, AZ USA. [Ortiz, Alberto] IIS Fdn Jimenez Diaz UAM, Madrid, Spain. [Ota, Erika] Lukes Int Univ, Tokyo, Japan. [Schutte, Aletta E.] HART, Mafikeng, South Africa. [Oyekale, Abayomi Samuel] Hypertens NorthWest Univ, Mafikeng, South Africa. [Pa, Mahesh] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Eun-Kee] Kosin Univ, Dept Med Human & Social Med, Coll Med, Busan, South Korea. [Patten, Scott B.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Tonelli, Marcello] Univ Calgary, Calgary, AB, Canada. [Pedro, Joao Mario] Hlth Res Ctr Angola, Caxito, Angola. [Pereira, David M.] Univ Porto, REQUIMTE LAQV, Lab Farm, Dept Quim,Fac Farm, Oporto, Portugal. [Perico, Norberto; Remuzzi, Giuseppe] IRCCS Ist Ric Farmacol Mario Negri, Bergamo, Italy. [Pesudovs, Konrad] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Univ Witwatersrand, Johannesburg, South Africa. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] Exposure Assessment & Environm Hlth Indicators, German Environm Agcy, Berlin, Germany. [Polinder, Suzanne] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Prasad, Noela M.] Fred Hollows Fdn, Sydney, NSW, Australia. [Prasad, Noela M.] Ctr Eye Res Australia, Melbourne, Vic, Australia. [Qorbani, Mostafa] Alborz Univ Med Sci, Sch Med, Dept Community Med, Karaj, Iran. [Radfar, Amir] AT Still Univ, Kirksville, MO USA. [Rafay, Anwar] Contech Sch Publ Hlth, Lahore, Pakistan. [Rahman, Mahfuzar] Res & Evaluat Div, BRAC, Dhaka, Bangladesh. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] UMIT, ERAWEB Program, Hall In Tirol, Austria. [Raju, Murugesan] Univ Missouri, Columbia, MO USA. [Ranganathan, Kavitha] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Refaat, Amany H.] Walden Univ, Minneapolis, MN USA. [Refaat, Amany H.] Suez Canal Univ, Ismailia, Egypt. [Remuzzi, Giuseppe] Univ Milan, Dept Biomed & Clin Sci Sacco L, Milan, Italy. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ricci, Stefano] UO Neurol USL Umbria 1, Citta Di Castello, Italy. [Rojas-Rueda, David] Inst Salud Global Barcelona, Barcelona, Spain. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Sackey, Ben Benasco] World Hlth Org, Accra, Ghana. [Sanabria, Juan R.] Marshall Univ, Edwards Sch Med J, Huntington, WV USA. [Sanabria, Juan R.] Case Western Reserve Univ, Cleveland, OH USA. [Dolores Sanchez-Nino, Maria] IIS Fdn Jimenez Diaz, Madrid, Spain. [Sarmiento-Suarez, Rodrigo] Univ Ciencias Aplicadas Ambient, Bogota, Colombia. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schneider, Ione J. C.; Santos Silva, Diego Augusto] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Schutte, Aletta E.] South African Med Res Council, Potchefstroom, South Africa. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shahraz, Saeid] Tufts Med Ctr, Boston, MA USA. [Shaikh, Masood Ali] Independent Consultant, Karachi, Pakistan. [Sharma, Rajesh] Indian Inst Technol Ropar, Rupnagar, India. [Shen, Jiabin] Res Inst, Nationwide Childrens Hosp, Columbus, OH USA. [Shigematsu, Mika] Natl Inst Infect Dis, Tokyo, Japan. [Shigematsu, Mika] Sandia Natl Labs, Albuquerque, NM USA. [Shin, Min-Jeong] Korea Univ, Dept Publ Hlth Sci, Grad Sch, Seoul, South Korea. [Yoon, Seok-Jun] Korea Univ, Dept Prevent Med, Coll Med, Seoul, South Korea. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Silverberg, Jonathan I.] Northwestern Univ, Feinberg Sch Med, Chicago, IL USA. [Yan, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL USA. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skogen, Jens Christoffer] Alcohol & Drug Res Western Norway, Stavanger, Norway. [Soreide, Kjetil] Stavanger Univ Hosp, Stavanger, Norway. [Sreeramareddy, Chandrashekhar T.] Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia. 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EM cjlm@uw.edu RI Tonelli, Marcello/B-3028-2009; Amini, Heresh/B-3076-2010; Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Patton, George/B-5246-2013; Malta, Deborah/H-7880-2012; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Franklin, Richard/H-1731-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; OI Mirrakhimov, Erkin/0000-0003-2982-6108; Degenhardt, Louisa/0000-0002-8513-2218; Gouda, Hebe/0000-0002-5709-4509; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Amini, Heresh/0000-0002-4825-1322; Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Patton, George/0000-0001-5039-8326; Malta, Deborah/0000-0002-8214-5734; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Leung, Ricky/0000-0002-2852-6771; Kieling, Christian/0000-0001-7691-4149; Gething, Peter/0000-0001-6759-5449; Rai, Dheeraj/0000-0002-7239-3523; Taylor, Hugh/0000-0002-9437-784X; Pishgar, Farhad/0000-0003-0703-8442; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Franklin, Richard/0000-0003-1864-4552; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; Heydarpour, Pouria/0000-0001-5644-7555; Vlassov, Vasiliy/0000-0001-5203-549X FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 65 TC 13 Z9 13 U1 59 U2 59 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1603 EP 1658 PG 56 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000009 ER PT J AU Forouzanfar, MH Afshin, A Alexander, LT Anderson, HR Bhutta, ZA Biryukov, S Brauer, M Burnett, R Cercy, K Charlson, FJ Cohen, AJ Dandona, L Estep, K Ferrari, AJ Frostad, JJ Fullman, N Gething, PW Godwin, WW Griswold, M Kinfu, Y Kyu, HH Larson, HJ Liang, X Lim, SS Liu, PY Lopez, AD Lozano, R Marczak, L Mensah, GA Mokdad, AH Moradi-Lakeh, M Naghavi, M Neal, B Reitsma, MB Roth, GA Salomon, JA Sur, PJ Vos, T Wagner, JA Wang, H Zhao, Y Zhou, M Aasvang, GM Abajobir, AA Abate, KH Abbafati, C Abbas, KM Abd-Allah, F Abdulle, AM Abera, SF Abraham, B Abu-Raddad, LJ Abyu, GY Adebiyi, AO Adedeji, IA Ademi, Z Adou, AK Adsuar, JC Agardh, EE Agarwal, A Agrawal, A Kiadaliri, AA Ajala, ON Akinyemiju, TF Al-Aly, Z Alam, K Alam, NKM Aldhahri, SF Aldridge, RW Alemu, ZA Ali, R Alkerwi, A Alla, F Allebeck, P Alsharif, U Altirkawi, KA Martin, EA Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Amini, H Ammar, W Amrock, SM Andersen, HH Anderson, BO Antonio, CAT Anwar, P Arnlov, J Al Artaman Asayesh, H Asghar, RJ Assadi, R Atique, S Avokpaho, EFGA Awasthi, A Quintanilla, BPA Azzopardi, P Bacha, U Badawi, A Bahit, MC Balakrishnan, K Barac, A Barber, RM Barker-Collo, SL Barnighausen, T Barquera, S Barregard, L Barrero, LH Basu, S Bans, C Bazargan-Hejazi, S Beardsley, J Bedi, N Beghi, E Bell, ML Bello, AK Bennett, DA Bensenor, IM Berhane, A Bernabe, E Betsu, BD Beyene, AS Bhala, N Bhansali, A Bhatt, S Biadgilign, S Bikbov, B Bisanzio, D Bjertness, E Blore, JD Borschmann, R Boufous, S Bourne, RRA Brainin, M Brazinova, A Breitborde, NJK Brenner, H Broday, DM Brugha, TS Brunekreef, B Butt, ZA Cahill, LE Calabria, B Campos-Nonato, IR Cardenas, R Carpenter, D Casey, DC Castaneda-Oquela, CA Rivas, JC Castro, RE Catala-Lopez, F Chang, JC Chiang, PPC Chibalabala, M Chimed-Ochir, O Chisumpa, VH Chitheer, AA Choi, JYJ Christensen, H Christopher, DJ Ciobanu, LG Coates, MM Colquhoun, SM Cooper, LT Cooperrider, K Cornaby, L Cortinovis, M Crump, JA Cuevas-Nasu, L Damasceno, A Dandona, R Darby, SC Dargan, PI das Neves, J Davis, AC Davletov, K de Castro, EF De la Cruz-Gongora, V De Leo, D Degenhardt, L Del Gobbo, LC del Pozo-Cruz, B Dellavalle, RP Deribew, A Des Jarlais, DC Dharmaratne, SD Dhillon, PK Diaz-Tome, C Dicker, D Ding, EL Dorsey, ER Doyle, KE Driscoll, TR Duan, L Dubey, M Duncan, BB Elyazar, I Endries, AY Ermakov, SP Erskine, HE Eshrati, B Esteghamati, A Fahimi, S Faraon, EJA Farid, TA Farinha, CSES Faro, A Farvid, MS Farzadfar, F Feigin, VL Fereshtehnejad, SM Fernandes, JG Fischer, F Fitchett, JRA Fleming, T Foigt, N Foreman, K Fowkes, FGR Franklin, RC Furst, T Futran, ND Gakidou, E Garcia-Basteiro, AL Gebrehiwot, TT Gebremedhin, AT Geleijnse, JM 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Harikrishnan, Sivadasanpillai Maria Haro, Josep Hassanvand, Mohammad Sadegh Hassen, Tahir Ahmed Havmoeller, Rasmus Beatriz Heredia-Pi, Ileana Francisco Hernandez-Llanes, Norberto Heydarpour, Pouria Hoek, Hans W. Hoffman, Howard J. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hoy, Damian G. Hsairi, Mohamed Htet, Aung Soe Hu, Guoqing Huang, John J. Husseini, Abdullatif Hutchings, Sally J. Huybrechts, Inge Iburg, Kim Moesgaard Idrisov, Bulat T. Ileanu, Bogdan Vasile Inoue, Manami Jacobs, Troy A. Jacobsen, Kathryn H. Jahanmehr, Nader Jakovljevic, Mihajlo B. Jansen, Henrica A. F. M. Jassal, Simerjot K. Javanbakht, Mehdi Jayatilleke, Achala Upendra Jee, Sun Ha Jeemon, Panniyammakal Jha, Vivekanand Jiang, Ying Jibat, Tariku Jin, Ye Johnson, Catherine O. Jonas, Jost B. Kabir, Zubair Kalkonde, Yogeshwar Kamal, Ritul Kan, Haidong Karch, Andre Karema, Corine Kakizi Karimkhani, Chante Kasaeian, Amir Kaul, Anil Kawakami, Norito Kazi, Dhruv S. 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Shaheen, Amira Shahraz, Saeid Shaikh, Masood Ali Levy, Teresa Shamah Sharma, Rajesh She, Jun Sheikhbahaei, Sara Shen, Jiabin Sheth, Kevin N. Shi, Peilin Shibuya, Kenji Shigematsu, Mika Shin, Min-Jeong Shiri, Rahman Shishani, Kawkab Shiue, Ivy Shrime, Mark G. Sigfusdottir, Inga Dora Silva, Diego Augusto Santos Alves Silveira, Dayane Gabriele Silverberg, Jonathan I. Simard, Edgar P. Sindi, Shireen Singh, Abhishek Singh, Jasvinder A. Singh, Prashant Kumar Slepak, Erica Leigh Soljak, Michael Soneji, Samir Sorensen, Reed J. D. Sposato, Luciano A. Sreeramareddy, Chandrashekhar T. Stathopoulou, Vasiliki Steckling, Nadine Steel, Nicholas Stein, Dan J. Stein, Murray B. Stockl, Heidi Stranges, Saverio Stroumpoulis, Konstantinos Sunguya, Bruno F. Swaminathan, Soumya Sykes, Bryan L. Szoeke, Cassandra E. I. Tabares-Seisdedos, Rafael Takahashi, Ken Talongwa, Roberto Tchio Landon, Nikhil Tanne, David Tavakkoli, Mohammad Taye, Belaynew Wasie Taylor, Hugh R. Tedla, Bemnet Amare Tefera, Worku Mekonnen Tegegne, Teketo Kassaw Tekle, Dejen Yemane Terkawi, Abdullah Sulieman Thakur, J. S. Thomas, Bernadette A. Thomas, Matthew Lloyd Thomson, Alan J. Thorne-Lyman, Andrew L. Thrift, Amanda G. Thurston, George D. Tillmann, Taavi Tobe-Gai, Ruoyan Tobollik, Myriam Topor-Madry, Roman Topouzis, Fotis Towbin, Jeffrey Allen Bach Xuan Tran Dimbuene, Zacharie Tsala Tsilimparis, Nikolaos Tura, Abera Kenay Tuzcu, Emin Murat Tyrovolas, Stefanos Ukwaja, Kingsley N. Undurraga, Eduardo A. Uneke, Chigozie Jesse Uthman, Olalekan A. van Donkelaar, Aaron van Os, Jim Varakin, Yuri Y. Vasankari, Tommi Veerman, J. Lennert Venketasubramanian, Narayanaswamy Violante, Francesco S. Vollset, Stein Emil Wagner, Gregory R. Waller, Stephen G. Wang, JianLi Wang, Linhong Wang, Yanping Weichenthal, Scott Weiderpass, Elisabete Weintraub, Robert G. Werdecker, Andrea Westerman, Ronny Whiteford, Harvey A. Wijeratne, Tissa Wiysonge, Charles Shey Wolfe, Charles D. A. Won, Sungho Woolf, Anthony D. Wubshet, Mamo Xavier, Denis Xu, Gelin Yadav, Ajit Kumar Yakob, Bereket Yalew, Ayalnesh Zemene Yano, Yuichiro Yaseri, Mehdi Ye, Pengpeng Yip, Paul Yonemoto, Naohiro Yoon, Seok-Jun Younis, Mustafa Z. Yu, Chuanhua Zaidi, Zoubida Zaki, Maysaa El Sayed Zhu, Jun Zipkin, Ben Zodpey, Sanjay Zuhlke, Liesl Joanna Murray, Christopher J. L. CA GBD 2015 Risk Factors TI Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 SO LANCET LA English DT Article ID ISCHEMIC-HEART-DISEASE; DOSE-RESPONSE METAANALYSIS; BODY-MASS INDEX; ALCOHOL-CONSUMPTION; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; NONCOMMUNICABLE DISEASES; ECONOMIC-DEVELOPMENT; COST-EFFECTIVENESS; REDUCED MORTALITY AB Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Copyright (C) The Author(s). Published by Elsevier Ltd. 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[Alemu, Zewdie Aderaw; Tegegne, Teketo Kassaw] Debre Markos Univ, Debre Markos, Ethiopia. [Alkerwi, Ala'a] Luxembourg Inst Hlth LIH, Strassen, Luxembourg. [Alla, Francois; Guillemin, Francis] Univ Lorraine, Sch Publ Hlth, Nancy, France. [Allebeck, Peter; Rabiee, Rynaz H. S.] Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden. [Fereshtehnejad, Seyed-Mohammad] Karolinska Inst, Dept Neurobiol, Care Sci & Soc NVS, Stockholm, Sweden. [Kivipelto, Miia] Karolinska Inst, Aging Res Ctr, Stockholm, Sweden. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Havmoeller, Rasmus; Sindi, Shireen] Karolinska Inst, Stockholm, Sweden. [Alsharif, Ubai] Charite, Berlin, Germany. [Alvarez Martin, Elena] Govt Delegat Natl Plan Drugs, Minist Hlth, Spanish Observ Drugs, Social Policy & Equal, Madrid, Spain. [Alvis-Guzman, Nelson] Univ Cartagena, Cartagena De Indias, Colombia. [Amare, Azmeraw T.; Melaku, Yohannes Adama] Univ Adelaide, Sch Med, Adelaide, SA, Australia. [Ciobanu, Liliana G.] Univ Adelaide, Adelaide, SA, Australia. [Amare, Azmeraw T.] Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar, Ethiopia. [Taye, Belaynew Wasie] Bahir Dar Univ, Bahir Dar, Ethiopia. [Amberbir, Alemayehu] Dignitas Int, Zomba, Malawi. [Amegah, Adeladza Kofi] Univ Cape Coast, Cape Coast, Ghana. [Amini, Heresh] Kurdistan Univ Med Sci, Environm Hlth Res Ctr, Sanandaj, Iran. [Amini, Heresh; Fuerst, Thomas] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Karema, Corine Kakizi] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Ammar, Walid] Minist Publ Hlth, Beirut, Lebanon. [Amrock, Stephen Marc] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Andersen, Hjalte H.] Aalborg Univ, Fac Med, Dept Hlth Sci & Technol, Ctr Sensory Motor Interact, Aalborg, Denmark. [Antonio, Carl Abelardo T.] Univ Philippines Manila, Dept Hlth Policy & Adm, Coll Publ Hlth, Manila, Philippines. [Aquino Faraon, Emerito Jose] Univ Philippines Manila, Coll Publ Hlth, Manila, Philippines. [Arnlov, Johan; Larsson, Anders] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Arnlov, Johan] Dalarna Univ, Falun, Sweden. Univ Manitoba, Winnipeg, MB, Canada. [Asayesh, Hamid] Qom Univ Med Sci, Sch Paramed, Dept Emergency Med, Qom, Iran. [Asghar, Rana Jawad] South Asian Publ Hlth Forum, Islamabad, Pakistan. [Assadi, Reza] Mashhad Univ Med Sci, Mashhad, Iran. [Atique, Suleman] Taipei Med Univ, Grad Inst Biomed Informat, Taipei, Taiwan. [Avokpaho, Euripide Frinel G. Arthur] Inst Rech Clin Benin, Cotonou, Benin. [Avokpaho, Euripide Frinel G. Arthur] Lab Etud & Rech Act Sante LERAS Afrique, Parakou, Benin. [Awasthi, Ashish] Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India. [Quintanilla, Beatriz Paulina Ayala] La Trobe Univ, Judith Lumley Ctr Mother Infant & Family Hlth Res, Melbourne, Vic, Australia. [Quintanilla, Beatriz Paulina Ayala] Peruvian Natl Inst Hlth, Lima, Peru. [Azzopardi, Peter] South Australian Hlth & Med Res Inst, Wardliparingga Aboriginal Res Unit, Adelaide, SA, Australia. [Bacha, Umar] Univ Management & Technol, Sch Hlth Sci, Lahore, Pakistan. [Badawi, Alaa] Publ Hlth Agcy Canada, Toronto, ON, Canada. [Bahit, Maria C.] INECO Neurociencias, Rosario, Santa Fe, Argentina. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Dept Environm Hlth Engn, Madras, Tamil Nadu, India. [Barac, Aleksandra] Univ Belgrade, Fac Med, Belgrade, Serbia. [Barker-Collo, Suzanne L.] Univ Auckland, Sch Psychol, Auckland, New Zealand. [del Pozo-Cruz, Borja] Univ Auckland, Auckland, New Zealand. [Baernighausen, Till] Africa Hlth Res Inst, Mtubatuba, South Africa. [Baernighausen, Till; Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Barregard, Lars] Univ Gothenburg, Dept Occupat & Environm Hlth, Gothenburg, Sweden. [Petzold, Max] Univ Gothenburg, Hlth Metr Unit, Gothenburg, Sweden. [Barrero, Lope H.] Pontificia Univ Javeriana, Sch Engn, Dept Ind Engn, Bogota, Colombia. [Basu, Sanjay; Del Gobbo, Liana C.] Stanford Univ, Stanford, CA 94305 USA. [Bazargan-Hejazi, Shahrzad] Charles R Drew Univ Med & Sci, Coll Med, 1621 E 120th St, Los Angeles, CA 90059 USA. [Bazargan-Hejazi, Shahrzad] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bazargan-Hejazi, Shahrzad] Kermanshah Univ Med Sci, Kermanshah, Iran. [Beardsley, Justin] Univ Oxford, Ho Chi Minh City, Vietnam. [Bedi, Neeraj] Coll Publ Hlth & Trop Med, Jazan, Saudi Arabia. [Beghi, Ettore] IRCCS Ist Ric Farmacol Mario Negri, Milan, Italy. [Sheth, Kevin N.] Yale Univ, Sch Med, New Haven, CT USA. [Bell, Michelle L.] Yale Univ, New Haven, CT USA. [Bello, Aminu K.] Univ Alberta, Edmonton, AB, Canada. [Santos, Itamar S.] Univ Sao Paulo, Dept Internal Med, Sao Paulo, Brazil. [Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Sao Paulo, Brazil. [Berhane, Adugnaw] Debre Berhane Univ, Debre Berhan, Ethiopia. [Wolfe, Charles D. A.] Kings Coll London, Div Hlth & Social Care Res, London, England. [Bernabe, Eduardo] Kings Coll London, London, England. Haramaya Univ, Coll Hlth & Med Sci, Harar, Ethiopia. [Beyene, Addisu Shunu; Hassen, Tahir Ahmed; Mesfin, Yonatan Moges] Haramaya Univ, Harar, Ethiopia. [Bhala, Neeraj] Queen Elizabeth Hosp Birmingham, Birmingham, W Midlands, England. [Bhala, Neeraj] Univ Otago, Sch Med, Wellington, New Zealand. [Bhansali, Anil] Postgrad Inst Med Educ & Res, Chandigarh, India. [Biadgilign, Sibhatu] Independent Publ Hlth Consultants, Addis Ababa, Ethiopia. [Bikbov, Boris] Acad VI Shumakov Fed Res Ctr Transplantol & Artif, Dept Nephrol Issues Transplanted Kidney, Moscow, Russia. [Bjertness, Espen] Univ Oslo, Dept Community Med, Oslo, Norway. [Htet, Aung Soe] Univ Oslo, Oslo, Norway. [Boufous, Soufiane] Univ New South Wales, Transport & Rd Safety TARS Res, Kensington, NSW, Australia. [Degenhardt, Louisa] Univ New South Wales, Natl Drug & Alcohol Res Ctr, Kensington, NSW, Australia. [Resnikoff, Serge] Univ New South Wales, Brien Holden Vision Inst, Kensington, NSW, Australia. [Calabria, Bianca] Univ New South Wales, Kensington, NSW, Australia. [Bourne, Rupert R. A.] Anglia Ruskin Univ, Vis & Eye Res Unit, Cambridge, England. [Brainin, Michael] Danube Univers Krems, Krems, Austria. [Brazinova, Alexandra; Majdan, Marek] Trnava Univ, Dept Publ Hlth, Fac Hlth Sci & Social Work, Trnava, Slovakia. [Brazinova, Alexandra] Int Neurotrauma Res Org, Vienna, Austria. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Breitborde, Nicholas J. K.] Ohio State Univ, Columbus, OH 43210 USA. [Brenner, Hermann; Schoettker, Ben] German Canc Res Ctr, Heidelberg, Germany. [Broday, David M.] Technion, Haifa, Israel. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Brunekreef, Bert; Kromhout, Hans] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Butt, Zahid A.] Al Shifa Trust Eye Hosp, Rawalpindi, Pakistan. [van Donkelaar, Aaron] Dalhousie Univ, Dept Phys & Atmospher Sci, Halifax, NS, Canada. [Cahill, Leah E.; Martin, Randall V.] Dalhousie Univ, Halifax, NS, Canada. [Calabria, Bianca] Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth, Canberra, ACT, Australia. [Cardenas, Rosario] Metropolitan Autonomous Univ, Mexico City, DF, Mexico. [Carpenter, David] Univ Albany, Rensselaer, NY USA. [Castaneda-Oquela, Carlos A.] Colombian Natl Hlth Observ, Inst Nacl Salud, Bogota, Colombia. [Castaneda-Oquela, Carlos A.] Univ Nacl Colombia, Dept Publ Hlth, Epidemiol & Publ Hlth Evaluat Grp, Bogota, Colombia. [Castillo Rivas, Jacqueline] Caja Costarricense Seguro Social, San Jose, Costa Rica. [Castillo Rivas, Jacqueline] Univ Costa Rica, San Pedro, Montes De Oca, Costa Rica. [Estanislao Castro, Ruben] Univ Diego Portales, Santiago, Chile. [Catala-Lopez, Ferran] Univ Valencia, Dept Med, INCLIVA Hlth Res Inst, Valencia, Spain. [Catala-Lopez, Ferran] CIBERSAM, Valencia, Spain. [Catala-Lopez, Ferran] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan. [Chiang, Peggy Pei-Chia] Gold Coast Hlth, Clin Governance Unit, Southport, Qld, Australia. [Chibalabala, Mirriam] Crowd Watch Africa, Lusaka, Zambia. [Chimed-Ochir, Odgerel] Univ Occupat & Environm Hlth, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Inst Ind Ecol Sci, Kitakyushu, Fukuoka, Japan. [Takahashi, Ken] Univ Occupat & Environm Hlth, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Chisumpa, Vesper Hichilombwe; Mapoma, Chabila C.; Masiye, Felix] Univ Zambia, Lusaka, Zambia. [Chisumpa, Vesper Hichilombwe] Univ Witwatersrand, Johannesburg, South Africa. [Chitheer, Abdulaal A.] Minist Hlth, Baghdad, Iraq. [Choi, Jee-Young Jasmine] Seoul Natl Univ, Med Lib, Seoul, South Korea. [Christensen, Hanne] Bispebjerg Hosp, Copenhagen, Denmark. [Christopher, Devasahayam Jesudas] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Cooper, Leslie Trumbull] Mayo Clin, Jacksonville, FL 32224 USA. Mario Negri Inst Pharmacol Res, Milan, Italy. [Crump, John A.] Univ Otago, Ctr Int Hlth, Dunedin Sch Med, Dunedin, New Zealand. [Poulton, Richie G.] Univ Otago, Dunedin, New Zealand. [Damasceno, Albertino] Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique. [Dargan, Paul I.] Guys & St Thomas NHS Fdn Trust, London, England. [das Neves, Jose] Univ Porto, Inst Invest & Inovacao Saude i3S, Oporto, Portugal. [das Neves, Jose] Univ Porto, INEB Inst Engn Biomed, Oporto, Portugal. [Davis, Adrian C.; Newton, John N.; Steel, Nicholas] Publ Hlth England, London, England. [Davletov, Kairat] Kazakh Natl Med Univ, Sch Publ Hlth, Alma Ata, Kazakhstan. [De Leo, Diego] Griffith Univ, Brisbane, Qld, Australia. [Dellavalle, Robert P.] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Colorado Sch Publ Hlth, Aurora, CO USA. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Des Jarlais, Don C.] Mt Sinai Beth Israel, New York, NY USA. [Des Jarlais, Don C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dharmaratne, Samath D.] Univ Peradeniya, Fac Med, Dept Community Med, Peradeniya, Sri Lanka. [Jeemon, Panniyammakal] Publ Hlth Fdn India, Ctr Control Chron Condit, Gurgaon, India. [Dhillon, Preet K.; Lal, Dharmesh Kumar; Zodpey, Sanjay] Publ Hlth Fdn India, Gurgaon, India. [Diaz-Tome, Cesar] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Dorsey, E. Ray] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Doyle, Kerrie E.] RMIT Univ, Bundoora, Vic, Australia. [Dubey, Manisha; Rahman, Mohammad Hifz Ur; Ram, Usha; Singh, Abhishek; Yadav, Ajit Kumar] Int Inst Populat Sci, Bombay, Maharashtra, India. [Duncan, Bruce Bartholow; Kieling, Christian; Schmidt, Maria Ines] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Duncan, Bruce Bartholow] Univ Nouth Carolina, Chapel Hill, NC USA. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Minist Hlth Russian Federat, Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Farzadfar, Farshad; Kasaeian, Amir; Parsaeian, Mahboubeh] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Tehran, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Populat Sci Inst, Tehran, Iran. [Fahimi, Saman; Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Tehran, Iran. [Hassanvand, Mohammad Sadegh] Univ Tehran Med Sci, Ctr Air Pollut Res, Inst Environm Res, Tehran, Iran. [Heydarpour, Pouria] Univ Tehran Med Sci, Multiple Sclerosis Res Ctr, Neurosci Inst, Tehran, Iran. [Kasaeian, Amir] Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Parsaeian, Mahboubeh] Univ Tehran Med Sci, Dept Epidemiol & Biostat, Sch Publ Hlth, Tehran, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Tehran, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Tehran, Iran. [Aquino Faraon, Emerito Jose] Dept Hlth, Manila, Philippines. [Farid, Talha A.; Khan, Abdur Rahman] Univ Louisville, Louisville, KY USA. [Sofia E Sa Farinha, Carla] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sofia E Sa Farinha, Carla] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Feigin, Valery L.] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Fernandes, Jefferson G.] German Hosp Oswaldo Cruz, Inst Educ & Sci, Sao Paulo, Brazil. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Shiue, Ivy] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Fowkes, F. Gerry R.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Franklin, Richard C.] James Cook Univ, Townsville, Qld, Australia. [Garcia-Basteiro, Alberto L.] Manhica Hlth Res Ctr, Manhica, Mozambique. [Garcia-Basteiro, Alberto L.] Barcelona Inst Global Hlth, Barcelona, Spain. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Med Prevent, Paris, France. [Tefera, Worku Mekonnen] Univ Addis Ababa, Coll Hlth Sci, Sch Publ Hlth, Addis Ababa, Ethiopia. [Giref, Ababi Zergaw; Haile, Demewoz; Jibat, Tariku; Manamo, Wondimu Ayele Ayele] Univ Addis Ababa, Addis Ababa, Ethiopia. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. Haramaya Univ, Coll Hlth & Med Sci, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Martinez-Raga, Jose] Univ Valencia, Univ Hosp Doctor Peset, Valencia, Spain. [Carmen Gomez-Cabrera, Mari] Univ Valencia, Valencia, Spain. [Carmen Gomez-Cabrera, Mari] INCLIVA Biomed Res Inst, Valencia, Spain. [Gona, Philimon] Univ Massachusetts, Boston, MA 02125 USA. [Goodridge, Amador] Inst Invest Cient & Servicios Alta Tecnol INDICAS, Ciudad Del Saber, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Affairs, Palikir, Micronesia. [Goto, Atsushi] Natl Canc Ctr, Div Epidemiol, Ctr Publ Hlth Sci, Tokyo, Japan. [Inoue, Manami] Natl Canc Ctr, Tokyo, Japan. [Gugnani, Harish Chander] St James Sch Med, Dept Microbiol, The Quarter, Anguilla, Scotland. [Gugnani, Harish Chander] St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla, Scotland. West Virginia Bur Publ Hlth, Charleston, WV USA. Eternal Heart Care Ctr & Res Inst, Jaipur, Rajasthan, India. [Gutierrez, Reyna A.; Orozco, Ricardo] Natl Inst Psychiat Ramon Fuente, Mexico City, DF, Mexico. [Haagsma, Juanita A.] Univ Med Ctr, Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Hailu, Gessessew Bugssa] Kilte Awlaelo Hlth & Demog Surveillance Syst, Mekelle, Ethiopia. [Halasa, Yara A.; Undurraga, Eduardo A.] Brandeis Univ, Waltham, MA USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Handal, Alexis J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Maria Haro, Josep] Parc Sanitari Sant Joan Deu CIBERSAM, St Boi De Llobregat, Barcelona, Spain. [Maria Haro, Josep] Univ Barcelona, Barcelona, Spain. [Francisco Hernandez-Llanes, Norberto] Comis Nacl Adicc, Mexico City, DF, Mexico. [Hoek, Hans W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Tura, Abera Kenay] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Horino, Masako] Dept Hlth & Human Serv, Nevada Div Publ & Behav Hlth, Carson City, NV USA. [Horita, Nobuyuki] Yokohama City Univ, Dept Pulmonol, Grad Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Pacific Community, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Salah Azaiz Inst, Dept Epidemiol, Tunis, Tunisia. [Htet, Aung Soe] Minist Hlth, Int Relat Div, Nay Pyi Taw, Myanmar. [Hu, Guoqing] Cent S Univ, Sch Publ Hlth, Dept Epidemiol & Hlth Stat, Changsha, Hunan, Peoples R China. [Husseini, Abdullatif] Birzeit Univ, Birzeit, Israel. [Huybrechts, Inge] Int Agcy Res Canc IARC, Lyon, France. [Huybrechts, Inge] Univ Ghent, Ghent, Belgium. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. [Kwan, Gene F.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ileanu, Bogdan Vasile; Pana, Adrian] Bucharest Univ Econ Studies, Bucharest, Romania. [Inoue, Manami] Univ Tokyo, Grad Sch Med, Tokyo, Japan. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Jacobs, Troy A.] HIDN, USAID Global Hlth Bur, MCH Div, Washington, DC USA. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA USA. [Jahanmehr, Nader] Shahid Beheshti Univ Med Sci, Sch Publ Hlth, Tehran, Iran. [Yaseri, Mehdi] Shahid Beheshti Univ Med Sci, Ophthalm Res Ctr, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Jansen, Henrica A. F. M.] UNFPA Asia & Pacific Reg Off, Bangkok, Thailand. [Jassal, Simerjot K.] Univ Calif San Diego, VA San Diego, San Diego, CA 92103 USA. [Stein, Murray B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jee, Sun Ha] Yonsei Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Jeemon, Panniyammakal] Ctr Chron Dis Control, New Delhi, India. [Jibat, Tariku] Univ Addis Ababa, Debre Zeit, Ethiopia. [Jha, Vivekanand] George Inst Global Hlth India, New Delhi, India. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kalkonde, Yogeshwar] Soc Educ Act & Res Community Hlth, Gadchiroli, India. [Kamal, Ritul] CSIR Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Fudan Univ, Dept Pulm Med, Zhongshan Hosp, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karema, Corine Kakizi] Qual & Equity Hlth Care, Kigali, Rwanda. [Karimkhani, Chante] Case Western Univ Hosp, Cleveland, OH USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kazi, Dhruv S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Kemp, Andrew Haddon] Swansea Univ, Swansea, W Glam, Wales. [Parry, Charles D.] South African Med Researcil, Alcohol Tobacco & Other Drug Res Unit, Cape Town, South Africa. [Kengne, Andre Pascal; Matzopoulos, Richard; Wiysonge, Charles Shey] South African Med Researcil, Cape Town, South Africa. [Matzopoulos, Richard] Univ Cape Town, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa. [Kengne, Andre Pascal] Univ Cape Town, Cape Town, South Africa. [Keren, Andre] Assuta Hosp, Assuta Hashalom, Tel Aviv, Israel. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khan, Gulfaraz] United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Microbiol & Immunol, Al Ain, U Arab Emirates. [Khang, Young-Ho] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Won, Sungho] Seoul Natl Univ, Grad Sch Publ Hlth, Seoul, South Korea. [Khera, Sahil] New York Med Coll, Valhalla, NY 10595 USA. [Khoja, Tawfik Ahmed Muthafer] Execut Board Hlth Ministers Council Cooperat Coun, Riyadh, Saudi Arabia. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kieling, Christian] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. Korea Hlth Ind Dev Inst, Cheongju, South Korea. [Kim, Daniel] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Kimokoti, Ruth W.] Simmons Coll, Boston, MA 02115 USA. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Koyanagi, Ai] Parc Sanitari St Joan Deu CIBERSAM, Res & Dev Unit, Barcelona, Spain. [Kravchenko, Michael; Varakin, Yuri Y.] Res Ctr Neurol, Moscow, Russia. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. 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EM cjlm@uw.edu RI Davletov, Kairat/S-1792-2016; Ribeiro, Antonio/C-2707-2009; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; Hankey, Graeme /H-4968-2014; Kravchenko, Michael/B-2596-2012; Patton, George/B-5246-2013; Malta, Deborah/H-7880-2012; Varakin, Yuriy/C-8634-2012; Brenner, Hermann/B-4627-2017; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Amini, Heresh/B-3076-2010; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Patten, Scott/B-4434-2011; Scott, James/D-5900-2012; Giussani, Giorgia/E-8057-2017; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; OI Ribeiro, Antonio/0000-0002-2740-0042; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Hankey, Graeme /0000-0002-6044-7328; Kravchenko, Michael/0000-0001-5187-5518; Patton, George/0000-0001-5039-8326; Malta, Deborah/0000-0002-8214-5734; Brenner, Hermann/0000-0002-6129-1572; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; Kemp, Andrew/0000-0003-1146-3791; Charlson, Fiona/0000-0003-2876-5040; das Neves, Jose/0000-0002-2317-2759; Degenhardt, Louisa/0000-0002-8513-2218; Awasthi, Ashish/0000-0002-9308-9782; Bisanzio, Donal/0000-0002-7832-2291; Jacobsen, Kathryn/0000-0002-4198-6246; Bernabe, Eduardo/0000-0002-1858-3713; Atique, Suleman/0000-0002-5149-0703; Piel, Frederic B./0000-0001-8131-7728; Altirkawi, Khalid/0000-0002-7331-4196; Hoek, Hans/0000-0001-6353-5465; NORMAN, ROSANA/0000-0002-9742-1957; Xu, Gelin/0000-0002-6194-0341; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Heydarpour, Pouria/0000-0001-5644-7555; Alkerwi, Ala'a/0000-0002-7448-3936; Ahmad Kiadaliri, Aliasghar/0000-0002-4254-9099; Kieling, Christian/0000-0001-7691-4149; Javanbakht, Mehdi/0000-0002-8661-8439; Gething, Peter/0000-0001-6759-5449; Husseini, Abdullatif/0000-0001-8767-5956; Taylor, Hugh/0000-0002-9437-784X; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Amini, Heresh/0000-0002-4825-1322; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Patten, Scott/0000-0001-9871-4041; Scott, James/0000-0002-0744-0688; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Miller, Ted/0000-0002-0958-2639 FU Bill AMP; Melinda Gates Foundation FX Bill & Melinda Gates Foundation. NR 139 TC 18 Z9 18 U1 79 U2 79 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 8 PY 2016 VL 388 IS 10053 BP 1659 EP 1724 PG 66 WC Medicine, General & Internal SC General & Internal Medicine GA DY7BU UT WOS:000385285000010 ER PT J AU Yosef, N Regev, A AF Yosef, Nir Regev, Aviv TI Writ large: Genomic dissection of the effect of cellular environment on immune response SO SCIENCE LA English DT Review ID REGULATORY T-CELLS; LINEAGE COMMITMENT; HEMATOPOIETIC STEM; GENE-EXPRESSION; RNA-SEQ; NETWORK; TRANSCRIPTION; MACROPHAGES; HOMEOSTASIS; PLASTICITY AB Cells of the immune system routinely respond to cues from their local environment and feed back to their surroundings through transient responses, choice of differentiation trajectories, plastic changes in cell state, and malleable adaptation to their tissue of residence. Genomic approaches have opened the way for comprehensive interrogation of such orchestrated responses. Focusing on genomic profiling of transcriptional and epigenetic cell states, we discuss how they are applied to investigate immune cells faced with various environmental cues. We highlight some of the emerging principles on the role of dense regulatory circuitry, epigenetic memory, cell type fluidity, and reuse of regulatory modules in achieving and maintaining appropriate responses to a changing environment. These provide a first step toward a systematic understanding of molecular circuits in complex tissues. C1 [Yosef, Nir] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA. [Yosef, Nir] MIT & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Cambridge, MA 02140 USA. [Regev, Aviv] MIT, Koch Inst Integrat Canc Biol, Dept Biol, Cambridge, MA 02140 USA. RP Yosef, N (reprint author), Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA.; Yosef, N (reprint author), Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA.; Yosef, N (reprint author), MIT & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.; Regev, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Regev, A (reprint author), MIT, Howard Hughes Med Inst, Cambridge, MA 02140 USA.; Regev, A (reprint author), MIT, Koch Inst Integrat Canc Biol, Dept Biol, Cambridge, MA 02140 USA. EM niryosef@berkeley.edu; aregev@broadinstitute.org FU Howard Hughes Medical Institute; NIH [U01MH105979, U01HG007910] FX A.R. was supported by the Howard Hughes Medical Institute. N.Y. was supported by NIH grants U01MH105979 and U01HG007910. A.R. is a member of the science advisory board of ThermoFisher Scientific and Syros Pharmaceuticals and a consultant for Driver Group. NR 59 TC 2 Z9 2 U1 9 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 7 PY 2016 VL 354 IS 6308 SI SI BP 64 EP 68 DI 10.1126/science.aaf5453 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EC0GT UT WOS:000387777900029 PM 27846493 ER PT J AU Mezza, T Shirakawa, J Martinez, R Hu, J Giaccari, A Kulkarni, RN AF Mezza, Teresa Shirakawa, Jun Martinez, Rachael Hu, Jiang Giaccari, Andrea Kulkarni, Rohit N. TI Nuclear Export of FoxO1 Is Associated with ERK Signaling in -Cells Lacking Insulin Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE beta cell (-cell); FOXO; insulin; insulin receptor; signal transduction ID PANCREATIC BETA-CELLS; GENE-EXPRESSION; PROTEIN-KINASE; GLUCOSE-HOMEOSTASIS; ADIPOSE-TISSUE; IN-VIVO; SECRETION; MICE; ACTIVATION; GROWTH AB The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate -cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches: 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either -cell specific insulin receptor knock-out (IRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ -cells and a significant decrease in % nuclear FoxO1+ -cells compared with corresponding vehicle-treated groups. In contrast, in IRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ -cells in either experiment; however, pERK+ -cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ cells was evident in response to glucose gavage or insulin infusion. Treatment of control and IRKO -cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ -cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in IRKO -cells. These data suggest insulin acts on -cells in an endocrine manner in the normal situation; and that in -cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling. C1 [Mezza, Teresa; Shirakawa, Jun; Martinez, Rachael; Hu, Jiang; Kulkarni, Rohit N.] Harvard Med Sch, Harvard Stem Cell Inst, Brigham & Womens Hosp, Islet Cell & Regenerat Biol,Joslin Diabet Ctr,Dep, Boston, MA 02215 USA. [Mezza, Teresa; Giaccari, Andrea] Univ Cattolica Sacro Cuore, Ctr Endocrine & Metab Dis, Policlin Gemelli, I-00168 Rome, Italy. RP Kulkarni, RN (reprint author), Joslin Diabet Ctr, Islet Cell & Regenerat Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM Rohit.Kulkarni@joslin.harvard.edu FU National Institutes of Health, Diabete Ricerca [R01 DK67536, R01 DK103215]; European Society for Clinical Nutrition and Metabolism; European Foundation for the study of Diabetes and Universita Cattolica del Sacro Cuore, Linea [D3.2 2015]; Japan Society for the Promotion of Science (JSPS) FX This work was supported by Grants R01 DK67536 (to R. N. K.) and R01 DK103215 (to R. N. K.) from the National Institutes of Health, Diabete Ricerca (to A. G. and T. M.), European Society for Clinical Nutrition and Metabolism (to T. M.), European Foundation for the study of Diabetes and Universita Cattolica del Sacro Cuore, Linea D3.2 2015 (to A. G.), and the Japan Society for the Promotion of Science (JSPS) (to J. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 30 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 7 PY 2016 VL 291 IS 41 BP 21485 EP 21495 DI 10.1074/jbc.M116.735738 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DZ6UX UT WOS:000385999200016 PM 27535223 ER PT J AU Glajch, KE Ferraiuolo, L Mueller, KA Stopford, MJ Prabhkar, V Gravanis, A Shaw, PJ Sadri-Vakili, G AF Glajch, Kelly E. Ferraiuolo, Laura Mueller, Kaly A. Stopford, Matthew J. Prabhkar, Varsha Gravanis, Achille Shaw, Pamela J. Sadri-Vakili, Ghazaleh TI MicroNeurotrophins Improve Survival in Motor Neuron-Astrocyte Co-Cultures but Do Not Improve Disease Phenotypes in a Mutant SOD1 Mouse Model of Amyotrophic Lateral Sclerosis SO PLOS ONE LA English DT Article ID CILIARY NEUROTROPHIC FACTOR; BLOOD-BRAIN-BARRIER; DEHYDROEPIANDROSTERONE DHEA PROTECTS; FACTOR GENE-THERAPY; SPINAL-CORD; FAMILIAL ALS; NEURODEGENERATIVE DISORDERS; INTRATHECAL BDNF; CONTROLLED-TRIAL; FACTOR PREVENTS AB Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by loss of motor neurons. ALS patients experience rapid deterioration in muscle function with an average lifespan of 3-5 years after diagnosis. Currently, the most effective therapeutic only extends lifespan by a few months, thus highlighting the need for new and improved therapies. Neurotrophic factors (NTFs) are important for neuronal development, maintenance, and survival. NTF treatment has previously shown efficacy in pre-clinical ALS models. However, clinical trials using NTFs produced no major improvements in ALS patients, due in part to the limited blood brain barrier (BBB) penetration. In this study we assessed the potential neuroprotective effects of a novel class of compounds known as MicroNeurotrophins (MNTs). MNTs are derivatives of Dehydroepiandrosterone (DHEA), an endogenous neurosteroid that can cross the BBB and bind to tyrosine kinase receptors mimicking the pro-survival effects of NTFs. Here we sought to determine whether MNTs were neuroprotective in two different models of ALS. Our results demonstrate that BNN27 (10 mu M) attenuated loss of motor neurons co-cultured with astrocytes derived from human ALS patients with SOD1 mutations via the reduction of oxidative stress. Additionally, in the G93A SOD1 mouse, BNN27 (10 mg/kg) treatment attenuated motor behavioral impairment in the paw grip endurance and rotarod tasks at postnatal day 95 in female but not male mice. In contrast, BNN27 (10 mg/kg and 50 mg/kg) treatment did not alter any other behavioral outcome or neuropathological marker in male or female mice. Lastly, BNN27 was not detected in post-mortem brain or spinal cord tissue of treated mice due to the rapid metabolism of BNN27 by mouse hepatocytes relative to human hepatocytes. Together, these findings demonstrate that BNN27 treatment failed to yield significant neuroprotective effects in the G93A SOD1 model likely due to its rapid rate of metabolism in mice. C1 [Glajch, Kelly E.; Mueller, Kaly A.; Prabhkar, Varsha; Sadri-Vakili, Ghazaleh] Massachusetts Gen Hosp, MIND, NeuroEpigenet Lab, Boston, MA 02129 USA. [Ferraiuolo, Laura; Stopford, Matthew J.; Shaw, Pamela J.] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, 385A Glossop Rd, Sheffield S10 2HQ, S Yorkshire, England. [Gravanis, Achille] Univ Crete, Sch Med, Inst Mol Biol & Biotechnol FORTH, Dept Pharmacol, Iraklion 71003, Greece. RP Sadri-Vakili, G (reprint author), Massachusetts Gen Hosp, MIND, NeuroEpigenet Lab, Boston, MA 02129 USA. EM gsadrivakili@mgh.harvard.edu RI Ferraiuolo, Laura/E-5834-2010 OI Ferraiuolo, Laura/0000-0001-9118-5714 FU ALS World Wide FX This study was supported by ALS World Wide. NR 90 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 7 PY 2016 VL 11 IS 10 AR e0164103 DI 10.1371/journal.pone.0164103 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UW UT WOS:000385698100023 PM 27716798 ER PT J AU Yuan, H Liu, HL Liu, ZS Owzar, K Han, YH Su, L Wei, YY Hung, RJ McLaughlin, J Brhane, Y Brennan, P Bickeboeller, H Rosenberger, A Houlston, RS Caporaso, N Landi, MT Heinrich, J Risch, A Christiani, DC Gumus, ZH Klein, RJ Amos, CI Wei, QY AF Yuan, Hua Liu, Hongliang Liu, Zhensheng Owzar, Kouros Han, Younghun Su, Li Wei, Yongyue Hung, Rayjean J. McLaughlin, John Brhane, Yonathan Brennan, Paul Bickeboeller, Heike Rosenberger, Albert Houlston, Richard S. Caporaso, Neil Landi, Maria Teresa Heinrich, Joachim Risch, Angela Christiani, David C. Gumus, Zeynep H. Klein, Robert J. Amos, Christopher I. Wei, Qingyi TI A Novel Genetic Variant in Long Non-coding RNA Gene NEXN-AS1 is Associated with Risk of Lung Cancer SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; SUSCEPTIBILITY LOCUS; POOLED ANALYSIS; DISEASE; EXPRESSION; 5P15.33; ARCHITECTURE; METAANALYSIS; REPLICATION AB Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 x 10(-7)) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 x 10(-9)). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility. C1 [Yuan, Hua] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing, Jiangsu, Peoples R China. [Yuan, Hua] Nanjing Med Univ, Affiliated Hosp Stomatol, Dept Oral & Maxillofacial Surg, Nanjing, Jiangsu, Peoples R China. [Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Owzar, Kouros; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Community & Family Med, Hanover, NC USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Su, Li; Wei, Yongyue; Christiani, David C.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Hung, Rayjean J.; Brhane, Yonathan] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Bickeboeller, Heike; Rosenberger, Albert] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany. [Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London, England. [Caporaso, Neil; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Heinrich, Joachim] Inst Epidemiol 1, German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Neuherberg, Germany. [Heinrich, Joachim] Univ Munich, Univ Hosp Munich, Inst & Outpatient Clin Occupat Social & Environm, Munich, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] DKFZ German Canc Res Ctr, Dept Epigenom & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, TLRC H, Heidelberg, Germany. [Gumus, Zeynep H.; Klein, Robert J.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA.; Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. EM qingyi.wei@duke.edu RI Hung, Rayjean/A-7439-2013; Risch, Angela/H-2669-2013 OI Risch, Angela/0000-0002-8026-5505 FU Transdisciplinary Research in Cancer of the Lung (TRICL) Study on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19-CA148127]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; Cancer Care Ontario Chair Award; Cancer Research UK [C1298/A8780, C1298/A8362]; NCRN; HEAL; Sanofi-Aventis; NIH [5R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, U19CA148127, P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753, HHSN268200782096C]; Roy Castle Lung Cancer Foundation, UK; Deutsche Krebshilfe [70-2919]; Helmholtz-DAAD fellowship [A/07/97379]; GSF - German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; National Genome Research Network (NGFN); DFG [BI576/2-1, BI 576/2-2]; Helmholtzgemeinschaft (HGF); Federal office for Radiation Protection [BfS: STSch4454]; Institut National du Cancer, France; European Community [LSHG-CT-2005-512113]; Norwegian Cancer Association; Functional Genomics Programme of Research Council of Norway; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; US National Cancer Institute, NIH [R01 CA111703, UO1 CA63673]; Fred Hutchinson Cancer Research Center; US National Cancer Institute [R01 CA092039]; FP7 grant [REGPOT245536]; Estonian Government [SF0180142s08]; EU RDF in the frame of Centre of Excellence in Genomics; Estoinian Research Infrastructure's Roadmap; University of Tartu [SP1GVARENG]; IARC; Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; NCI [NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]; CPRIT grant [RP100443]; NIH (National Cancer Institute) [CA092824, CA090578, CA074386]; GENADDICT [LSHMCT-2004-005166]; National Institutes of Health [R01-DA017932]; Duke Cancer Institute as part of the P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute; Duke Cancer Institute, Duke University Medical Center; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University; LUNGevity Foundation; [U01 HG007033] FX TRICL: This work was supported by the Transdisciplinary Research in Cancer of the Lung (TRICL) Study, U19-CA148127 on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. The Toronto study was supported by Canadian Cancer Society Research Institute(020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to RH The ICR study was supported by Cancer Research UK (C1298/A8780 andC1298/A8362-Bobby Moore Fund for Cancer Research UK) and NCRN, HEAL and Sanofi-Aventis. Additional funding was obtained from NIH grants (5R01CA055769, 5R01CA127219, 5R01CA133996, and 5R01CA121197). The Liverpool Lung Project (LLP) was supported by The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the Wellcome Trust Case Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The work was additionally supported by a Helmholtz-DAAD fellowship (A/07/97379 to MNT) and by the NIH (U19CA148127). The KORA Surveys were financed by the GSF, which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Lung Cancer in the Young study (LUCY) was funded in part by the National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Muenchen. Support for the Central Europe, HUNT2/Tromso and CARET genome-wide studies was provided by Institut National du Cancer, France. Support for the HUNT2/Tromso genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT-2005-512113), the Norwegian Cancer Association and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Support for the CARET genome-wide study was also provided by grants from the US National Cancer Institute, NIH (R01 CA111703 and UO1 CA63673), and by funds from the Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Cancer Institute (R01 CA092039). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap and by University of Tartu (SP1GVARENG). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for MNT). The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II) and part of PLCO were supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004) from the NCI.; PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota(NO1-CN-25513), Washington University(NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 andRO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753) and CPRIT grant (RP100443). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN268200782096C). The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, and CA074386. deCODE: The project was funded in part by GENADDICT: LSHMCT-2004-005166), the National Institutes of Health (R01-DA017932). As Duke Cancer Institute members, Q.W. and K.O. acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: NIH CA014236). Q.W. was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. Hua Yuan was sponsored by Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University. We also acknowledge support from U01 HG007033 (to R.J.K.) and LUNGevity Foundation (to Z.H.G.). NR 38 TC 1 Z9 1 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 7 PY 2016 VL 6 AR 34234 DI 10.1038/srep34234 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY1CS UT WOS:000384833100001 PM 27713484 ER PT J AU Silberstein, L Goncalves, KA Kharchenko, PV Turcotte, R Kfoury, Y Mercier, F Baryawno, N Severe, N Bachand, J Spencer, JA Papazian, A Lee, D Chitteti, BR Srour, EF Hoggatt, J Tate, T Lo Celso, C Ono, N Nutt, S Heino, J Sipila, K Shioda, T Osawa, M Lin, CP Hu, GF Scadden, DT AF Silberstein, Lev Goncalves, Kevin A. Kharchenko, Peter V. Turcotte, Raphael Kfoury, Youmna Mercier, Francois Baryawno, Ninib Severe, Nicolas Bachand, Jacqueline Spencer, Joel A. Papazian, Ani Lee, Dongjun Chitteti, Brahmananda Reddy Srour, Edward F. Hoggatt, Jonathan Tate, Tiffany Lo Celso, Cristina Ono, Noriaki Nutt, Stephen Heino, Jyrki Sipila, Kalle Shioda, Toshihiro Osawa, Masatake Lin, Charles P. Hu, Guo-fu Scadden, David T. TI Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators SO Cell Stem Cell LA English DT Article ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW NICHE; IN-SITU; PROGENITORS; QUIESCENCE; IDENTIFICATION; REGENERATION; MAINTENANCE; ANGIOGENIN; EXPRESSION AB Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function. C1 [Silberstein, Lev; Kfoury, Youmna; Mercier, Francois; Baryawno, Ninib; Severe, Nicolas; Bachand, Jacqueline; Spencer, Joel A.; Papazian, Ani; Lee, Dongjun; Hoggatt, Jonathan; Tate, Tiffany; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02445 USA. [Silberstein, Lev; Kharchenko, Peter V.; Turcotte, Raphael; Kfoury, Youmna; Mercier, Francois; Baryawno, Ninib; Severe, Nicolas; Bachand, Jacqueline; Spencer, Joel A.; Papazian, Ani; Lee, Dongjun; Hoggatt, Jonathan; Tate, Tiffany; Lin, Charles P.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Silberstein, Lev; Kfoury, Youmna; Mercier, Francois; Baryawno, Ninib; Severe, Nicolas; Bachand, Jacqueline; Spencer, Joel A.; Papazian, Ani; Lee, Dongjun; Hoggatt, Jonathan; Tate, Tiffany; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Goncalves, Kevin A.; Hu, Guo-fu] Tufts Univ, Sackler Sch Grad Biomed Sci, Grad Program Cellular & Mol Physiol, Boston, MA 02111 USA. [Goncalves, Kevin A.; Hu, Guo-fu] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. [Kharchenko, Peter V.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Turcotte, Raphael; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02445 USA. [Chitteti, Brahmananda Reddy; Srour, Edward F.] Indiana Univ, Indianapolis, IN 46202 USA. [Lo Celso, Cristina] Imperial Coll London, London SW7 2AZ, England. [Ono, Noriaki] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Nutt, Stephen] Walter & Eliza Hall Res Inst, Parkville, Vic 3052, Australia. [Heino, Jyrki; Sipila, Kalle] Univ Turku, Turku 20014, Finland. [Shioda, Toshihiro] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Osawa, Masatake] Gifu Univ, Gifu 5011193, Japan. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02445 USA.; Scadden, DT (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Scadden, DT (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Hu, GF (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Grad Program Cellular & Mol Physiol, Boston, MA 02111 USA.; Hu, GF (reprint author), Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. EM guo-fu.hu@tufts.edu; david_scadden@harvard.edu OI lee, dongjun/0000-0001-6828-401X FU Leukemia and Lymphoma Research UK; Leukemia and Lymphoma Society; T32 training fellowship; NIH [K25AG037596, RO1DK107784, RO1HL096372, R01CA105241, R01NS065237, F31HL128127]; Sackler Dean's Fellow award; Sackler Families Collaborative Cancer Biology award; National Health and Medical Research Council of Australia; Victorian State Government; Australian Government NHMRC IRIIS FX We are grateful to David Clapham and Long-Jun Wu for technical advice and to Jayaraj Rajagopal, Andrew Lane, and Ya-Chieh Hsu for critical reading of the manuscript. We thank Charles Dinarello for technical advice; Laura Prickett, Kathryn Folz-Donahue, and Meredith Weglarz for cell sorting; and Edward Fox at the Dana Farber Cancer Institute Microarray core for cDNA sequencing. D.T.S. is a shareholder in Fate Therapeutics and a consultant for Fate Therapeutics, Hospira, GSK, and Bone Therapeutics. L.S., P.V.K., G.H., K.A.G., and D.T.S. filed patent applications related to the findings described in the manuscript. The work was supported by fellowship awards from Leukemia and Lymphoma Research UK and Leukemia and Lymphoma Society (to L.S.); a T32 training fellowship (to J.H.); NIH grants K25AG037596 (to P.V.K.), RO1DK107784 and RO1HL096372 (to D.T.S.), R01CA105241 and R01NS065237 (to G.H.), and F31HL128127 (to K.A.G.); a Sackler Dean's Fellow award (to K.A.G.); a Sackler Families Collaborative Cancer Biology award (to K.A.G. and G.H.); a National Health and Medical Research Council of Australia fellowship (to S.N.); the Victorian State Government Operational Infrastructure Support (to S.N.); and the Australian Government NHMRC IRIIS (to S.N.). NR 43 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 6 PY 2016 VL 19 IS 4 BP 530 EP 543 DI 10.1016/j.stem.2016.07.004 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3FS UT WOS:000389473800015 PM 27524439 ER PT J AU Barrow, JJ Balsa, E Verdeguer, F Tavares, CDJ Soustek, MS Hollingsworth, LR Jedrychowski, M Vogel, R Paulo, JA Smeitink, J Gygi, SP Doench, J Root, DE Puigserver, P AF Barrow, Joeva J. Balsa, Eduardo Verdeguer, Francisco Tavares, Clint D. J. Soustek, Meghan S. Hollingsworth, Louis R. Jedrychowski, Mark Vogel, Rutger Paulo, Joao A. Smeitink, Jan Gygi, Steve P. Doench, John Root, David E. Puigserver, Pere TI Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations SO MOLECULAR CELL LA English DT Article ID HEREDITARY OPTIC NEUROPATHY; OXIDATIVE-PHOSPHORYLATION; BET BROMODOMAINS; CELLS; DISORDERS; CHROMATIN; TARGET; BRD4; DEHYDROGENASE; COACTIVATOR AB Mitochondrial diseases comprise a heterogeneous group of genetically inherited disorders that cause failures in energetic and metabolic function. Boosting residual oxidative phosphorylation (OXPHOS) activity can partially correct these failures. Herein, using a high-throughput chemical screen, we identified the bromodomain inhibitor I-BET 525762A as one of the top hits that increases COX5a protein levels in complex I (CI) mutant cybrid cells. In parallel, bromo-domain-containing protein 4 (BRD4), a target of I-BET 525762A, was identified using a genome-wide CRISPR screen to search for genes whose loss of function rescues death of CI-impaired cybrids grown under conditions requiring OXPHOS activity for survival. We show that I-BET525762A or loss of BRD4 remodeled the mitochondrial proteome to increase the levels and activity of OXPHOS protein complexes, leading to rescue of the bioenergetic defects and cell death caused by mutations or chemical inhibition of CI. These studies show that BRD4 inhibition may have therapeutic implications for the treatment of mitochondrial diseases. C1 [Barrow, Joeva J.; Balsa, Eduardo; Verdeguer, Francisco; Tavares, Clint D. J.; Soustek, Meghan S.; Hollingsworth, Louis R.; Vogel, Rutger; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Barrow, Joeva J.; Balsa, Eduardo; Verdeguer, Francisco; Tavares, Clint D. J.; Soustek, Meghan S.; Jedrychowski, Mark; Vogel, Rutger; Paulo, Joao A.; Gygi, Steve P.; Puigserver, Pere] Harvard Med Sch, Dept Cell Biol, Boston, MA 02215 USA. [Doench, John; Root, David E.; Puigserver, Pere] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Vogel, Rutger; Smeitink, Jan] Radboud Univ Nijmegen, Med Ctr Nijmegen, Radboud Ctr Mitochondrial Med, NL-6500 HB Nijmegen, Netherlands. RP Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Puigserver, P (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02215 USA.; Puigserver, P (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM pere_puigserver@dfci.harvard.edu OI Doench, John/0000-0002-3707-9889 FU NIH; NIDDK [RO1DK081418, R24DK080261]; Alfonso Martin Escudero fellowship; EMBO; [R01DK081418-06S1] FX We thank all the members of the Puigserver lab and Edward Chouchani for discussions regarding this project. MELAS, MERRF, COX10 and Reiske KO mouse fibroblasts, and ND6-mutated LHON cybrids were a generous gift from Carlos Moraes at the University of Miami. ACAD9-mutated patient-derived fibroblasts were obtained from Michio Hirano at Columbia University. We thank the Institute of Chemistry and Cell Biology at Harvard Medical School and the Broad Institute at M.I.T. for their training, advice, and facilities. These studies were supported in part by NIH and NIDDK grants RO1DK081418 (P.P.) and R24DK080261 (P.P.). J.J.B. was supported in part by a diversity supplement award under R01DK081418-06S1 parental grant (P.P.). E.B.M. was supported in part by an Alfonso Martin Escudero fellowship and an EMBO postdoctoral fellowship. J.S. is the founding CEO of Khondrion. NR 44 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 6 PY 2016 VL 64 IS 1 BP 163 EP 175 DI 10.1016/j.molcel.2016.08.023 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RO UT WOS:000389514900017 PM 27666594 ER PT J AU Azimi, E Reddy, VB Shade, KTC Anthony, RM Talbot, S Pereira, PJS Lerner, EA AF Azimi, Ehsan Reddy, Vemuri B. Shade, Kai-Ting C. Anthony, Robert M. Talbot, Sebastien Pereira, Paula Juliana Seadi Lerner, Ethan A. TI Dual action of neurokinin-1 antagonists on Mas-related GPCRs SO JCI INSIGHT LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SUBSTANCE-P ANTAGONISTS; CHRONIC URTICARIA; TACHYKININ RECEPTORS; SCRATCHING BEHAVIOR; GENE X2; ITCH; CELLS; MICE; PATHOPHYSIOLOGY AB The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists. C1 [Azimi, Ehsan; Reddy, Vemuri B.; Pereira, Paula Juliana Seadi; Lerner, Ethan A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Shade, Kai-Ting C.; Anthony, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. [Talbot, Sebastien] Childrens Hosp Boston, FM Kirby Neurobiol Ctr, Boston, MA USA. [Pereira, Paula Juliana Seadi] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Biol Celular & Mol, Porto Alegre, RS, Brazil. RP Lerner, EA (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, 3rd Flr,149 13th St, Charlestown, MA 02129 USA. EM elerner@magh.harvard.edu FU NIAID NIH HHS [U19 AI110495]; NIAMS NIH HHS [R21 AR067399, DP2 AR068272, R01 AR057744] NR 39 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD OCT 6 PY 2016 VL 1 IS 16 AR e89362 DI 10.1172/jci.insight.89362 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1PC UT WOS:000387124700009 PM 27734033 ER PT J AU Doan, RN Bae, BI Cubelos, B Chang, C Hossain, AA Al-Saad, S Mukaddes, NM Oner, O Al-Saffar, M Balkhy, S Gascon, GG Nieto, M Walsh, CA AF Doan, Ryan N. Bae, Byoung-Il Cubelos, Beatriz Chang, Cindy Hossain, Amer A. Al-Saad, Samira Mukaddes, Nahit M. Oner, Ozgur Al-Saffar, Muna Balkhy, Soher Gascon, Generoso G. Nieto, Marta Walsh, Christopher A. CA Homozygosity Mapping Consortium TI Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior SO CELL LA English DT Article ID AUTISM SPECTRUM DISORDERS; GOLABI-BEHMEL-SYNDROME; HIGH-RESOLUTION MAP; HUMAN GENOME; GENETIC-VARIANTS; CEREBRAL-CORTEX; MOUSE-BRAIN; HUMAN-CELLS; EVOLUTION; NEURONS AB Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome'' sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. C1 [Doan, Ryan N.; Bae, Byoung-Il; Chang, Cindy; Hossain, Amer A.; Al-Saffar, Muna; Walsh, Christopher A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA. [Doan, Ryan N.; Bae, Byoung-Il; Chang, Cindy; Hossain, Amer A.; Al-Saffar, Muna; Walsh, Christopher A.] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Cubelos, Beatriz] Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severo Ochoa, Dept Mol Biol, Nicolas Cabrera 1, E-28049 Madrid, Spain. [Cubelos, Beatriz; Nieto, Marta] CSIC, CNB, Dept Mol & Cellular Biol, Darwin 3,Campus Cantoblanco, Madrid 28049, Spain. [Al-Saad, Samira] Kuwait Ctr Autism, Kuwait 73455, Kuwait. [Mukaddes, Nahit M.] Istanbul Inst Child & Adolescent Psychiat, TR-34365 Istanbul, Turkey. [Oner, Ozgur] Bahcesehir Univ, Sch Med, Dept Child & Adolescent Psychiat, TR-34353 Istanbul, Turkey. [Al-Saffar, Muna] United Arab Emirates Univ, Coll Med & Hlth Sci, Dept Pediat, POB 17666, Al Ain, U Arab Emirates. [Balkhy, Soher] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Jeddah 21499, Saudi Arabia. [Gascon, Generoso G.] Massachusetts Gen Hosp, Dept Neurol Pediat Neurol, Boston, MA 02114 USA. [Walsh, Christopher A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Walsh, Christopher A.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Walsh, Christopher A.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Bae, Byoung-Il] Yale Univ, Sch Med, Dept Neurosurg, 333 Cedar St, New Haven, CT 06510 USA. RP Walsh, CA (reprint author), Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA.; Walsh, CA (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA.; Walsh, CA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Walsh, CA (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA.; Walsh, CA (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. EM christopher.walsh@childrens.harvard.edu FU NIH T32 fellowship from Fundamental Neurobiology Training Grant [5 T32 NS007484-14]; Nancy Lurie Marks Postdoctoral Fellowship; NIH Exploratory/Developmental Research Grant [NINDS 1 R21 NS091865-01]; Paul G. Allen Family Foundation; NIMH [RC2MH089952, RO1MH083565]; NIH [NCRR 1S10RR028832-01]; MICINN [SAF2014-52119-R]; National Institute of Mental Health [1U24MH081810] FX We thank J. Partlow and B. Barry for human subject enrollment; N. Hatem and A. Lam for sample preparation and cloning; D. Gonzalez for immunofluorescence; K. Girskis for the primary neurosphere culturing; and members of the Walsh lab for comments. R.N.D. was supported by an NIH T32 fellowship from the Fundamental Neurobiology Training Grant (5 T32 NS007484-14) and the Nancy Lurie Marks Postdoctoral Fellowship. B.-I. B. was supported by NIH Exploratory/Developmental Research Grant (NINDS 1 R21 NS091865-01). C.A.W. was supported by the Paul G. Allen Family Foundation and the NIMH (RC2MH089952 and RO1MH083565). Annotation was performed using Harvard Medical School's Orchestra computing cluster, supported by NIH grant NCRR 1S10RR028832-01. C.A.W. is an Investigator of the Howard Hughes Medical Institute. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. M.N. work is funded by grant MICINN SAF2014-52119-R. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). NR 76 TC 3 Z9 3 U1 10 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 6 PY 2016 VL 167 IS 2 BP 341 EP + DI 10.1016/j.cell.2016.08.071 PG 26 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HM UT WOS:000386343100012 PM 27667684 ER PT J AU Mills, EL Kelly, B Logan, A Costa, ASH Varma, M Bryant, CE Tourlomousis, P Dabritz, JHM Gottlieb, E Latorre, I Corr, SC McManus, G Ryan, D Jacobs, HT Szibor, M Xavier, RJ Braun, T Frezza, C Murphy, MP O'Neill, LA AF Mills, Evanna L. Kelly, Beth Logan, Angela Costa, Ana S. H. Varma, Mukund Bryant, Clare E. Tourlomousis, Panagiotis Dabritz, J. Henry M. Gottlieb, Eyal Latorre, Isabel Corr, Sinead C. McManus, Gavin Ryan, Dylan Jacobs, Howard T. Szibor, Marten Xavier, Ramnik J. Braun, Thomas Frezza, Christian Murphy, Michael P. O'Neill, Luke A. TI Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages SO CELL LA English DT Article ID INTERLEUKIN-10 IL-10; ELECTRON-TRANSPORT; REPERFUSION INJURY; DIMETHYL FUMARATE; RESPIRATORY-CHAIN; CELL-ACTIVATION; DENDRITIC CELL; IL-1-BETA; HYPOXIA; ALPHA AB Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state. C1 [Mills, Evanna L.; Kelly, Beth; McManus, Gavin; Ryan, Dylan; O'Neill, Luke A.] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland. [Logan, Angela; Murphy, Michael P.] MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. [Costa, Ana S. H.; Frezza, Christian] Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England. [Varma, Mukund; Latorre, Isabel; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Varma, Mukund; Latorre, Isabel; Xavier, Ramnik J.] Harvard Med Sch, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Gastrointestinal Unit, Boston, MA 02114 USA. [Bryant, Clare E.; Tourlomousis, Panagiotis] Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge CB23 8AQ, England. [Dabritz, J. Henry M.; Gottlieb, Eyal] Beatson Inst, Canc Res UK, Canc Metab Res Unit, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland. [Corr, Sinead C.] Trinity Coll Dublin, Sch Genet & Microbiol, Moyne Inst Preventat Med, Dept Microbiol, Dublin 2, Ireland. [Jacobs, Howard T.; Szibor, Marten] Univ Helsinki, Inst Biotechnol, POB 56, FIN-00014 Helsinki, Finland. [Jacobs, Howard T.; Szibor, Marten] Univ Tampere, BioMediTech, Tampere 33014, Finland. [Jacobs, Howard T.; Szibor, Marten] Univ Tampere, Tampere Univ Hosp, Tampere 33014, Finland. [Szibor, Marten; Braun, Thomas] Max Planck Inst Heart & Lung Res, Ludwigstr 43, D-61231 Bad Nauheim, Germany. [Mills, Evanna L.] GlaxoSmithKline, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England. RP O'Neill, LA (reprint author), Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland.; Murphy, MP (reprint author), MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. EM mpm@mrc-mbu.cam.ac.uk; laoneill@tcd.ie RI Costa, Ana /H-2852-2012; Gottlieb, Eyal/G-6450-2010; OI Costa, Ana /0000-0001-8932-6370; Gottlieb, Eyal/0000-0002-9770-0956; Latorre, Isabel/0000-0003-0638-1783 FU UK MRC [MC_U105663142]; Wellcome Trust [110159/Z/15/Z]; Science Foundation Ireland [12/IA/1531]; Wellcome Trust (oneill-wellcome-trust-metabolic); Irish Research Council; Academy of Finland (CoE grant) [272376]; European Research Council [232738]; Tampere University Hospital Medical Research Fund; Sigrid Juselius Foundation; MRC Core Fund FX This work was supported by funds and grants from the UK MRC MC_U105663142 (to M.P.M.), The Wellcome Trust (grant number 110159/Z/15/Z to M.P.M.), and Science Foundation Ireland (grant number [12/IA/1531]), the European Research Council, The Wellcome Trust (oneill-wellcome-trust-metabolic), and the Irish Research Council (to L.A.O.). Funding was provided by Academy of Finland (CoE grant 272376 to H.T.J.), the European Research Council (advanced grant 232738 to H.T.J.), the Tampere University Hospital Medical Research Fund, and the Sigrid Juselius Foundation (to H.T.J.). C.F. and A.S.H.C. were supported by an MRC Core Fund to the MRC Cancer Unit. NR 41 TC 14 Z9 14 U1 36 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 6 PY 2016 VL 167 IS 2 BP 457 EP + DI 10.1016/j.cell.2016.08.064 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EA1HM UT WOS:000386343100021 PM 27667687 ER PT J AU Akeju, O Kim, SE Vazquez, R Rhee, J Pavone, KJ Hobbs, LE Purdon, PL Brown, EN AF Akeju, Oluwaseun Kim, Seong-Eun Vazquez, Rafael Rhee, James Pavone, Kara J. Hobbs, Lauren E. Purdon, Patrick L. Brown, Emery N. TI Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations SO PLOS ONE LA English DT Article ID MECHANICALLY VENTILATED PATIENTS; CRITICALLY-ILL PATIENTS; HYPNOTIC RESPONSE; AGONIST DEXMEDETOMIDINE; POSTOPERATIVE DELIRIUM; SYSTEMIC INFLAMMATION; GENERAL-ANESTHESIA; COHERENCE ANALYSIS; ELDERLY-PATIENTS; LOCUS-COERULEUS AB An improved understanding of the neural correlates of altered arousal states is fundamental for precise brain state targeting in clinical settings. More specifically, electroencephalogram recordings are now increasingly being used to relate drug-specific oscillatory dynamics to clinically desired altered arousal states. Dexmedetomidine is an anesthetic adjunct typically administered in operating rooms and intensive care units to produce and maintain a sedative brain state. However, a high-density electroencephalogram characterization of the neural correlates of the dexmedetomidine-induced altered arousal state has not been previously accomplished. Therefore, we administered dexmedetomidine (1mcg/kg bolus over 10 minutes, followed by 0.7mcg/kg/hr over 50 minutes) and recorded high-density electroencephalogram signals in healthy volunteers, 18-36 years old (n = 8). We analyzed the data with multitaper spectral and global coherence methods. We found that dexmedetomidine was associated with increased slow-delta oscillations across the entire scalp, increased theta oscillations in occipital regions, increased spindle oscillations in frontal regions, and decreased beta oscillations across the entire scalp. The theta and spindle oscillations were globally coherent. During recovery from this state, these electroencephalogram signatures reverted towards baseline signatures. We report that dexmedetomidineinduced electroencephalogram signatures more closely approximate the human sleep onset process than previously appreciated. We suggest that these signatures may be targeted by real time visualization of the electroencephalogram or spectrogram in clinical settings. Additionally, these signatures may aid the development of control systems for principled neurophysiological based brain-state targeting. C1 [Akeju, Oluwaseun; Vazquez, Rafael; Rhee, James; Pavone, Kara J.; Hobbs, Lauren E.; Purdon, Patrick L.; Brown, Emery N.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Kim, Seong-Eun; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. RP Akeju, O (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. EM oluwaseun.akeju@mgh.harvard.edu OI Vazquez-Garcia, Rafael/0000-0001-8876-474X FU National Institutes of Health (Bethesda, MD) [R01 AG053582, TR01 GM104948]; Foundation of Anesthesia Education and Research, Rochester, Minnesota; Massachusetts General Hospital Faculty Development Award, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX This work was supported by the National Institutes of Health (Bethesda, MD) R01 AG053582 (to OA) and TR01 GM104948 (to ENB); Foundation of Anesthesia Education and Research, Rochester, Minnesota (to OA); Massachusetts General Hospital Faculty Development Award, Boston, MA (to OA); and by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 58 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0163431 DI 10.1371/journal.pone.0163431 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600025 PM 27711165 ER PT J AU Liu, S Cadaneanu, RM Zhang, BH Huo, LH Lai, K Li, XM Galet, C Grogan, TR Elashoff, D Freedland, SJ Rettig, M Aronson, WJ Knudsen, BS Lewis, MS Garraway, IP AF Liu, Sandy Cadaneanu, Radu M. Zhang, Baohui Huo, Lihong Lai, Kevin Li, Xinmin Galet, Colette Grogan, Tristan R. Elashoff, David Freedland, Stephen J. Rettig, Matthew Aronson, William J. Knudsen, Beatrice S. Lewis, Michael S. Garraway, Isla P. TI Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone SO PLOS ONE LA English DT Article ID EPITHELIAL-CELLS; GENE-EXPRESSION; BREAST-CANCER; BASAL-CELLS; IN-VIVO; IDENTIFICATION; SUBPOPULATION; REGENERATION; POPULATIONS; PROGRESSION AB Background Benign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation. To identify the TIC niche in human prostate tissue, differential keratin (KRT) expression was evaluated. Results Gene expression data generated from Affymetrix Gene Chip human U133 Plus 2.0 array of sorted adult and fetal epithelial cells revealed KRT13 to be significantly enriched in FC and TIC compared to basal cells (BC) and luminal cells (LC) (p<0.001). Enriched KRT13 expression was confirmed by RT-PCR and cytospin immunostaining. Immunohistochemical analysis of KRT13 expression revealed rare KRT13(+) epithelia throughout prostatic ducts/acini in adult tissue specimens and differentiated tubules in 24-week recombinant grafts, In contrast, abundant KRT13 expression was observed in developing ducts/acini in fetal prostate and cord-like structures composing 8-week recombinant grafts. Immunostaining of a prostate tissue microarray revealed KRT13(+) tumor foci in approximately 9% of cases, and this subset displayed significantly shorter time to recurrence (p = 0.031), metastases (p = 0.032), and decreased overall survival (p = 0.004). Diagnostic prostate needle biopsies (PNBX) from untreated patients with concurrent bone metastases (clinical stage M1) displayed KRT13(+) tumor foci, as did bone metastatic foci. Conclusions The expression profile of KRT13 in benign fetal and adult prostate tissue and in recombinant grafts, as well as the frequency of KRT13 expression in primary and metastatic prostate cancer indicates that it may be a marker of a stem/progenitor-like cell state that is co-opted in aggressive tumor cells. KRT13 is enriched in benign stem-like cells that display androgen-resistance, apoptosis-resistance, and branching morphogenesis properties. Collectively our data demonstrate that KRT13 expression is associated with poor prognosis at multiple stages of disease progression and may represent an important biomarker of adverse outcome in patients with prostate cancer. C1 [Liu, Sandy] Univ Calif Los Angeles, David Geffen Sch Med, Dept Hematol Oncol, Los Angeles, CA 90095 USA. [Cadaneanu, Radu M.; Zhang, Baohui; Huo, Lihong; Lai, Kevin; Galet, Colette; Rettig, Matthew; Aronson, William J.; Garraway, Isla P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Li, Xinmin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Grogan, Tristan R.; Elashoff, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Stat Core, Los Angeles, CA 90095 USA. [Freedland, Stephen J.] Durham VA Med Ctr, Dept Surg, Urol Sect, Durham, NC USA. [Rettig, Matthew; Aronson, William J.; Garraway, Isla P.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Aronson, William J.; Garraway, Isla P.] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Surg, Urol Sect, Los Angeles, CA 90073 USA. [Knudsen, Beatrice S.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Lewis, Michael S.] Greater Los Angeles Vet Affairs Hlth Syst, Dept Pathol, Los Angeles, CA USA. RP Garraway, IP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA.; Garraway, IP (reprint author), Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA.; Garraway, IP (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Dept Surg, Urol Sect, Los Angeles, CA 90073 USA. EM igarraway@mednet.ucla.edu FU Jean Perkins Foundation; Prostate Cancer Foundation (PCF) Creativity Award; Movember/PCF GAP1 Unique TMAs Project; Stephen Spielberg Team Science Award; DOD [PC131996, PC130244, PC030868]; NIH/NCI [P01 CA098912-09, U54 CA143931, P50CA09231]; NIH [R01CA131255, P50CA092131]; NIH/NCATS UCLA CTSI [UL1TR000124]; National Institutes of Health [CA-16042, AI-28697]; JCCC; UCLA AIDS Institute; David Geffen School of Medicine at UCLA FX This work was supported by Jean Perkins Foundation (IG); Prostate Cancer Foundation (PCF) Creativity Award (BK); Movember/PCF GAP1 Unique TMAs Project (IG, ML, and BK); Stephen Spielberg Team Science Award (BK); DOD PC131996 (IG, ML, and BK); DOD PC130244 (IG and ML); NIH/NCI P01 CA098912-09 (IG and BK); NIH/NCI U54 CA143931 (IG); NIH R01CA131255 and P50CA092131 (BK); NIH/NCATS UCLA CTSI Grant UL1TR000124 (TG and DE); DOD PC030868 (MR); NIH/NCI P50CA09231 (WA and MR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Flow cytometry/FACS was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and is supported by National Institutes of Health awards CA-16042 and AI-28697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. Procurement of fetal tissues is supported by the Center for AIDS Research at UCLA, under the leadership of Dr. Dong Sun An. NR 35 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 6 PY 2016 VL 11 IS 10 AR e0163232 DI 10.1371/journal.pone.0163232 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UR UT WOS:000385697600019 PM 27711225 ER PT J AU Harel, T Yoon, WH Garone, C Gu, S Coban-Akdemir, Z Eldomery, MK Posey, JE Jhangiani, SN Rosenfeld, JA Cho, MT Fox, S Withers, M Brooks, SM Chiang, T Duraine, L Erdin, S Yuan, B Shao, YR Moussallem, E Lamperti, C Donati, MA Smith, JD McLaughlin, HM Eng, CM Walkiewicz, M Xia, F Pippucci, T Magini, P Seri, M Zeviani, M Hirano, M Hunter, JV Srour, M Zanigni, S Lewis, RA Muzny, DM Lotze, TE Boerwinkle, E Gibbs, RA Hickey, SE Graham, BH Yang, YP Buhas, D Martin, DM Potocki, L Graziano, C Bellen, HJ Lupski, JR AF Harel, Tamar Yoon, Wan Hee Garone, Caterina Gu, Shen Coban-Akdemir, Zeynep Eldomery, Mohammad K. Posey, Jennifer E. Jhangiani, Shalini N. Rosenfeld, Jill A. Cho, Megan T. Fox, Stephanie Withers, Marjorie Brooks, Stephanie M. Chiang, Theodore Duraine, Lita Erdin, Serkan Yuan, Bo Shao, Yunru Moussallem, Elie Lamperti, Costanza Donati, Maria A. Smith, Joshua D. McLaughlin, Heather M. Eng, Christine M. Walkiewicz, Magdalena Xia, Fan Pippucci, Tommaso Magini, Pamela Seri, Marco Zeviani, Massimo Hirano, Michio Hunter, Jill V. Srour, Myriam Zanigni, Stefano Lewis, Richard Alan Muzny, Donna M. Lotze, Timothy E. Boerwinkle, Eric Gibbs, Richard A. Hickey, Scott E. Graham, Brett H. Yang, Yaping Buhas, Daniela Martin, Donna M. Potocki, Lorraine Graziano, Claudio Bellen, Hugo J. Lupski, James R. CA Univ Washington Ctr Mendelian TI Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COPY-NUMBER VARIATION; DOMAIN-CONTAINING 3A; LOSS-OF-FUNCTION; DEVELOPMENTAL DELAY; OPTIC ATROPHY; DROSOPHILA-MELANOGASTER; TRANSMISSION GENETICS; MOLECULAR FINDINGS; GENOMIC DISORDERS; CPG DINUCLEOTIDES AB ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific over expression of bor(R534W), the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor(WT) resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations. C1 [Harel, Tamar; Gu, Shen; Coban-Akdemir, Zeynep; Eldomery, Mohammad K.; Posey, Jennifer E.; Jhangiani, Shalini N.; Rosenfeld, Jill A.; Withers, Marjorie; Yuan, Bo; Shao, Yunru; Moussallem, Elie; Eng, Christine M.; Walkiewicz, Magdalena; Xia, Fan; Lewis, Richard Alan; Gibbs, Richard A.; Graham, Brett H.; Yang, Yaping; Potocki, Lorraine; Bellen, Hugo J.; Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Yoon, Wan Hee; Duraine, Lita; Bellen, Hugo J.] Baylor Coll Med, Dept Mol & Human Genet, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Yoon, Wan Hee; Duraine, Lita; Bellen, Hugo J.] Baylor Coll Med, Howard Hughes Med Inst, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Garone, Caterina] MRC Mitochondrial Biol Unit, Cambridge CB2 OXY, England. [Jhangiani, Shalini N.; Chiang, Theodore; Muzny, Donna M.; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Rosenfeld, Jill A.; Yuan, Bo; Eng, Christine M.; Walkiewicz, Magdalena; Xia, Fan; Yang, Yaping] Baylor Coll Med, Baylor Genet, Houston, TX 77030 USA. [Cho, Megan T.; McLaughlin, Heather M.] GeneDx, Gaithersburg, MD 20877 USA. [Fox, Stephanie; Buhas, Daniela] Montreal Childrens Hosp, Med Genet Dept, Montreal, PQ H4A 3J1, Canada. [Brooks, Stephanie M.; Hickey, Scott E.] Ohio State Univ, Dept Pediat, Coll Med, Div Mol & Human Genet,Nationwide Childrens Hosp, Columbus, OH 43205 USA. [Erdin, Serkan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Erdin, Serkan] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lamperti, Costanza; Zeviani, Massimo] Fdn Carlo Besta Inst Neurol IRCCS, Unit Mol Neurogenet, I-20126 Milan, Italy. [Donati, Maria A.] Univ Florence, Meyer Childrens Hosp, Metab & Muscular Unit, I-50132 Florence, Italy. [Smith, Joshua D.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Pippucci, Tommaso; Seri, Marco; Graziano, Claudio] Univ Bologna, Med Genet Unit, Policlin St Orsola Malpighi, I-40138 Bologna, Italy. [Magini, Pamela; Seri, Marco] Univ Bologna, Dept Med & Surg Sci, Med Genet Unit, I-40138 Bologna, Italy. [Hirano, Michio] Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10032 USA. [Hunter, Jill V.] Texas Childrens Hosp, Dept Pediat Radiol, Houston, TX 77030 USA. [Srour, Myriam] McGill Univ, Dept Pediat Neurol & Neurosurg, Montreal, PQ H4A 3J1, Canada. [Zanigni, Stefano] St Orsola Marcello Malpighi Hosp, Funct MR Unit, I-40138 Bologna, Italy. [Zanigni, Stefano] Univ Bologna, Dept Biomed & Neuromotor Sci DIBINEM, I-40123 Bologna, Italy. [Lewis, Richard Alan; Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lewis, Richard Alan; Lotze, Timothy E.; Potocki, Lorraine; Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Lotze, Timothy E.] Texas Childrens Hosp, Dept Pediat Neurol, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Buhas, Daniela] McGill Univ, Human Genet Dept, Montreal, PQ H3A 0G4, Canada. [Martin, Donna M.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Martin, Donna M.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Bellen, Hugo J.] Baylor Coll Med, Program Dev Biol, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Bellen, Hugo J.] Baylor Coll Med, Div Neurosci, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. RP Harel, T; Lupski, JR (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Lupski, JR (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.; Lupski, JR (reprint author), Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.; Lupski, JR (reprint author), Texas Childrens Hosp, Houston, TX 77030 USA. EM harel.tamar@gmail.com; jlupski@bcm.edu OI Graham, Brett/0000-0001-8451-8154; Erdin, Serkan/0000-0001-6587-2625 FU US National Human Genome Research Institute/National Heart Lung and Blood Institute Baylor Hopkins Center for Mendelian Genomics (NHGRI/NHLBI) [U54HG006542]; Intellectual Developmental Disabilities Research Center, IDDRC (Clinical Translational Core) [NICHD HD083092]; NHGRI/NHLBI University of Washington Center for Mendelian Genomics [2UM1HG006493]; National Institute of Neurological Disease and Stroke (NINDS) [RO1NS058529]; NIH/NIGMS Medical Genetics Research Fellowship Program [T32 GM07526]; European Commission [705560]; Undiagnosed Diseases Network (UDN) [1U54NS093793-01]; Genetic Resource Association of Texas (GReAT), Houston, Texas; NIH [R01 DC009410]; Dointa B. Sullivan, MD Research Professorship FX We thank the families for their collaboration and participation in this study. This work was supported in part by the US National Human Genome Research Institute/National Heart Lung and Blood Institute Baylor Hopkins Center for Mendelian Genomics (NHGRI/NHLBI, U54HG006542), the Intellectual Developmental Disabilities Research Center, IDDRC (NICHD HD083092, Clinical Translational Core), and the NHGRI/NHLBI University of Washington Center for Mendelian Genomics (2UM1HG006493). This work was also supported in part by the National Institute of Neurological Disease and Stroke (NINDS, RO1NS058529) to J.R.L. T.H. and J.E.P. are supported by the NIH/NIGMS T32 GM07526 Medical Genetics Research Fellowship Program. C. Garone is supported by European Commission Project 705560, Marie Curie Individual Fellowship. H.J.B. is supported by the Undiagnosed Diseases Network (UDN, 1U54NS093793-01). R.A.L. is supported in part by the Genetic Resource Association of Texas (GReAT), Houston, Texas. D.M. Martin is supported by the NIH (R01 DC009410) and the Dointa B. Sullivan, MD Research Professorship. NR 65 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 831 EP 845 DI 10.1016/j.ajhg.2016.08.007 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700004 PM 27640307 ER PT J AU Shashi, V Pena, LDM Kim, K Burton, B Hempel, M Schoch, K Walkiewicz, M McLaughlin, HM Cho, M Stong, N Hickey, SE Shuss, CM Freemark, MS Bellet, JS Keels, MA Bonner, MJ El-Dairi, M Butler, M Kranz, PG Stumpel, CTRM Klinkenberg, S Oberndorff, K Alawi, M Santer, R Petrovski, S Kuismin, O Korpi-Heikkila, S Pietilainen, O Aarno, P Kurki, MI Hoischen, A Need, AC Goldstein, DB Kortum, F AF Shashi, Vandana Pena, Loren D. M. Kim, Katherine Burton, Barbara Hempel, Maja Schoch, Kelly Walkiewicz, Magdalena McLaughlin, Heather M. Cho, Megan Stong, Nicholas Hickey, Scott E. Shuss, Christine M. Freemark, Michael S. Bellet, Jane S. Keels, Martha Ann Bonner, Melanie J. El-Dairi, Maysantoine Butler, Megan Kranz, Peter G. Stumpel, Constance T. R. M. Klinkenberg, Sylvia Oberndorff, Karin Alawi, Malik Santer, Rene Petrovski, Slave Kuismin, Outi Korpi-Heikkila, Satu Pietilainen, Olli Aarno, Palotie Kurki, Mitja I. Hoischen, Alexander Need, Anna C. Goldstein, David B. Kortuem, Fanny CA Undiagnosed Dis Network TI De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BOHRING-OPITZ SYNDROME; INTELLECTUAL DISABILITY; RECIPROCAL REGULATION; MUTATIONS; GENES; GENOMICS; HOMOLOG; FAMILY AB The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes. C1 [Shashi, Vandana; Pena, Loren D. M.; Schoch, Kelly] Duke Hlth, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. [Kim, Katherine; Burton, Barbara] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Chicago, IL 60611 USA. [Hempel, Maja; Kortuem, Fanny] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany. [Walkiewicz, Magdalena] Baylor Coll Med, Houston, TX 77030 USA. [McLaughlin, Heather M.; Cho, Megan] GeneDx, Gaithersburg, MD 20877 USA. [Stong, Nicholas; Petrovski, Slave; Goldstein, David B.] Columbia Univ, Inst Genom Med, New York, NY 10032 USA. [Hickey, Scott E.; Shuss, Christine M.] Nationwide Childrens Hosp, Div Mol & Human Genet, Columbus, OH 43082 USA. [Undiagnosed Dis Network] NIH, Common Fund, Bldg 10, Bethesda, MD 20892 USA. [Freemark, Michael S.] Duke Hlth, Dept Pediat, Div Endocrinol & Diabet, Durham, NC 27710 USA. [Bellet, Jane S.; Keels, Martha Ann] Duke Hlth, Dept Pediat, Durham, NC 27710 USA. [Bellet, Jane S.] Duke Hlth, Dept Dermatol, Durham, NC 27710 USA. [Keels, Martha Ann] Duke Hlth, Dept Surg, Durham, NC 27710 USA. [Bonner, Melanie J.] Duke Hlth, Psychiat & Behav Sci, Durham, NC 27710 USA. [El-Dairi, Maysantoine] Duke Hlth, Duke Eye Ctr, Durham, NC 27710 USA. [Butler, Megan] Duke Hlth, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Durham, NC 27710 USA. [Kranz, Peter G.] Duke Hlth, Dept Radiol, Div Neuroradiol, Durham, NC 27710 USA. [Stumpel, Constance T. R. M.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6202 AZ Maastricht, Netherlands. [Stumpel, Constance T. R. M.] Maastricht Univ, Med Ctr, Sch Oncol & Dev Biol, NL-6202 AZ Maastricht, Netherlands. [Klinkenberg, Sylvia] Maastricht Univ, Med Ctr, Dept Neurol, NL-6202 AZ Maastricht, Netherlands. [Oberndorff, Karin] Zuyderland Med Ctr, Dept Pediat, NL-6162 BG Sittard, Netherlands. [Alawi, Malik] Univ Med Ctr Hamburg Eppendorf, Bioinformat Serv Facil, D-20246 Hamburg, Germany. [Alawi, Malik] Univ Hamburg, Ctr Bioinformat, D-20246 Hamburg, Germany. [Alawi, Malik] Leibniz Inst Expt Virol, Heinrich Pette Inst, Virus Genom, D-20246 Hamburg, Germany. [Santer, Rene] Univ Med Ctr Hamburg Eppendorf, Dept Paediat, D-20246 Hamburg, Germany. [Petrovski, Slave] Univ Melbourne, Dept Med, Austin Hlth, Melbourne, Vic 3050, Australia. [Petrovski, Slave] Univ Melbourne, Royal Melbourne Hosp, Melbourne, Vic 3050, Australia. [Kuismin, Outi] Oulu Univ Hosp, Med Res Ctr Oulu, PEDEGO Res Unit, Oulu 90014, Finland. [Kuismin, Outi] Univ Oulu, Oulu 90014, Finland. [Kuismin, Outi] Oulu Univ Hosp, Dept Clin Genet, Oulu 90029, Finland. [Kuismin, Outi; Aarno, Palotie] Univ Helsinki, Inst Mol Med Finland, FIN-00290 Helsinki, Finland. [Korpi-Heikkila, Satu] Ctr Intellectual Disabil Care, Northern Ostrobothnia Hosp Dist, Oulu 90220, Finland. [Pietilainen, Olli; Aarno, Palotie] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Pietilainen, Olli] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Aarno, Palotie] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Aarno, Palotie; Kurki, Mitja I.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Aarno, Palotie; Kurki, Mitja I.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Aarno, Palotie] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kurki, Mitja I.] Broad Inst MIT & Harvard, Genet Anal Platform, Cambridge, MA 02142 USA. [Hoischen, Alexander] Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [Need, Anna C.] Imperial Coll London, Dept Med, Div Brain Sci, London W12 0NN, England. RP Shashi, V (reprint author), Duke Hlth, Dept Pediat, Div Med Genet, Durham, NC 27710 USA. EM vandana.shashi@duke.edu RI Hoischen, Alexander/D-1282-2013; OI Hoischen, Alexander/0000-0002-8072-4476; Wangler, Michael/0000-0001-5245-5910; Graham, Brett/0000-0001-8451-8154 FU Undiagnosed Diseases Network [1U01HG007672-01]; Deutsche Forschungsgemeinschaft [KO 4576/1-1]; Pairnomix LLC; Sanofi- Genzyme; Shire; Biomarin; Ultragenyx; Alexion; Armagen; ReGenX Bio FX We are grateful to the inidividuals and their families who contributed to this study and allowed us to publish their information and pictures. We thank I. Jantke for skillful technical assistance. This work was supported by the Undiagnosed Diseases Network (1U01HG007672-01 to V.S.) and the Deutsche Forschungsgemeinschaft (KO 4576/1-1 to F.K.). The authors disclose the following: the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular testing offered at the Baylor Genetics Laboratories (M.W.); D.B.G. has received consultancy fees and has equity ownership in Pairnomix LLC; H.M.M. and M.C. are employees of GeneDx; B.B. has received honoraria, consulting fees, or funding for clinical trials from Sanofi- Genzyme, Shire, Biomarin, Ultragenyx, Alexion, Armagen, and ReGenX Bio; and E.A.A. from the Undiagnosed Diseases Network is a co-founder of Personalis Inc. NR 33 TC 2 Z9 2 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 6 PY 2016 VL 99 IS 4 BP 991 EP 999 DI 10.1016/j.ajhg.2016.08.017 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DY7UB UT WOS:000385333700020 PM 27693232 ER PT J AU Stone, RM AF Stone, Richard M. TI Thrombosis in AML? Yes, but when to worry? SO BLOOD LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA AB In this issue of Blood, Libourel et al report the incidence and risk factors for thrombosis in newly diagnosed adults with acute myeloid leukemia (AML). Their data suggested a thrombosis prevalence of 8.7% in younger and 10.4% in older adults with AML; patients at greater risk exhibit disseminated intravascular coagulation (DIC) at diagnosis and high D-dimer levels in particular.(1) C1 [Stone, Richard M.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 6 PY 2016 VL 128 IS 14 BP 1784 EP 1785 DI 10.1182/blood-2016-08-734715 PG 2 WC Hematology SC Hematology GA DZ3HW UT WOS:000385737900003 ER PT J AU Plesner, T Arkenau, HT Gimsing, P Krejcik, J Lemech, C Minnema, MC Lassen, U Laubach, JP Palumbo, A Lisby, S Basse, L Wang, JP Sasser, AK Guckert, ME de Boer, C Khokhar, NZ Yeh, H Clemens, PL Ahmadi, T Lokhorst, HM Richardson, PG AF Plesner, Torben Arkenau, Hendrik-Tobias Gimsing, Peter Krejcik, Jakub Lemech, Charlotte Minnema, Monique C. Lassen, Ulrik Laubach, Jacob P. Palumbo, Antonio Lisby, Steen Basse, Linda Wang, Jianping Sasser, A. Kate Guckert, Mary E. de Boer, Carla Khokhar, Nushmia Z. Yeh, Howard Clemens, Pamela L. Ahmadi, Tahamtan Lokhorst, Henk M. Richardson, Paul G. TI Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma SO BLOOD LA English DT Article ID HUMAN CD38 ANTIBODY; PLUS DEXAMETHASONE; OPEN-LABEL; CELLS; POMALIDOMIDE; COMBINATION; MONOTHERAPY; INTERFERENCE; BLOOD AB Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (>= 5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade <= 2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumabmonotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029. C1 [Plesner, Torben; Krejcik, Jakub] Vejle Hosp, Vejle, Denmark. [Plesner, Torben; Krejcik, Jakub] Univ Southern Denmark, Kabbeltoft 25, DK-7100 Vejle, Denmark. [Arkenau, Hendrik-Tobias; Lemech, Charlotte] UCL, Sarah Cannon Res Inst, London, England. [Gimsing, Peter; Lassen, Ulrik] Univ Copenhagen, Dept Haematol, Rigshosp, Copenhagen, Denmark. [Minnema, Monique C.] Univ Med Ctr Utrecht, Dept Hematol, Utrecht, Netherlands. [Krejcik, Jakub; Richardson, Paul G.] Harvard Med Sch, LeBow Inst Myeloma Therapeut, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA USA. [Palumbo, Antonio] Univ Turin, Div Hematol, Myeloma Unit, Turin, Italy. [Lisby, Steen; Basse, Linda] Genmab AS, Copenhagen, Denmark. [Wang, Jianping] Janssen Res & Dev LLC, Raritan, NJ USA. [Sasser, A. Kate; Guckert, Mary E.; Khokhar, Nushmia Z.; Yeh, Howard; Clemens, Pamela L.; Ahmadi, Tahamtan] Janssen Res & Dev LLC, Spring House, PA USA. [de Boer, Carla] Janssen Biol, Leiden, Netherlands. [Lokhorst, Henk M.] Vrije Univ, Med Ctr, Dept Hematol, Amsterdam, Netherlands. RP Plesner, T (reprint author), Univ Southern Denmark, Kabbeltoft 25, DK-7100 Vejle, Denmark.; Plesner, T (reprint author), Vejle Hosp, Dept Haematol, Kabbeltoft 25, DK-7100 Vejle, Denmark. EM torben.plesner@rsyd.dk FU Janssen Research & Development, LLC; Genmab A/S; Janssen Global Services, LLC FX This study was funded by Janssen Research & Development, LLC and Genmab A/S. Medical writing and editorial assistance were provided by Erica Chevalier-Larsen and Christopher Jones of MedErgy and were funded by Janssen Global Services, LLC. NR 30 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 6 PY 2016 VL 128 IS 14 BP 1821 EP 1828 DI 10.1182/blood-2016-07-726729 PG 8 WC Hematology SC Hematology GA DZ3HW UT WOS:000385737900009 ER PT J AU Xiang, M Kim, H Ho, VT Walker, SR Bar-Natan, M Anahtar, M Liu, SH Toniolo, PA Kroll, Y Jones, N Giaccone, ZT Heppler, LN Ye, DQ Marineau, JJ Shaw, D Bradner, JE Blonquist, T Neuberg, D Hetz, C Stone, RM Soiffer, RJ Frank, DA AF Xiang, Michael Kim, Haesook Ho, Vincent T. Walker, Sarah R. Bar-Natan, Michal Anahtar, Melodi Liu, Suhu Toniolo, Patricia A. Kroll, Yasmin Jones, Nichole Giaccone, Zachary T. Heppler, Lisa N. Ye, Darwin Q. Marineau, Jason J. Shaw, Daniel Bradner, James E. Blonquist, Traci Neuberg, Donna Hetz, Claudio Stone, Richard M. Soiffer, Robert J. Frank, David A. TI Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent SO BLOOD LA English DT Article ID PNEUMOCYSTIS-CARINII-PNEUMONIA; SIGNAL TRANSDUCER; MULTIPLE-MYELOMA; COMPETING RISK; CANCER; CELLS; INTERLEUKIN-6; ACTIVATOR; PHOSPHORYLATION; TRANSFORMATION AB The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans. C1 [Xiang, Michael; Ho, Vincent T.; Walker, Sarah R.; Bar-Natan, Michal; Anahtar, Melodi; Liu, Suhu; Toniolo, Patricia A.; Kroll, Yasmin; Jones, Nichole; Giaccone, Zachary T.; Heppler, Lisa N.; Ye, Darwin Q.; Marineau, Jason J.; Shaw, Daniel; Bradner, James E.; Stone, Richard M.; Soiffer, Robert J.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Haesook; Blonquist, Traci; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Ho, Vincent T.; Walker, Sarah R.; Stone, Richard M.; Soiffer, Robert J.; Frank, David A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Ho, Vincent T.; Walker, Sarah R.; Stone, Richard M.; Soiffer, Robert J.; Frank, David A.] Harvard Med Sch, Boston, MA USA. [Hetz, Claudio] Univ Chile, Gerosci Ctr Brain Hlth & Metab, Santiago, Chile. [Hetz, Claudio] Univ Chile, Fac Med, Biomed Neurosci Inst, Santiago, Chile. [Xiang, Michael] Stanford Sch Med, Dept Radiat Oncol, Stanford, CA USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM david_frank@dfci.harvard.edu FU National Cancer Institute, National Institutes of Health [R01-CA160979]; When Everyone Survives Foundation (Duluth, GA); Gabrielle's Angel Foundation (New York, NY); Lymphoma Research Foundation (New York, NY); DeGregorio Family Foundation (Pleasantville, NY); Kittredge Foundation; Brent Leahey Fund; National Institute of General Medical Sciences [T32GM007753, F30 CA165740-01]; [Millennium Nucleus-P-07-011-F]; [FONDAP-15150012] FX This work was supported by the National Cancer Institute, National Institutes of Health (grant R01-CA160979); When Everyone Survives Foundation (Duluth, GA); Gabrielle's Angel Foundation (New York, NY); Lymphoma Research Foundation (New York, NY); the DeGregorio Family Foundation (Pleasantville, NY); the Kittredge Foundation; the Brent Leahey Fund (D.A.F.); the National Institute of General Medical Sciences (grants T32GM007753 and F30 CA165740-01) (M.X.); and Millennium Nucleus-P-07-011-F and FONDAP-15150012 (C.H.). This research was also supported by a generous gift from Stephen P. Koster. NR 37 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 6 PY 2016 VL 128 IS 14 BP 1845 EP 1853 DI 10.1182/blood-2015-07-660506 PG 9 WC Hematology SC Hematology GA DZ3HW UT WOS:000385737900012 ER PT J AU Carrasco, MP Machado, M Goncalves, L Sharma, M Gut, J Lukens, AK Wirth, DF Andre, V Duarte, MT Guedes, RC dos Santos, DJVA Rosenthal, PJ Mazitschek, R Prudencio, M Moreira, R AF Carrasco, Marta P. Machado, Marta Goncalves, Lidia Sharma, Moni Gut, Jiri Lukens, Amanda K. Wirth, Dyann F. Andre, Vania Duarte, Maria Teresa Guedes, Rita C. dos Santos, Daniel J. V. A. Rosenthal, Philip J. Mazitschek, Ralph Prudencio, Miguel Moreira, Rui TI Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites SO CHEMMEDCHEM LA English DT Article DE antiprotozoal agents; azaaurones; erythrocytic stage; liver stage; malaria ID CYSTEINE PROTEASE INHIBITORS; PLASMODIUM-FALCIPARUM; LIVER-STAGE; SELECTIVE INHIBITORS; ANTIMALARIAL-DRUG; DISCOVERY; POTENT; MECHANISMS; RESISTANCE; AURONES AB The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver stage of P.berghei, yielding compounds with dual-stage activity and sub-micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P.falciparum Dd2-ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron-transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual-stage antimalarials. C1 [Carrasco, Marta P.; Goncalves, Lidia; Sharma, Moni; Guedes, Rita C.; dos Santos, Daniel J. V. A.; Moreira, Rui] Univ Lisbon, Res Inst Med IMed ULisboa, Fac Pharm, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal. [Machado, Marta; Prudencio, Miguel] Univ Lisbon, Inst Med Mol, Fac Med, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal. [Gut, Jiri; Rosenthal, Philip J.] Univ Calif San Francisco, Dept Med, San Francisco Gen Hosp, 1001 Potrero Ave, San Francisco, CA 94110 USA. [Lukens, Amanda K.; Wirth, Dyann F.; Mazitschek, Ralph] Broad Inst, Program Infect Dis, Cambridge, MA 02142 USA. [Lukens, Amanda K.; Wirth, Dyann F.; Mazitschek, Ralph] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Andre, Vania; Duarte, Maria Teresa] Univ Lisbon, Ctr Quim Estrutural, Inst Super Tecn, P-1049001 Lisbon, Portugal. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. [Mazitschek, Ralph] Harvard Med Sch, Richard B Simches Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. [Carrasco, Marta P.] Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden. [dos Santos, Daniel J. V. A.] Univ Porto, LAQV REQUIMTE, Dept Chem & Biochem, Fac Sci, Rua Campo Alegre 823, P-4100 Oporto, Portugal. RP Carrasco, MP (reprint author), Univ Lisbon, Res Inst Med IMed ULisboa, Fac Pharm, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal.; Prudencio, M (reprint author), Univ Lisbon, Inst Med Mol, Fac Med, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal.; Carrasco, MP (reprint author), Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden. EM marta.carrasco@chem.gu.se; mprudencio@medicina.ulisboa.pt RI dos Santos, Daniel/D-5355-2013; Moreira, Rui/G-7485-2011; Guedes, Rita/K-5836-2013; iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, MedChem /B-4834-2014; iMed.ULisboa, NanoBB /B-5393-2014; iMed.ULisboa, NatProdChem /B-5387-2014; OI dos Santos, Daniel/0000-0001-7798-8641; Moreira, Rui/0000-0003-0727-9852; Guedes, Rita/0000-0002-5790-9181; Carrasco, Marta/0000-0002-7775-2919; Andre, Vania/0000-0001-5599-8355 FU Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) [PTDC/SAUF-CF/098734/2008, UID/DTP/04138/2013]; FCT [SFRH/BD/61611/2009, SFRH/BPD/94692/2013] FX This work was supported financially by the Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) through projects PTDC/SAUF-CF/098734/2008 and UID/DTP/04138/2013. FCT is also acknowledged for grants SFRH/BD/61611/2009 (to M.P.C.) and SFRH/BPD/94692/2013 (to M.S.). We thank Dr. Joao Lavrado for technical assistance and support in preparing the manuscript. NR 44 TC 1 Z9 1 U1 9 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD OCT 6 PY 2016 VL 11 IS 19 BP 2194 EP 2204 DI 10.1002/cmdc.201600327 PG 11 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DZ2JO UT WOS:000385668300009 PM 27538856 ER PT J AU Hehir-Kwa, JY Marschall, T Kloosterman, WP Francioli, LC Baaijens, JA Dijkstra, LJ Abdellaoui, A Koval, V Thung, DT Wardenaar, R Renkens, I Coe, BP Deelen, P de Ligt, J Lameijer, EW van Dijk, F Hormozdiari, F Uitterlinden, AG van Duijn, CM Eichler, EE de Bakker, PIW Swertz, MA Wijmenga, C van Ommen, GJB Slagboom, PE Boomsma, DI Schonhuth, A Ye, K Guryev, V AF Hehir-Kwa, Jayne Y. Marschall, Tobias Kloosterman, Wigard P. Francioli, Laurent C. Baaijens, Jasmijn A. Dijkstra, Louis J. Abdellaoui, Abdel Koval, Vyacheslav Thung, Djie Tjwan Wardenaar, Rene Renkens, Ivo Coe, Bradley P. Deelen, Patrick de Ligt, Joep Lameijer, Eric-Wubbo van Dijk, Freerk Hormozdiari, Fereydoun Uitterlinden, Andre G. van Duijn, Cornelia M. Eichler, Evan E. de Bakker, Paul I. W. Swertz, Morris A. Wijmenga, Cisca van Ommen, Gert-Jan B. Slagboom, P. Eline Boomsma, Dorret I. Schonhuth, Alexander Ye, Kai Guryev, Victor CA Genome Netherlands Consortium TI A high-quality human reference panel reveals the complexity and distribution of genomic structural variants SO NATURE COMMUNICATIONS LA English DT Article ID COPY NUMBER VARIATION; GENETIC ARCHITECTURE; SUSCEPTIBILITY; DISEASE; ASSOCIATION; IMPUTATION; DELETION; DATABASE; IMPACT; TRIOS AB Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals. C1 [Hehir-Kwa, Jayne Y.; Thung, Djie Tjwan] Radboud Univ Nijmegen, Med Ctr, Donders Inst, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Marschall, Tobias] Univ Saarland, Ctr Bioinformat, D-66123 Saarbrucken, Germany. [Marschall, Tobias] Max Planck Inst Informat, D-66123 Saarbrucken, Germany. [Kloosterman, Wigard P.; Francioli, Laurent C.; Renkens, Ivo; de Ligt, Joep; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Genet, Ctr Mol Med, NL-3584 CG Utrecht, Netherlands. [Francioli, Laurent C.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Francioli, Laurent C.] Broad Inst, Cambridge, MA 02142 USA. [Francioli, Laurent C.] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Baaijens, Jasmijn A.; Dijkstra, Louis J.; Schonhuth, Alexander] Ctr Wiskunde & Informat, Life Sci Grp, NL-1098 XG Amsterdam, Netherlands. [Abdellaoui, Abdel; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Koval, Vyacheslav; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Wardenaar, Rene; Guryev, Victor] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, NL-9713 AD Groningen, Netherlands. [Wardenaar, Rene] Univ Groningen, Groningen Bioinformat Ctr, NL-9747 AG Groningen, Netherlands. [Coe, Bradley P.; Hormozdiari, Fereydoun; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA. [Coe, Bradley P.; Hormozdiari, Fereydoun; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98105 USA. [Deelen, Patrick; van Dijk, Freerk; Swertz, Morris A.; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Lameijer, Eric-Wubbo; van Ommen, Gert-Jan B.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [van Dijk, Freerk; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9700 RB Groningen, Netherlands. [Uitterlinden, Andre G.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CG Utrecht, Netherlands. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands. [Ye, Kai] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Ye, Kai] Xi An Jiao Tong Univ, Sch Elect & Informat Engn, Xian 710049, Peoples R China. [Ye, Kai] Xi An Jiao Tong Univ, Affiliated Hosp 1, Xian 710061, Peoples R China. RP Schonhuth, A (reprint author), Ctr Wiskunde & Informat, Life Sci Grp, NL-1098 XG Amsterdam, Netherlands.; Guryev, V (reprint author), Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, NL-9713 AD Groningen, Netherlands.; Ye, K (reprint author), Washington Univ, Genome Inst, St Louis, MO 63108 USA.; Ye, K (reprint author), Xi An Jiao Tong Univ, Sch Elect & Informat Engn, Xian 710049, Peoples R China.; Ye, K (reprint author), Xi An Jiao Tong Univ, Affiliated Hosp 1, Xian 710061, Peoples R China. EM a.schoenhuth@cwi.nl; kaiye@xjtu.edu.cn; v.guryev@umcg.nl RI Slagboom, P. Eline/R-4790-2016; OI Slagboom, P. Eline/0000-0002-2875-4723; de Ligt, Joep/0000-0002-0348-419X; Karssen, Lennart C./0000-0002-1959-342X FU Biobanking and Biomolecular Research Infrastructure (BBMRI-NL) - Netherlands Organization for Scientific Research (NWO [184.021.007]; BBMRI-NL [CP2011-36]; Netherlands Organization for Scientific Research (NWO) through Veni grant [016.166.015]; Netherlands Organization for Scientific Research (NWO) through Vidi grant [639.072.309]; U.S. National Institutes of Health (NIH) [R01HG002385]; NIH [U41HG007497] FX The GoNL Project is funded by the Biobanking and Biomolecular Research Infrastructure (BBMRI-NL), which is financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007). BBMRI-NL funded K.Y. for validation experiments, CP2011-36. The Netherlands Organization for Scientific Research (NWO) has funded J.Y.H.-K. through Veni grant 016.166.015 and A.S. through Vidi grant 639.072.309. This work was supported, in part, by a U.S. National Institutes of Health (NIH) grant R01HG002385 and NIH U41HG007497 to E.E.E. E.E.E. is an investigator of the Howard Hughes Medical Institute. NR 42 TC 2 Z9 2 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT 6 PY 2016 VL 7 AR 12989 DI 10.1038/ncomms12989 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ0UI UT WOS:000385554800001 PM 27708267 ER PT J AU Dimopoulos, MA Oriol, A Nahi, H San-Miguel, J Bahlis, NJ Usmani, SZ Rabin, N Orlowski, RZ Komarnicki, M Suzuki, K Plesner, T Yoon, SS Ben Yehuda, D Richardson, PG Goldschmidt, H Reece, D Lisby, S Khokhar, NZ O'Rourke, L Chiu, C Qin, X Guckert, M Ahmadi, T Moreau, P AF Dimopoulos, M. A. Oriol, A. Nahi, H. San-Miguel, J. Bahlis, N. J. Usmani, S. Z. Rabin, N. Orlowski, R. Z. Komarnicki, M. Suzuki, K. Plesner, T. Yoon, S. -S. Ben Yehuda, D. Richardson, P. G. Goldschmidt, H. Reece, D. Lisby, S. Khokhar, N. Z. O'Rourke, L. Chiu, C. Qin, X. Guckert, M. Ahmadi, T. Moreau, P. CA POLLUX Investigators TI Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIBODY DARATUMUMAB; OPEN-LABEL; INTERFERENCE; MONOTHERAPY; ELOTUZUMAB; SURVIVAL; CRITERIA; CD38 AB BACKGROUND Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. METHODS In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. RESULTS At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. CONCLUSIONS The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. C1 [Dimopoulos, M. A.] Univ Athens, Athens, Greece. [Oriol, A.] Hosp Badalona Germans Trias & Pujol, Inst Josep Carreras, Inst Catala Oncol, Barcelona, Spain. [San-Miguel, J.] Univ Navarra Clin, Inst Invest Sanitaria Navarra, Ctr Invest Med Aplicada, Pamplona, Spain. [Nahi, H.] Karolinska Inst, Stockholm, Sweden. [Nahi, H.] Karolinska Univ Hosp Huddinge, Div Hematol, Dept Med, Stockholm, Sweden. [Bahlis, N. J.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Reece, D.] Princess Margaret Canc Ctr, Canc Clin Res Unit, Toronto, ON, Canada. [Usmani, S. Z.] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Rabin, N.] Univ Coll London Hosp NHS Trust, Dept Haematol, London, England. [Orlowski, R. Z.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Komarnicki, M.] Poznan Univ Med Sci, Dept Hematol & Stem Cell Transplantat, Poznan, Poland. [Suzuki, K.] Japanese Red Cross Med Ctr, Dept Hematol, Tokyo, Japan. [Plesner, T.] Vejle Hosp, Vejle, Denmark. [Plesner, T.] Univ Southern Denmark, Vejle, Denmark. [Lisby, S.] Genmab, Copenhagen, Denmark. [Yoon, S. -S.] Seoul Natl Univ, Dept Internal Med, Coll Med, Seoul, South Korea. [Ben Yehuda, D.] Hadassah Hebrew Univ Med Ctr, Dept Hematol, Jerusalem, Israel. [Richardson, P. G.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Goldschmidt, H.] Univ Heidelberg Hosp, Heidelberg, Germany. [Goldschmidt, H.] German Canc Res Ctr, Heidelberg, Germany. [Khokhar, N. Z.; O'Rourke, L.; Chiu, C.; Qin, X.; Guckert, M.; Ahmadi, T.] Janssen Res & Dev, Spring House, PA USA. [Moreau, P.] Univ Hosp Hotel Dieu, Dept Hematol, Nantes, France. RP Dimopoulos, MA (reprint author), Univ Athens, Sch Med, Alexandra Hosp, 80 Vas Sofias, Athens 11528, Greece. EM mdimop@med.uoa.gr RI FACON, THIERRY/M-9736-2014; richard, chrystelle/K-8595-2015; OI FACON, THIERRY/0000-0001-7705-8460; nahi, hareth/0000-0003-4711-5094 FU Janssen Research and Development; Janssen; Celgene; Amgen; Novartis; Millennium; Onyx; Bristol-Myers Squibb; Merck Sharp and Dohme; Skyline; Sanofi; Array BioPharma; Takeda Pharmaceutical; Pharmacyclics; Janssen-Cilag; BioTheryX; Forma Therapeutics; Incyte; Rigel Pharmaceuticals; Spectrum Pharmaceuticals; Chugai; Otsuka Pharmaceutical; Merck FX Supported by Janssen Research and Development.; Dr. Dimopoulos reports receiving fees for serving on advisory boards from Janssen, Celgene, Amgen, and Novartis and grant support from Janssen; Dr. Oriol, receiving fees for serving on advisory boards from Celgene, Janssen, and Amgen; Dr. San-Miguel, receiving fees for serving on advisory boards from Celgene, Novartis, Janssen, Millennium, Onyx, Bristol-Myers Squibb, Merck Sharp and Dohme, and Amgen; Dr. Bahlis, receiving fees for serving on advisory boards, lecture fees, and grant support from Celgene, Janssen, and Amgen; Dr. Usmani, receiving fees for serving on advisory boards and committees from Celgene, Skyline, Sanofi, Janssen, Array BioPharma, and Bristol-Myers Squibb, consulting fees from Amgen (formerly Onyx) and Takeda Pharmaceutical (formerly Millennium), lecture fees from Celgene, Amgen, and Takeda Pharmaceutical, and grant support from Celgene, Amgen, Takeda Pharmaceutical, Sanofi, Janssen, Array BioPharma, Pharmacyclics, and Bristol-Myers Squibb; Dr. Rabin, receiving fees for serving on advisory boards from Bristol-Myers Squibb, Takeda Pharmaceutical, Novartis, and Amgen, lecture fees from Janssen-Cilag and Celgene, and travel support from Janssen-Cilag and Takeda Pharmaceutical; Dr. Orlowski, receiving fees for serving on advisory boards from BioTheryX, Forma Therapeutics, Bristol-Myers Squibb, Incyte, Rigel Pharmaceuticals, Amgen, and Takeda Pharmaceutical and grant support from Bristol-Myers Squibb, Amgen, Takeda Pharmaceutical, and Spectrum Pharmaceuticals; Dr. Plesner, receiving grants from Janssen and honoraria from Janssen and Genmab during the conduct of the trial; Dr. Richardson, receiving fees for serving on advisory boards from Celgene and Janssen; Dr. Goldschmidt, receiving fees for serving on advisory boards from Celgene, Janssen, Novartis, Bristol-Myers Squibb, Onyx, Amgen, and Takeda Pharmaceutical and research support to his institution from Celgene, Janssen, Novartis, Chugai, Bristol-Myers Squibb, and Millennium; Dr. Reece, receiving consulting fees from Janssen, Celgene, Takeda Pharmaceutical, Bristol-Myers Squibb, and Amgen, honoraria from Janssen, Celgene, Takeda Pharmaceutical, Bristol-Myers Squibb, Novartis, and Amgen, and research support from Janssen, Celgene, Takeda Pharmaceutical, Otsuka Pharmaceutical, Bristol-Myers Squibb, Merck, Novartis, and Amgen; Dr. Lisby, being an employee of Genmab; Dr. Khokhar, Ms. O'Rourke, Dr. Chiu, Mr. Qin, Ms. Guckert, and Dr. Ahmadi, being employees of Janssen; Ms. O'Rourke and Ms. Guckert, holding stock in Johnson & Johnson; and Dr. Moreau, receiving fees for serving on advisory boards and participating in symposia from Celgene, Novartis, Takeda Pharmaceutical, Amgen, and Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported. NR 32 TC 25 Z9 25 U1 15 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 6 PY 2016 VL 375 IS 14 BP 1319 EP 1331 DI 10.1056/NEJMoa1607751 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA DY3EZ UT WOS:000384974900005 PM 27705267 ER PT J AU Bucholz, EM Butala, NM Ma, SG Normand, SLT Krumholz, HM AF Bucholz, Emily M. Butala, Neel M. Ma, Shuangge Normand, Sharon-Lise T. Krumholz, Harlan M. TI Life Expectancy after Myocardial Infarction, According to Hospital Performance SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STANDARDIZED MORTALITY-RATES; COOPERATIVE CARDIOVASCULAR PROJECT; QUALITY-OF-CARE; 30-DAY MORTALITY; HEART-FAILURE; OUTCOMES; ASSOCIATION; IMPROVEMENT; INTERVENTION; READMISSION AB BACKGROUND Thirty-day risk-standardized mortality rates after acute myocardial infarction are commonly used to evaluate and compare hospital performance. However, it is not known whether differences among hospitals in the early survival of patients with acute myocardial infarction are associated with differences in long-term survival. METHODS We analyzed data from the Cooperative Cardiovascular Project, a study of Medicare beneficiaries who were hospitalized for acute myocardial infarction between 1994 and 1996 and who had 17 years of follow-up. We grouped hospitals into five strata that were based on case-mix severity. Within each case-mix stratum, we compared life expectancy among patients admitted to high-performing hospitals with life expectancy among patients admitted to low-performing hospitals. Hospital performance was defined by quintiles of 30-day risk-standardized mortality rates. Cox proportional-hazards models were used to calculate life expectancy. RESULTS The study sample included 119,735 patients with acute myocardial infarction who were admitted to 1824 hospitals. Within each case-mix stratum, survival curves of the patients admitted to hospitals in each risk-standardized mortality rate quintile separated within the first 30 days and then remained parallel over 17 years of follow-up. Estimated life expectancy declined as hospital risk-standardized mortality rate quintile increased. On average, patients treated at high-performing hospitals lived between 0.74 and 1.14 years longer, depending on hospital case mix, than patients treated at low-performing hospitals. When 30-day survivors were examined separately, there was no significant difference in unadjusted or adjusted life expectancy across hospital risk-standardized mortality rate quintiles. CONCLUSIONS In this study, patients admitted to high-performing hospitals after acute myocardial infarction had longer life expectancies than patients treated in low-performing hospitals. This survival benefit occurred in the first 30 days and persisted over the long term. C1 [Bucholz, Emily M.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Butala, Neel M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Normand, Sharon-Lise T.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Normand, Sharon-Lise T.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ma, Shuangge] Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Krumholz, Harlan M.] Yale Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. [Krumholz, Harlan M.] Yale Sch Med, Sect Cardiovasc Med, Dept Internal Med, New Haven, CT USA. [Krumholz, Harlan M.] Yale Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT USA. [Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, 20 York St, New Haven, CT 06504 USA. RP Krumholz, HM (reprint author), Yale Sch Med, Dept Internal Med, 1 Church St,Suite 200, New Haven, CT 06510 USA. EM harlan.krumholz@yale.edu FU National Heart, Lung, and Blood Institute (NHLBI); National Institute of General Medical Sciences (NIGMS) Medical Scientist Training Program; NHLBI [F30HL120498-01A1, U01 HL105270]; NIGMS Medical Scientist Training Program [T32GM07205]; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences Medical Scientist Training Program FX Funded by the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences Medical Scientist Training Program.; Supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of General Medical Sciences (NIGMS) Medical Scientist Training Program. Dr. Bucholz is supported by F30 Training grant F30HL120498-01A1 from the NHLBI and by NIGMS Medical Scientist Training Program grant T32GM07205. Dr. Krumholz was supported by grant U01 HL105270 (Center for Cardiovascular Outcomes Research at Yale University) from the NHLBI during the time that the work was conducted. NR 32 TC 0 Z9 0 U1 6 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 6 PY 2016 VL 375 IS 14 BP 1332 EP 1342 DI 10.1056/NEJMoa1513223 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DY3EZ UT WOS:000384974900006 PM 27705249 ER PT J AU Kuang, YY Zheng, XH Li, CY Li, XM Cao, DC Tong, GX Lv, WH Xu, W Zhou, Y Zhang, XF Sun, ZP Mahboob, S Al-Ghanim, KA Li, JT Sun, XW AF Kuang, You-Yi Zheng, Xian-Hu Li, Chun-Yan Li, Xiao-Min Cao, Ding-Chen Tong, Guang-Xiang Lv, Wei-Hua Xu, Wei Zhou, Yi Zhang, Xiao-Feng Sun, Zhi-Peng Mahboob, Shahid Al-Ghanim, Khalid A. Li, Jiong-Tang Sun, Xiao-Wen TI The genetic map of goldfish (Carassius auratus) provided insights to the divergent genome evolutions in the Cyprinidae family SO SCIENTIFIC REPORTS LA English DT Article ID TISSUE GROWTH-FACTOR; COMMON CARP; CRUCIAN CARP; LINKAGE MAP; WIDE ASSOCIATION; FACTOR CTGF/CCN2; DRAFT GENOME; GIBEL CARP; SEQUENCE; REVEALS AB A high-density linkage map of goldfish (Carassius auratus) was constructed using RNA-sequencing. This map consists of 50 linkage groups with 8,521 SNP markers and an average resolution of 0.62 cM. Approximately 84% of markers are in protein-coding genes orthologous to zebrafish proteins. We performed comparative genome analysis between zebrafish and medaka, common carp, grass carp, and goldfish to study the genome evolution events in the Cyprinidae family. The comparison revealed large synteny blocks among Cyprinidae fish and we hypothesized that the Cyprinidae ancestor undergone many inter-chromosome rearrangements after speciation from teleost ancestor. The study also showed that goldfish genome had one more round of whole genome duplication (WGD) than zebrafish. Our results illustrated that most goldfish markers were orthologous to genes in common carp, which had four rounds of WGD. Growth-related regions and genes were identified by QTL analysis and association study. Function annotations of the associated genes suggested that they might regulate development and growth in goldfish. This first genetic map enables us to study the goldfish genome evolution and provides an important resource for selective breeding of goldfish. C1 [Kuang, You-Yi; Zheng, Xian-Hu; Cao, Ding-Chen; Tong, Guang-Xiang; Lv, Wei-Hua; Xu, Wei; Zhang, Xiao-Feng; Sun, Zhi-Peng; Sun, Xiao-Wen] Chinese Acad Fishery Sci, Heilongjiang River Fisheries Res Inst, Harbin 150070, Peoples R China. [Li, Chun-Yan; Li, Xiao-Min; Li, Jiong-Tang] Chinese Acad Fishery Sci, Ctr Appl Aquat Genom, Beijing 10014, Peoples R China. [Li, Chun-Yan] Tianjin Fisheries Res Inst, Tianjin 300221, Peoples R China. [Zhou, Yi] Boston Childrens Hosp, Div Hematol Oncol, Stem Cell Program, Boston, MA 02115 USA. [Zhou, Yi] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mahboob, Shahid; Al-Ghanim, Khalid A.] King Saud Univ, Coll Sci, Dept Zool, POB 2455, Riyadh 11451, Saudi Arabia. RP Sun, XW (reprint author), Chinese Acad Fishery Sci, Heilongjiang River Fisheries Res Inst, Harbin 150070, Peoples R China. EM sunxw2002@163.com RI Rana, Shahid/P-1131-2014 OI Rana, Shahid/0000-0003-4969-5387 FU Special Scientific Research Funds for Central Non-profit Institutes Special Funds, Chinese Academy of Fishery Sciences [2015B03XK01]; National Natural Science Foundation of China [31402353]; China Ministry of Science and Technology 863 Hi-Tech Research and Development Program [2011AA100402]; King Saud University [RG-1435-012] FX This study was supported by the Special Scientific Research Funds for Central Non-profit Institutes Special Funds, Chinese Academy of Fishery Sciences (2015B03XK01), National Natural Science Foundation of China (31402353) and China Ministry of Science and Technology 863 Hi-Tech Research and Development Program (2011AA100402). The authors would like to express their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project No. RG-1435-012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 0 Z9 0 U1 18 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 6 PY 2016 VL 6 AR 34849 DI 10.1038/srep34849 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY0CJ UT WOS:000384764200001 PM 27708388 ER PT J AU Liu, Y Scirica, BM Stultz, CM Guttag, JV AF Liu, Yun Scirica, Benjamin M. Stultz, Collin M. Guttag, John V. TI Beatquency domain and machine learning improve prediction of cardiovascular death after acute coronary syndrome SO SCIENTIFIC REPORTS LA English DT Article ID HEART-RATE-VARIABILITY; ACUTE MYOCARDIAL-INFARCTION; PERIOD VARIABILITY; FREQUENCY-ANALYSIS; ARTERIAL-PRESSURE; POWER SPECTRUM; ROC CURVE; MORTALITY; INTERVAL; CLASSIFICATION AB Frequency domain measures of heart rate variability (HRV) are associated with adverse events after a myocardial infarction. However, patterns in the traditional frequency domain (measured in Hz, or cycles per second) may capture different cardiac phenomena at different heart rates. An alternative is to consider frequency with respect to heartbeats, or beatquency. We compared the use of frequency and beatquency domains to predict patient risk after an acute coronary syndrome. We then determined whether machine learning could further improve the predictive performance. We first evaluated the use of pre-defined frequency and beatquency bands in a clinical trial dataset (N = 2302) for the HRV risk measure LF/HF (the ratio of low frequency to high frequency power). Relative to frequency, beatquency improved the ability of LF/HF to predict cardiovascular death within one year (Area Under the Curve, or AUC, of 0.730 vs. 0.704, p < 0.001). Next, we used machine learning to learn frequency and beatquency bands with optimal predictive power, which further improved the AUC for beatquency to 0.753 (p < 0.001), but not for frequency. Results in additional validation datasets (N = 2255 and N = 765) were similar. Our results suggest that beatquency and machine learning provide valuable tools in physiological studies of HRV. C1 [Liu, Yun; Stultz, Collin M.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Liu, Yun; Stultz, Collin M.] Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Scirica, Benjamin M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Scirica, Benjamin M.] Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Stultz, Collin M.; Guttag, John V.] MIT, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Guttag, John V.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Stultz, CM (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Stultz, CM (reprint author), Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Stultz, CM (reprint author), MIT, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM cmstultz@mit.edu FU Agency of Science, Technology, and Research (A*STAR), Singapore; Quanta Computer, Taiwan; General Electric, USA; Gilead Sciences FX This work was supported by the Agency of Science, Technology, and Research (A*STAR), Singapore, Quanta Computer, Taiwan, and General Electric, USA. The clinical trial was supported by CV Therapeutics (now Gilead Sciences). NR 46 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 6 PY 2016 VL 6 AR 34540 DI 10.1038/srep34540 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DY0BD UT WOS:000384761000001 PM 27708350 ER PT J AU Boujelben, A Watson, M McDougall, S Yen, YF Gerstner, ER Catana, C Deisboeck, T Batchelor, TT Boas, D Rosen, B Kalpathy-Cramer, J Chaplain, MAJ AF Boujelben, Ahmed Watson, Michael McDougall, Steven Yen, Yi-Fen Gerstner, Elizabeth R. Catana, Ciprian Deisboeck, Thomas Batchelor, Tracy T. Boas, David Rosen, Bruce Kalpathy-Cramer, Jayashree Chaplain, Mark A. J. TI Multimodality imaging and mathematical modelling of drug delivery to glioblastomas SO INTERFACE FOCUS LA English DT Article DE multimodality imaging; glioblastoma; drug delivery; perfusion; computational modelling and simulation ID LYMPHATIC VASCULAR SYSTEMS; ANTI-ANGIOGENIC THERAPY; COUPLED IN-VIVO; INTERSTITIAL PRESSURE; TARGETING STRATEGIES; TUMOR ANGIOGENESIS; MALIGNANT GLIOMAS; BLOOD PERFUSION; SOLID TUMORS; DIFFUSION AB Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization, and they typically exhibit a disrupted blood-brain barrier (BBB). Although it has been hypothesized that the 'normalization' of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of BBB integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper, we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated-flow rate, vessel permeability and tissue diffusion coefficient-interact nonlinearly to produce the observed average drug concentration in the microenvironment. C1 [Boujelben, Ahmed; Watson, Michael; McDougall, Steven] Heriot Watt Univ, Sch Petr Engn, Edinburgh EH14 4AS, Midlothian, Scotland. [Yen, Yi-Fen; Catana, Ciprian; Deisboeck, Thomas; Boas, David; Rosen, Bruce; Kalpathy-Cramer, Jayashree] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gerstner, Elizabeth R.; Batchelor, Tracy T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Chaplain, Mark A. J.] Univ St Andrews, Sch Math & Stat, St Andrews KY16 9SS, Fife, Scotland. RP Chaplain, MAJ (reprint author), Univ St Andrews, Sch Math & Stat, St Andrews KY16 9SS, Fife, Scotland. EM majc@st-andrews.ac.uk RI Chaplain, Mark/A-5355-2010 OI Chaplain, Mark/0000-0001-5727-2160 FU EPSRC [EP/N014642/1, EP/K032208/1]; NIH/NCI [U01CA154601, K23CA169021, R01-R01CA129371-01]; NIH/NIBIB [R01EB014894] FX S.M.c. and M.A.J.C. gratefully acknowledge support of EPSRC grant no. EP/N014642/1 ('EPSRC Centre for Multiscale Soft Tissue Mechanics-With Application to Heart & Cancer'). M.A.J.C. would like to thank the Isaac Newton Institute for Mathematical Sciences for its hospitality during the programme 'Coupling geometric PDEs with physics for cell morphology, motility and pattern formation' supported by EPSRC grant no. EP/K032208/1. J.K.-C., B.R. and Y.-F.Y. gratefully acknowledge NIH/NCI grant no. U01CA154601, E.R.G. acknowledges NIH/NCI grant no. K23CA169021 and C.C. acknowledges NIH/NIBIB grant no. R01EB014894. T.T.B. was supported by NIH/NCI grant R01-R01CA129371-01. NR 41 TC 1 Z9 1 U1 18 U2 19 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2042-8898 EI 2042-8901 J9 INTERFACE FOCUS JI Interface Focus PD OCT 6 PY 2016 VL 6 IS 5 AR 20160039 DI 10.1098/rsfs.2016.0039 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DU4OR UT WOS:000382192900007 PM 27708763 ER PT J AU Nwachukwu, BU Schairer, WW So, C Bernstein, JL Herndon, J Dodwell, ER AF Nwachukwu, Benedict U. Schairer, William W. So, Conan Bernstein, Jaime L. Herndon, James Dodwell, Emily R. TI The Early Impact of an Administrative Processing Fee on Manuscript Submissions at The Journal of Bone & Joint Surgery SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID ORTHOPEDIC RESEARCH; AMERICAN VOLUME; PUBLICATION AB Background: There was a dramatic increase in the volume of manuscripts submitted to The Journal of Bone & Joint Surgery (JBJS) between 2009 and 2012. This resulted in increased journal administrative costs. To offset this financial burden, in May 2013, JBJS started charging authors an administrative processing fee at the time of submission. The purpose of this study was to assess the impact of the administrative fee on the volume and characteristics of manuscripts submitted to JBJS. Methods: Our analysis included 866 manuscripts submitted to JBJS between November 2012 and November 2013. We compared manuscripts submitted 6 months prior to fee implementation and prior to the announcement (denoted as the baseline group), in the several months prior to fee implementation but after the fee implementation announcement (denoted as the fee announcement group), and in the 6 months after fee implementation (denoted as the fee implementation group). Manuscripts were reviewed for institutional and author demographic characteristics, as well as for general study characteristics. Results: In the first full calendar year (2014) after the implementation of the fee, the annual volume of submissions to JBJS declined by 33.5% compared with the annual submission volume in 2010 to 2012. In a comparative analysis, the geographical region of origin (p = 0.003), level of evidence (p < 0.0001), funding, and specialty differed between the 3 submission periods. However, subgroup analyses demonstrated that differences were attributable to the fee announcement group and that there were few important differences between the baseline and fee implementation groups. Reporting of funding information improved significantly between the baseline and fee implementation groups; in the post-fee implementation period, studies were more likely to have declared no external funding source (p = 0.001). Conclusions: The administrative processing fee at JBJS has been associated with a decrease in submission volume, but, overall, there has not been a change in the characteristics of studies submitted. However, decreased overall volume implies a decrease in the absolute number of high-level studies submitted to the journal. Administrative processing fees at high-volume journals may be a financially viable way to offset high administrative costs without substantially changing the characteristics of submitted articles. C1 [Nwachukwu, Benedict U.; Schairer, William W.; So, Conan; Bernstein, Jaime L.; Herndon, James; Dodwell, Emily R.] Hosp Special Surg, Dept Orthopaed Surg, New York, NY 10021 USA. [So, Conan] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Bernstein, Jaime L.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Herndon, James] Massachusetts Gen Hosp, Orthopaed Associates, Boston, MA 02114 USA. RP Nwachukwu, BU (reprint author), Hosp Special Surg, Dept Orthopaed Surg, New York, NY 10021 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02492 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 5 PY 2016 VL 98 IS 19 AR e82 DI 10.2106/JBJS.15.01118 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EN4AL UT WOS:000395949500002 PM 27707856 ER PT J AU Adams, DC Hariri, LP Miller, AJ Wang, Y Cho, JL Villiger, M Holz, JA Szabari, MV Hamilos, DL Harris, RS Griffith, JW Bouma, BE Luster, AD Medoff, BD Suter, MJ AF Adams, David C. Hariri, Lida P. Miller, Alyssa J. Wang, Yan Cho, Josalyn L. Villiger, Martin Holz, Jasmin A. Szabari, Margit V. Hamilos, Daniel L. Harris, R. Scott Griffith, Jason W. Bouma, Brett E. Luster, Andrew D. Medoff, Benjamin D. Suter, Melissa J. TI Birefringence microscopy platform for assessing airway smooth muscle structure and function in vivo SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; POLARIZATION MODE DISPERSION; BRONCHIAL THERMOPLASTY; AXIS ORIENTATION; SEVERE ASTHMA; FATAL ASTHMA; RESPONSIVENESS; ANOCOCCYGEUS; CONTRACTION; MORPHOLOGY AB The inability to visualize airway smooth muscle (ASM) cells in vivo is a major obstacle in understanding their role in normal physiology and diseases. At present, there is no imaging modality available to assess ASM in vivo. Confocal endomicroscopy lacks the penetration depth and field of view, and conventional optical coherence tomography (OCT) does not have sufficient contrast to differentiate ASM from surrounding tissues. We have developed a birefringence microscopy platform that leverages the micro-organization of tissue to add further dimension to traditional OCT. We have used this technology to validate ASM measurements in ex vivo swine and canine studies, visualize and characterize volumetric representations of ASM in vivo, and quantify and predict ASM contractile force as a function of optical retardation. We provide in vivo images and volumetric assessments of ASM in living humans and document structural disease variations in subjects with mild asthma. The opportunity to link inflammatory responses to ASM responses and to link ASM responses to clinical responses and outcomes could lead to an increased understanding of diseases of the airway and, ultimately, to improved patient outcomes. C1 [Adams, David C.; Miller, Alyssa J.; Wang, Yan; Cho, Josalyn L.; Holz, Jasmin A.; Szabari, Margit V.; Harris, R. Scott; Griffith, Jason W.; Medoff, Benjamin D.; Suter, Melissa J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Adams, David C.; Hariri, Lida P.; Wang, Yan; Villiger, Martin; Holz, Jasmin A.; Szabari, Margit V.; Bouma, Brett E.; Suter, Melissa J.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photo Med, Boston, MA 02114 USA. [Hariri, Lida P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cho, Josalyn L.; Hamilos, Daniel L.; Griffith, Jason W.; Luster, Andrew D.; Medoff, Benjamin D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammat Dis, Harvard Med Sch, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Suter, MJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. EM msuter@mgh.harvard.edu FU NIH [R01CA167827, EB105903, U19AI095261, R37AI040618]; Boston Scientific Corporation [2014A050616] FX This work was supported in part by the NIH (R01CA167827 awarded to M.J.S.) and in part by Boston Scientific Corporation (2014A050616 awarded to M.J.S.). B.E.B. and M.V. were supported by the NIH (EB105903 awarded to B.E.B.). The clinical studies were supported by the NIH (U19AI095261 and R37AI040618 awarded to A.D.L.). NR 39 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 5 PY 2016 VL 8 IS 359 AR 359ra131 DI 10.1126/scitranslmed.aag1424 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2UU UT WOS:000389441200003 PM 27708064 ER PT J AU Cho, JL Ling, MF Adams, DC Faustino, L Islam, SA Afshar, R Griffith, JW Harris, RS Ng, A Radicioni, G Ford, AA Han, AK Xavier, R Kwok, WW Boucher, R Moon, JJ Hamilos, DL Kesimer, M Suter, MJ Medoff, BD Luster, AD AF Cho, Josalyn L. Ling, Morris F. Adams, David C. Faustino, Lucas Islam, Sabina A. Afshar, Roshi Griffith, Jason W. Harris, Robert S. Ng, Aylwin Radicioni, Giorgia Ford, Amina A. Han, Andre K. Xavier, Ramnik Kwok, William W. Boucher, Richard Moon, James J. Hamilos, Daniel L. Kesimer, Mehmet Suter, Melissa J. Medoff, Benjamin D. Luster, Andrew D. TI Allergic asthma is distinguished by sensitivity of allergen-specific CD4(+) T cells and airway structural cells to type 2 inflammation SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; IN-VIVO; MODERATE ASTHMA; PULMONARY INFLAMMATION; ATOPIC SUBJECTS; SMOOTH-MUSCLE; CHALLENGE; EXPRESSION; RHINITIS; DISEASE AB Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4(+) T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4(+) T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation. C1 [Cho, Josalyn L.; Ling, Morris F.; Faustino, Lucas; Islam, Sabina A.; Afshar, Roshi; Griffith, Jason W.; Han, Andre K.; Moon, James J.; Hamilos, Daniel L.; Medoff, Benjamin D.; Luster, Andrew D.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Cho, Josalyn L.; Adams, David C.; Griffith, Jason W.; Harris, Robert S.; Han, Andre K.; Moon, James J.; Suter, Melissa J.; Medoff, Benjamin D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik] Harvard Univ, Broad Inst Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Radicioni, Giorgia; Ford, Amina A.; Boucher, Richard; Kesimer, Mehmet] Univ N Carolina, Marsico Lung Inst, Chapel Hill, NC 27599 USA. [Kwok, William W.] Benaroya Res Inst Virginia Mason, Seattle, WA 98101 USA. RP Luster, AD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. EM aluster@mgh.harvard.edu FU NIH [U19AI095261, R37AI040618, T32HL116275, R01CA167827, K08AI113083, R01HL103940] FX This work was supported by NIH grants U19AI095261, R37AI040618, and T32HL116275 (to A.D.L.); R01CA167827 (to M.J.S.); K08AI113083 (to J.L.C.); and R01HL103940 (to M.K.). NR 51 TC 1 Z9 1 U1 4 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 5 PY 2016 VL 8 IS 359 AR 359ra132 DI 10.1126/scitranslmed.aag1370 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2UU UT WOS:000389441200004 PM 27708065 ER PT J AU Malka, R Nathan, DM Higgins, JM AF Malka, Roy Nathan, David M. Higgins, John M. TI Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ESTIMATED AVERAGE GLUCOSE; FASTING PLASMA-GLUCOSE; NONDIABETIC SUBJECTS; POPULATION-DYNAMICS; GLYCEMIA; HBA1C; A1C; GLYCOSYLATION; HBA(1C); FRUCTOSAMINE AB The amount of glycated hemoglobin (HbA1c) in diabetic patients' blood provides the best estimate of the average blood glucose concentration over the preceding 2 to 3 months. It is therefore essential for disease management and is the best predictor of disease complications. Nevertheless, substantial unexplained glucose-independent variation in HbA1c makes its reflection of average glucose inaccurate and limits the precision of medical care for diabetics. The true average glucose concentration of a nondiabetic and a poorly controlled diabetic may differ by less than 15 mg/dl, but patients with identical HbA1c values may have true average glucose concentrations that differ by more than 60 mg/dl. We combined a mechanistic mathematical model of hemoglobin glycation and red blood cell kinetics with large sets of within-patient glucose measurements to derive patient-specific estimates of nonglycemic determinants of HbA1c, including mean red blood cell age. We found that between-patient variation in derived mean red blood cell age explains all glucose-independent variation in HbA1c. We then used our model to personalize prospective estimates of average glucose and reduced errors by more than 50% in four independent groups of greater than 200 patients. The current standard of care provided average glucose estimates with errors > 15 mg/dl for one in three patients. Our patient-specific method reduced this error rate to 1 in 10. Our personalized approach should improve medical care for diabetes using existing clinical measurements. C1 [Malka, Roy; Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Malka, Roy; Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Malka, Roy; Higgins, John M.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Nathan, David M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Nathan, David M.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Higgins, JM (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.; Higgins, JM (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM john_higgins@hms.harvard.edu FU NIH Director's New Innovator Award [DP2DK098087]; Abbott Diagnostics FX J.M.H. and R.M. were supported by an NIH Director's New Innovator Award (DP2DK098087) and by a research grant from Abbott Diagnostics. None of the funding agencies had any input on study design or decision to publish. NR 45 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 5 PY 2016 VL 8 IS 359 AR 359ra130 DI 10.1126/scitranslmed.aaf9304 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2UU UT WOS:000389441200002 PM 27708063 ER PT J AU Nasr, S Rosas, HD AF Nasr, Shahin Rosas, Herminia D. TI Impact of Visual Corticostriatal Loop Disruption on Neural Processing within the Parahippocampal Place Area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE caudate; Huntington's disease; PPA; scene and shape perception; visual categorization ID INTRINSIC FUNCTIONAL CONNECTIVITY; EARLY HUNTINGTONS-DISEASE; SCENE-SELECTIVE CORTEX; SURFACE-BASED ANALYSIS; RESTING-STATE FMRI; BASAL GANGLIA; HUMAN BRAIN; CAUDATE-NUCLEUS; CEREBRAL-CORTEX; STRUCTURAL CONNECTIVITY AB The caudate nucleus is a part of the visual corticostriatal loop (VCSL), receiving input from different visual areas and projecting back to the same cortical areas via globus pallidus, substantia nigra, and thalamus. Despite perceptual and navigation impairments in patients with VCSL disruption due to caudate atrophy (e.g., Huntington's disease, HD), the relevance of the caudate nucleus and VCSL on cortical visual processing is not fully understood. In a series of fMRI experiments, we found that the caudate showed a stronger functional connection to parahippocampal place area (PPA) compared with adjacent regions (e.g., fusiform face area, FFA) within the temporal visual cortex. Consistent with this functional link, the caudate showed a higher response to scenes compared with faces, similar to the PPA. Testing the impact of VCSL disruption on neural processes within PPA, HDpatients showed reduced scene-selective activity within PPA compared with healthy matched controls. In contrast, the level of selective activity in adjacent cortical and subcortical face-selective areas (i.e., FFA and amygdala) remained intact. These results show some of the first evidence for the direct impact and potential clinical significance of VCSL on the generation of "elective" activity within PPA. C1 [Nasr, Shahin; Rosas, Herminia D.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Nasr, Shahin] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. [Rosas, Herminia D.] Harvard Med Sch, Dept Neurol, Boston, MA 02114 USA. [Rosas, Herminia D.] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Boston, MA 02129 USA. RP Nasr, S (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu OI Nasr, Shahin/0000-0002-7546-9976 FU National Institutes of Health [R56-NS042861, 5P41-EB-015896-17]; Martinos Center for Biomedical Imaging FX This work was supported by the National Institutes of Health (Grant R56-NS042861 to H.D.R.) and the Martinos Center for Biomedical Imaging and National Institutes of Health (Grant 5P41-EB-015896-17). We thank Prof. Roger B.H. Tootell for help and unconditional support, all of our subjects, and the coordinators and research assistants who helped us during this study. NR 95 TC 0 Z9 0 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 5 PY 2016 VL 36 IS 40 BP 10456 EP 10471 DI 10.1523/JNEUROSCI.0741-16.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EC8BM UT WOS:000388365000020 PM 27707978 ER PT J AU Kang, HM Gravier, J Bao, K Wada, H Lee, JH Baek, Y El Fakhri, G Gioux, S Rubin, BP Coll, JL Choi, HS AF Kang, Homan Gravier, Julien Bao, Kai Wada, Hideyuki Lee, Jeong Heon Baek, Yoonji El Fakhri, Georges Gioux, Sylvain Rubin, Brian P. Coll, Jean-Luc Choi, Hak Soo TI Renal Clearable Organic Nanocarriers for Bioimaging and Drug Delivery SO ADVANCED MATERIALS LA English DT Article DE drug delivery; nanoparticles; optical imaging; renal clearance; theranostics ID CYCLODEXTRIN-CONJUGATED POLY(EPSILON-LYSINE); NEAR-INFRARED FLUOROPHORES; THERANOSTIC NANOMEDICINE; SILICA NANOPARTICLES; CANCER-THERAPY; PLATFORM; RELEASE; LIPOSOMES; SYSTEM; SIZE AB Renally cleared zwitterionic nanocarriers (H-Dots) are composed of a epsilon-polylysine backbone for charge variations, near-infrared fluorophores for bioimaging, and beta-cyclodextrins for potential drug delivery. H-Dots show ideal systemic circulation and rapid distribution, and excrete from normal tissue/organ via renal excretion after complete targeting to the tumor site without nonspecific uptake by the immune system. C1 [Kang, Homan; Gravier, Julien; Bao, Kai; Wada, Hideyuki; Lee, Jeong Heon; Baek, Yoonji; El Fakhri, Georges; Gioux, Sylvain; Choi, Hak Soo] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA. [Kang, Homan; Gravier, Julien; Bao, Kai; Wada, Hideyuki; Lee, Jeong Heon; Baek, Yoonji; El Fakhri, Georges; Gioux, Sylvain; Choi, Hak Soo] Harvard Med Sch, Boston, MA 02215 USA. [Gravier, Julien; Coll, Jean-Luc] Univ Grenoble Alpes, Inst Albert Bonniot, F-38000 Grenoble, France. [Gravier, Julien; Coll, Jean-Luc] INSERM, U1209, F-38000 Grenoble, France. [Rubin, Brian P.] Cleveland Clin, Dept Anat Pathol, Robert J Tomsich Pathol & Lab Med Inst, Lerner Res Inst, Cleveland, OH 44195 USA. [Rubin, Brian P.] Cleveland Clin, Dept Canc Biol, Robert J Tomsich Pathol & Lab Med Inst, Lerner Res Inst, Cleveland, OH 44195 USA. [Rubin, Brian P.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44195 USA. [Kang, Homan; Bao, Kai; Lee, Jeong Heon; Baek, Yoonji; El Fakhri, Georges; Choi, Hak Soo] Massachusetts Gen Hosp, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA 02114 USA. [Kang, Homan; Bao, Kai; Lee, Jeong Heon; Baek, Yoonji; El Fakhri, Georges; Choi, Hak Soo] Harvard Med Sch, Boston, MA 02114 USA. [Wada, Hideyuki] Hokkaido Univ, Grad Sch Med, Dept Surg Gastroenterol 2, Sapporo, Hokkaido 0608638, Japan. [Gioux, Sylvain] Univ Strasbourg, ICube Lab, F-67412 Illkirch Graffenstaden, France. RP Choi, HS (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA.; Choi, HS (reprint author), Harvard Med Sch, Boston, MA 02215 USA.; Coll, JL (reprint author), Univ Grenoble Alpes, Inst Albert Bonniot, F-38000 Grenoble, France.; Coll, JL (reprint author), INSERM, U1209, F-38000 Grenoble, France.; Choi, HS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA 02114 USA.; Choi, HS (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM jean-luc.coll@univ-grenoble-alpes.fr; hchoi12@mgh.harvard.edu OI Coll, Jean-Luc/0000-0002-2453-3552 FU European Project FP7 [PIOF-GA-2011-303069]; NIH/NIBIB [R01-EB-011523]; France Live Imaging (FLI-Grenoble; Infrastructure d'avenir en Biologie Sante) [ANR-11-NBS-0006]; Basic Science Research Program through the NRF of Korea [NRF-2014-R1A6A3A03057790] FX H.K. and J.G. contributed equally to this work. This study was supported by the following grants: European Project FP7 PIOF-GA-2011-303069 NanoPDT, NIH/NIBIB grant #R01-EB-011523, France Live Imaging (FLI-Grenoble; Infrastructure d'avenir en Biologie Sante, ANR-11-NBS-0006) and Basic Science Research Program through the NRF of Korea (NRF-2014-R1A6A3A03057790). NR 32 TC 4 Z9 4 U1 56 U2 56 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD OCT 5 PY 2016 VL 28 IS 37 BP 8162 EP 8168 DI 10.1002/adma.201601101 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DZ8EL UT WOS:000386103600008 PM 27414255 ER PT J AU Dean, DC Sojkova, J Hurley, S Kecskemeti, S Okonkwo, O Bendlin, BB Theisen, F Johnson, SC Alexander, AL Gallagher, CL AF Dean, Douglas C., III Sojkova, Jitka Hurley, Samuel Kecskemeti, Steven Okonkwo, Ozioma Bendlin, Barbara B. Theisen, Frances Johnson, Sterling C. Alexander, Andrew L. Gallagher, Catherine L. TI Alterations of Myelin Content in Parkinson's Disease: A Cross-Sectional Neuroimaging Study SO PLOS ONE LA English DT Article ID WHITE-MATTER; MULTIPLE-SCLEROSIS; STEADY-STATE; BRAIN MICROSTRUCTURE; MAGNETIC-RESONANCE; IMAGE REGISTRATION; NERVOUS-SYSTEM; WATER; RELAXATION; DIFFUSION AB Alterations to myelin may be a core pathological feature of neurodegenerative diseases. Although white matter microstructural differences have been described in Parkinson's disease (PD), it is unknown whether such differences include alterations of the brain's myelin content. Thus, the objective of the current study is to measure and compare brain myelin content between PD patients and age-matched controls. In this cross-sectional study, 63 participants from the Longitudinal MRI in Parkinson's Disease study underwent brain MRI, Unified Parkinson's Disease Rating Scale (UPDRS) scoring, and cognitive asessments. Subjects were imaged with the mcDEPSOT (multi-component driven equilibrium single pulse observation of T1 and T2), a multicomponent relaxometry technique that quantifies longitudinal and transverse relaxation rates (R-1 and R-2, respectively) and the myelin water fraction (VFM), a surrogate for myelin content. A voxel-wise approach was used to compare R-1, R-2, and VFM measures between PD and control groups, and to evaluate relationships with age as well as disease duration, UPDRS scores, and daily levodopa equivalent dose. PD subjects had higher VFM than controls in frontal and temporal white matter and bilateral thalamus. Greater age was strongly associated with lower VFM in both groups, while an age-by-group interaction suggested a slower rate of VFM decline in the left putamen with aging in PD. Within the PD group, measures of disease severity, including UPDRS, daily levodopa equivalent dose, and disease duration, were observed to be related with myelin content in diffuse brain regions. The age-by-group interaction suggests that either PD or dopaminergic therapies allay observed age-related myelin changes. The relationships between VFM and disease severity measures suggests that VFM may provide a surrogate marker for microstructural changes related to Parkinson's disease. C1 [Dean, Douglas C., III; Kecskemeti, Steven; Alexander, Andrew L.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Sojkova, Jitka; Theisen, Frances; Johnson, Sterling C.; Gallagher, Catherine L.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Sojkova, Jitka; Theisen, Frances; Gallagher, Catherine L.] Univ Wisconsin, Dept Neurol, Madison, WI 53706 USA. [Hurley, Samuel] Univ Oxford, Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford, Oxon, England. [Okonkwo, Ozioma; Bendlin, Barbara B.; Johnson, Sterling C.; Gallagher, Catherine L.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53706 USA. [Alexander, Andrew L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Phys, Madison, WI USA. [Alexander, Andrew L.] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. RP Gallagher, CL (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA.; Gallagher, CL (reprint author), Univ Wisconsin, Dept Neurol, Madison, WI 53706 USA.; Gallagher, CL (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53706 USA. EM gallagher@neurology.wisc.edu FU U.S. Department of Veterans Affairs [101CX000555]; National Institute of Child Health and Human Development [T32 HD007489, P30 HD003352, R21 HD078119]; National Institute on Aging [R01 AG027161, P50 AG033514, R01 AG037639] FX This work was supported by the U.S. Department of Veterans Affairs 101CX000555 to CLG; National Institute of Child Health and Human Development T32 HD007489 to DCD; National Institute of Child Health and Human Development P30 HD003352 Waisman Center; National Institute on Aging R01 AG027161 to SCJ; National Institute on Aging P50 AG033514 University of Wisconsin Madison; National Institute of Child Health and Human Development R21 HD078119 to ALA and the National Institute on Aging R01 AG037639 to BBB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 1 Z9 1 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 5 PY 2016 VL 11 IS 10 AR e0163774 DI 10.1371/journal.pone.0163774 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ2UN UT WOS:000385697200057 PM 27706215 ER PT J AU Gagnon, L Sakadzic, S Lesage, F Pouliot, P Dale, AM Devor, A Buxton, RB Boas, DA AF Gagnon, Louis Sakadzic, Sava Lesage, Frederic Pouliot, Philippe Dale, Anders M. Devor, Anna Buxton, Richard B. Boas, David A. TI Validation and optimization of hypercapnic-calibrated fMRI from oxygen-sensitive two-photon microscopy SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE calibrated fMRI; cerebral metabolism; two-photon microscopy; Monte Carlo simulations ID CEREBRAL-BLOOD-FLOW; OPTICAL COHERENCE TOMOGRAPHY; BOLD SIGNAL; EXTRACTION FRACTION; NEURONAL-ACTIVITY; FUNCTIONAL MRI; SOMATOSENSORY CORTEX; OXIDATIVE-METABOLISM; BRAIN ACTIVATION; NEURAL ACTIVITY AB Hypercapnic-calibrated fMRI allows the estimation of the relative changes in the cerebral metabolic rate of oxygen (rCMRO(2)) from combined BOLD and arterial spin labelling measurements during a functional task, and promises to permit more quantitative analyses of brain activity patterns. The estimation relies on a macroscopic model of the BOLD effect that balances oxygen delivery and consumption to predict haemoglobin oxygenation and the BOLD signal. The accuracy of calibrated fMRI approaches has not been firmly established, which is limiting their broader adoption. We use our recently developed microscopic vascular anatomical network model in mice as a ground truth simulator to test the accuracy of macroscopic, lumped-parameter BOLD models. In particular, we investigate the original Davis model and a more recent heuristic simplification. We find that these macroscopic models are inaccurate using the originally defined parameters, but that the accuracy can be significantly improved by redefining the model parameters to take on new values. In particular, we find that the parameter a that relates cerebral blood-volume changes to cerebral blood-flow changes is significantly smaller than typically assumed and that the optimal value changes with magnetic field strength. The results are encouraging in that they support the use of simple BOLD models to quantify BOLD signals, but further work is needed to understand the physiological interpretation of the redefined model parameters. This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. C1 [Gagnon, Louis; Sakadzic, Sava; Devor, Anna; Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gagnon, Louis] Univ Laval, Dept Med, Quebec City, PQ, Canada. [Gagnon, Louis; Lesage, Frederic; Pouliot, Philippe] Ecole Polytech, Dept Elect Engn, Montreal, PQ, Canada. [Dale, Anders M.; Devor, Anna] UCSD, Dept Neurosci & Radiol, La Jolla, CA USA. [Buxton, Richard B.] UCSD, Dept Radiol, La Jolla, CA USA. RP Gagnon, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Gagnon, L (reprint author), Univ Laval, Dept Med, Quebec City, PQ, Canada.; Gagnon, L (reprint author), Ecole Polytech, Dept Elect Engn, Montreal, PQ, Canada. EM lgagnon@nmr.mgh.harvard.edu FU NIH [P41RR14075, R01NS057476, R00NS067050, R01NS057198, R01EB000790]; American Heart Association [11SDG7600037]; Advanced Multimodal NeuroImaging Training Program [R90DA023427] FX This work was supported by NIH grants nos. P41RR14075, R01NS057476, R00NS067050, R01NS057198 and R01EB000790, American Heart Association grant no. 11SDG7600037, and the Advanced Multimodal NeuroImaging Training Program (R90DA023427 to L.G.). NR 68 TC 2 Z9 2 U1 5 U2 5 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 5 PY 2016 VL 371 IS 1705 AR 20150359 DI 10.1098/rstb.2015.0359 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DW2XP UT WOS:000383505900010 ER PT J AU Wong, SJ Gearhart, MD Taylor, AB Nanyes, DR Ha, DJ Robinson, AK Artigas, JA Lee, OJ Demeler, B Hart, PJ Bardwell, VJ Kim, CA AF Wong, Sarah J. Gearhart, Micah D. Taylor, Alexander B. Nanyes, David R. Ha, Daniel J. Robinson, Angela K. Artigas, Jason A. Lee, Oliver J. Demeler, Borries Hart, P. John Bardwell, Vivian J. Kim, Chongwoo A. TI KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1 SO STRUCTURE LA English DT Article ID INTERNAL TANDEM DUPLICATIONS; CLEAR-CELL SARCOMA; REPRESSIVE COMPLEX; H2A UBIQUITYLATION; CPG ISLANDS; REGULATOR; HOMOLOGS; PROTEINS; TARGETS; GENOME AB KDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repression. We investigated the molecular basis of recruitment using in vitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA-binding KDM2B/SKP1 heterodimer and the heterodimer of BCORL1 and PCGF1, a core component of PRC1.1. The crystal structure of the KDM2B/ SKP1/BCORL1/PCGF1 complex illustrates the crucial role played by the PCGF1/BCORL1 heterodimer. The BCORL1 PUFD domain positions residues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B, which is unique to the PCGF1-containing PRC1.1 complex. The structure also suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex and the possible molecular consequences of BCOR PUFD internal tandem duplications found in pediatric kidney and brain tumors. C1 [Wong, Sarah J.; Taylor, Alexander B.; Nanyes, David R.; Ha, Daniel J.; Robinson, Angela K.; Demeler, Borries; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, MSC 7760,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Wong, Sarah J.; Taylor, Alexander B.; Nanyes, David R.; Ha, Daniel J.; Robinson, Angela K.; Demeler, Borries; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, CTRC, MSC 7760,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Gearhart, Micah D.] Univ Minnesota, Masonic Canc Ctr, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Gearhart, Micah D.] Univ Minnesota, Ctr Dev Biol, Minneapolis, MN 55455 USA. [Artigas, Jason A.; Lee, Oliver J.; Kim, Chongwoo A.] Midwestern Univ, Dept Biochem, 19555 North 59th Ave, Glendale, AZ 85308 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Kim, CA (reprint author), Midwestern Univ, Dept Biochem, 19555 North 59th Ave, Glendale, AZ 85308 USA. EM ckim@midwestern.edu FU Welch Foundation [AQ-1813, AQ-1399]; NIGMS of the NIH [R01GM114338]; NIH [F31GM099418, R01CA071540, P41GM103403]; Minnesota Masonic Charities; University of Minnesota Medical School; National Science Foundation [ACI-1339649]; XSEDE [MCB-070039]; Vice President for Research and a National Cancer Institute P30 Cancer Center Support Grant [CA054174]; DOE [DE-AC02-06CH11357] FX C.A.K. was supported by the Welch Foundation (AQ-1813) and the NIGMS of the NIH under award number R01GM114338. S.J.W. was supported by the NIH (F31GM099418). V.J.B. was supported by the NIH (R01CA071540) and funds from the Minnesota Masonic Charities, and the University of Minnesota Medical School. B.D. acknowledges support from the National Science Foundation (ACI-1339649) and XSEDE (MCB-070039). P.J.H. was supported by the Welch Foundation (AQ-1399). The University of Texas Health Science Center at San Antonio (UTHSCSA) X-ray Crystallography Core Laboratory is supported in part by the Vice President for Research and a National Cancer Institute P30 Cancer Center Support Grant (CA054174) awarded to the CTRC at UTHSCSA. NECAT beamline 24-ID-C is supported in part by the NIH (P41GM103403) and the DOE (DE-AC02-06CH11357 NR 27 TC 2 Z9 2 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD OCT 4 PY 2016 VL 24 IS 10 BP 1795 EP 1801 DI 10.1016/j.str.2016.07.011 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EA6UF UT WOS:000386763800018 PM 27568929 ER PT J AU Sprague, BL Conant, EF Onega, T Garcia, MP Beaber, EF Herschorn, SD Lehman, CD Tosteson, ANA Lacson, R Schnall, MD Kontos, D Haas, JS Weaver, DL Barlow, WE AF Sprague, Brian L. Conant, Emily F. Onega, Tracy Garcia, Michael P. Beaber, Elisabeth F. Herschorn, Sally D. Lehman, Constance D. Tosteson, Anna N. A. Lacson, Ronilda Schnall, Mitchell D. Kontos, Despina Haas, Jennifer S. Weaver, Donald L. Barlow, William E. CA PROSPR Consortium TI Variation in Mammographic Breast Density Assessments Among Radiologists in Clinical Practice A Multicenter Observational Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID DATA SYSTEM; SCREENING MAMMOGRAPHY; UNITED-STATES; CANCER; RISK; LEGISLATION; COHORT; VARIABILITY; ACCURACY; MODEL AB Background: About half of the United States has legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts. Objective: To examine variation in breast density assessment across radiologists in clinical practice. Design: Cross-sectional and longitudinal analyses of prospectively collected observational data. Setting: 30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Participants: Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included. Measurements: Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "dense" for analyses), and patient age, race, and body mass index (BMI). Results: Overall, 36.9% of mammograms were rated as showing dense breasts. Across radiologists, this percentage ranged from 6.3% to 84.5% (median, 38.7% [interquartile range, 28.9% to 50.9%]), with multivariable adjustment for patient characteristics having little effect (interquartile range, 29.9% to 50.8%). Examination of patient subgroups revealed that variation in density assessment across radiologists was pervasive in all but the most extreme patient age and BMI combinations. Among women with consecutive mammograms interpreted by different radiologists, 17.2% (5909 of 34 271) had discordant assessments of dense versus nondense status. Limitation: Quantitative measures of mammographic breast density were not available for comparison. Conclusion: There is wide variation in density assessment across radiologists that should be carefully considered by providers and policymakers when considering supplemental screening strategies. The likelihood of a woman being told she has dense breasts varies substantially according to which radiologist interprets her mammogram. C1 [Sprague, Brian L.] Univ Vermont, Off Hlth Promot Res, 1 South Prospect St,UHC Room 4425, Burlington, VT 05401 USA. [Conant, Emily F.; Schnall, Mitchell D.] Univ Penn, Dept Radiol, Perelman Sch Med, 1 Silverstein,3400 Spruce St, Philadelphia, PA 19104 USA. [Onega, Tracy; Tosteson, Anna N. A.] Geisel Sch Med Dartmouth, Dartmouth Inst Hlth Policy & Clin Practice, 1 Med Ctr Dr HB7505, Lebanon, NH 03756 USA. [Garcia, Michael P.] Fred Hutchinson Canc Res Ctr, M3-C102,1100 Fairview Ave North, Seattle, WA 98109 USA. [Beaber, Elisabeth F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave North, Seattle, WA 98109 USA. [Herschorn, Sally D.] Univ Vermont, Dept Radiol, Med Ctr, 111 Colchester Ave, Burlington, VT 05401 USA. [Lehman, Constance D.] Massachusetts Gen Hosp, Radiol Associates, 15 Parkman St, Boston, MA 02114 USA. [Lacson, Ronilda] Brigham & Womens Hosp, Dept Radiol, Ctr Evidence Based Imaging, 20 Kent St, Brookline, MA 02445 USA. [Kontos, Despina] Univ Penn, Perelman Sch Med, Dept Radiol, Room D702,Richards Bldg,3700 Hamilton Walk, Philadelphia, PA 19104 USA. [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St, Boston, MA 02115 USA. [Weaver, Donald L.] Univ Vermont, Dept Pathol, Coll Med, 89 Beaumont Ave, Burlington, VT 05405 USA. [Barlow, William E.] Canc Res & Biostat, 1730 Minor Ave,Suite 1900, Seattle, WA 98101 USA. RP Sprague, BL (reprint author), Univ Vermont, Off Hlth Promot Res, 1 South Prospect St,UHC Room 4425, Burlington, VT 05401 USA. FU National Institutes of Health FX National Institutes of Health. NR 33 TC 2 Z9 2 U1 4 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 4 PY 2016 VL 165 IS 7 BP 457 EP + DI 10.7326/M15-2934 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DY0EY UT WOS:000384771300003 PM 27428568 ER PT J AU Fried, LF Palevsky, PM AF Fried, Linda F. Palevsky, Paul M. TI Decreasing Prevalence of Chronic Kidney Disease in the United States: A Cause for Optimism SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Fried, Linda F.; Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Renal Sect 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu NR 10 TC 1 Z9 1 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 4 PY 2016 VL 165 IS 7 BP 521 EP + DI 10.7326/M16-1649 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DY0EY UT WOS:000384771300012 PM 27479750 ER PT J AU Daneshvar, K Pondick, JV Kim, BM Zhou, C York, SR Macklin, JA Abualteen, A Tan, B Sigova, AA Marcho, C Tremblay, KD Mager, J Choi, MY Mullen, AC AF Daneshvar, Kaveh Pondick, Joshua V. Kim, Byeong-Moo Zhou, Chan York, Samuel R. Macklin, Jillian A. Abualteen, Ameed Tan, Bo Sigova, Alla A. Marcho, Chelsea Tremblay, Kimberly D. Mager, Jesse Choi, Michael Y. Mullen, Alan C. TI DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells SO CELL REPORTS LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; DIVERGENT TRANSCRIPTION; GENE-EXPRESSION; MOUSE EMBRYO; PROMOTERS; CHROMATIN; GASTRULATION; ORGANIZER; ELEMENTS; REVEALS AB Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm. C1 [Daneshvar, Kaveh; Pondick, Joshua V.; Kim, Byeong-Moo; Zhou, Chan; York, Samuel R.; Macklin, Jillian A.; Abualteen, Ameed; Tan, Bo; Choi, Michael Y.; Mullen, Alan C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Abualteen, Ameed; Choi, Michael Y.; Mullen, Alan C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tan, Bo] Guangzhou Univ Chinese Med, Sch Fundamental Med Sci, Guangzhou 510405, Guangdong, Peoples R China. [Sigova, Alla A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Marcho, Chelsea; Tremblay, Kimberly D.; Mager, Jesse] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. RP Mullen, AC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA.; Mullen, AC (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM acmullen@mgh.harvard.edu FU NIH [DK090122, DK104009]; MGH startup funds FX We would like to thank the MGH/HSCI Flow Cytometry Core Facility and Meredith Weglarz for technical support; the MGH/PBM microscopy core, Biosearch Technologies, and Marc Beal for assistance with RNA-FISH; and Kate Jeffrey, Konrad Hochedlinger, Igor Ulitsky, Cosmas Giallourakis, Abid Khan, and Jennifer Chen for helpful discussion. This work was supported by NIH grants DK090122 and DK104009 and MGH startup funds (A.C.M.). NR 59 TC 0 Z9 0 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD OCT 4 PY 2016 VL 17 IS 2 BP 353 EP 365 DI 10.1016/j.celrep.2016.09.017 PG 13 WC Cell Biology SC Cell Biology GA DZ4SS UT WOS:000385850700005 PM 27705785 ER PT J AU Isselbacher, EM Bonaca, MP Di Eusanio, M Froehlich, J Bassone, E Sechtem, U Pyeritz, R Patel, H Khoynezhad, A Eckstein, HH Jondeau, G Ramponi, F Abbasi, M Montgomery, D Nienaber, CA Eagle, K Lindsay, ME AF Isselbacher, Eric M. Bonaca, Marc P. Di Eusanio, Marco Froehlich, James Bassone, Eduardo Sechtem, Udo Pyeritz, Reed Patel, Himanshu Khoynezhad, Ali Eckstein, Hans-Henning Jondeau, Guillaume Ramponi, Fabio Abbasi, Mohammad Montgomery, Daniel Nienaber, Christoph A. Eagle, Kim Lindsay, Mark E. CA Int Registry Aortic Dissection TI Recurrent Aortic Dissection Observations From the International Registry of Aortic Dissection SO CIRCULATION LA English DT Article DE aorta; aortic aneurysm; Marfan syndrome ID MARFAN-SYNDROME; TGFBR2 MUTATIONS; ANEURYSM; DISEASE; REPAIR; DETERMINES; FATE AB BACKGROUND: Improved medical care after initial aortic dissection (AD) has led to increased survivorship and a population of individuals at risk for further cardiovascular events, including recurrent AD. Reports describing recurrent ADs have been restricted to small numbers of patients from single institutions. We used the IRAD (International Registry of Acute Aortic Dissection) database to examine the clinical profiles and outcomes of patients with recurrent AD. METHODS: We identified 204 patients enrolled in IRAD with recurrent AD. For the primary analysis, patient characteristics, interventions, and outcomes were analyzed and compared with 3624 patients with initial AD. Iterative logistic modeling was performed to investigate variables associated with recurrent AD. Cox regression analyses were used to determine variables associated with 5-year survival. A subset of recurrent AD patients was analyzed for anatomic and demographic details of initial and recurrent ADs. RESULTS: Patients with recurrent AD were more likely to have Marfan syndrome (21.5% versus 3.1%; P<0.001) but not bicuspid aortic valve (3.6% versus 3.2%; P=0.77). Descending aortic dimensions were greater in patients with recurrent AD than in patients with initial AD independently of sentinel dissection type (type A: 4.3 cm [3.5-5.6 cm] versus 3.3 cm [2.9-3.7 cm], P<0.001; type B: 5.0 cm [3.9-6.0 cm] versus 4.0 cm [3.5-4.8 cm], P<0.001), and this observation was accentuated among patients with Marfan syndrome. In multivariate analysis, the diagnosis of Marfan syndrome independently predicted recurrent AD (hazard ratio, 8.6; 95% confidence interval, 5.8-12.8; P<0.001). Patients with recurrent AD who presented with proximal followed by distal AD were younger than patients who experienced distal followed by proximal dissection AD (42.1 +/- 16.1 versus 54.3 +/- 14.8 years; P=0.004). CONCLUSIONS: Among those suffering acute aortic dissection, 5% have a history of a prior aortic dissection. Recurrent AD is strongly associated with Marfan syndrome. C1 [Isselbacher, Eric M.; Abbasi, Mohammad; Lindsay, Mark E.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Isselbacher, Eric M.; Lindsay, Mark E.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Abbasi, Mohammad; Lindsay, Mark E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lindsay, Mark E.] Massachusetts Gen Hosp, Dept Pediat, Div Pediat Cardiol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Bonaca, Marc P.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Di Eusanio, Marco] Univ Hosp S Orsola, Dept Cardiac Surg, Bologna, Italy. [Froehlich, James; Montgomery, Daniel; Eagle, Kim] Univ Michigan, Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Patel, Himanshu] Univ Michigan, Cardiac Surg, Ann Arbor, MI 48109 USA. [Bassone, Eduardo] Univ Salerno, Div Cardiol, Salerno, Italy. [Sechtem, Udo] Robert Bosch Krankenhaus, Dept Cardiol, Stuttgart, Germany. [Pyeritz, Reed] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pyeritz, Reed] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Khoynezhad, Ali] Cedars Sinai Med Ctr, Div Cardiothorac Surg, Los Angeles, CA 90048 USA. [Eckstein, Hans-Henning] Tech Univ Munich, Klinikum Rechts Isar, Dept Vasc & Endovasc Surg, Munich, Germany. [Jondeau, Guillaume] Univ Paris, Hop Bichat, Paris, France. [Ramponi, Fabio] Royal Prince Alfred Hosp, Dept Cardiothorac Surg, Sydney, NSW, Australia. [Nienaber, Christoph A.] Royal Brompton & Harefield NHS Trust, Cardiol & Aort Ctr, London, England. RP Lindsay, ME (reprint author), Massachusetts Gen Hosp, Richard B Simches Res Bldg,Room 3224, Boston, MA 02114 USA. EM lindsay.mark@mgh.harvard.edu FU Gore Medical; Metronic; Terumo Medical; Hewlett Foundation; Robert and Anne Aikens; Varbedian Fund for Aortic Research; Mardigian Foundation; Fredman Fellowship; Toomey Fund for Aortic Dissection Research FX IRAD is funded in part by Gore Medical, Metronic, Terumo Medical, The Hewlett Foundation, Robert and Anne Aikens, the Varbedian Fund for Aortic Research, and the Mardigian Foundation. Dr Lindsay is supported by the Fredman Fellowship and the Toomey Fund for Aortic Dissection Research. NR 27 TC 2 Z9 3 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 4 PY 2016 VL 134 IS 14 BP 1013 EP 1024 DI 10.1161/CIRCULATIONAHA.115.019359 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DZ2KC UT WOS:000385669700010 PM 27587434 ER PT J AU Cizmecioglu, O Ni, J Xie, SZ Zhao, JJ Roberts, TM AF Cizmecioglu, Onur Ni, Jing Xie, Shaozhen Zhao, Jean J. Roberts, Thomas M. TI Rac1-mediated membrane raft localization of PI3K/p110 beta is required for its activation by GPCRs or PTEN loss SO ELIFE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; PLASMA-MEMBRANE; LIPID RAFTS; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHOINOSITIDE 3-KINASES; SIGNAL-TRANSDUCTION; P110-BETA ISOFORMS; TUMOR-SUPPRESSOR; EGF RECEPTOR; P110-ALPHA AB We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110 alpha and p110 beta. We found that p110 beta localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110 beta to rafts alleviated the requirement for p110 beta-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110 alpha, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110 alpha allowed its EGFR-mediated activation by GPCRs. Notably, p110 beta dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110 beta. C1 [Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean J.; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean J.; Roberts, Thomas M.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Roberts, TM (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM thomas_roberts@dfci.harvard.edu FU National Institutes of Health [P50 CA168504-01A1, P50 CA165962-01A1, CA172461-01, P01-CA50661, CA30002]; Stand Up To Cancer Translational Research Grant [SU2C-AACR-DT0209] FX National Institutes of Health P50 CA168504-01A1 Jean J Zhao Thomas M Roberts; National Institutes of Health P50 CA165962-01A1 Jean J Zhao Thomas M Roberts; National Institutes of Health CA172461-01 Jean J Zhao; Stand Up To Cancer Translational Research Grant SU2C-AACR-DT0209 Jean J Zhao Thomas M Roberts; National Institutes of Health P01-CA50661 Thomas M Roberts; National Institutes of Health CA30002 Thomas M Roberts NR 45 TC 0 Z9 0 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 4 PY 2016 VL 5 AR e17635 DI 10.7554/eLife.17635 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DZ1YG UT WOS:000385637400001 ER PT J AU Lee, JJ Pedley, A Hoffmann, U Massaro, JM Fox, CS AF Lee, Jane J. Pedley, Alison Hoffmann, Udo Massaro, Joseph M. Fox, Caroline S. TI Association of Changes in Abdominal Fat Quantity and Quality With Incident Cardiovascular Disease Risk Factors SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; computed tomography; epidemiology; fat attenuation; subcutaneous adipose tissue; visceral adipose tissue ID SUBCUTANEOUS ADIPOSE-TISSUE; INTRAABDOMINAL VISCERAL FAT; CARDIOMETABOLIC RISK; BLOOD-PRESSURE; LONGITUDINAL CHANGES; INSULIN SENSITIVITY; JAPANESE-AMERICANS; METABOLIC SYNDROME; HITACHI HEALTH; OBESITY AB BACKGROUND Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are associated with adverse cardiometabolic risk profiles. OBJECTIVES This study explored the degree to which changes in abdominal fat quantity and quality are associated with changes in cardiovascular disease (CVD) risk factors. METHODS Study participants (n = 1,106; 44.1% women; mean baseline age 45.1 years) were drawn from the Framingham Heart Study Third Generation cohort who participated in the computed tomography (CT) substudy Exams 1 and 2. Participants were followed for 6.1 years on average. Abdominal adipose tissue volume in cm(3) and attenuation in Hounsfield units (HU) were determined by CT-acquired abdominal scans. RESULTS The mean fat volume change was an increase of 602 cm(3) for SAT and an increase of 703 cm(3) for VAT; the mean fat attenuation change was a decrease of 5.5 HU for SAT and an increase of 0.07 HU for VAT. An increase in fat volume and decrease in fat attenuation were associated with adverse changes in CVD risk factors. An additional 500 cm(3) increase in fat volume was associated with incident hypertension (odds ratio [OR]: 1.21 for SAT; OR: 1.30 for VAT), hypertriglyceridemia (OR: 1.15 for SAT; OR: 1.56 for VAT), and metabolic syndrome (OR: 1.43 for SAT; OR: 1.82 for VAT; all p < 0.05). Similar trends were observed for each additional 5 HU decrease in abdominal adipose tissue attenuation. Most associations remained significant even after further accounting for body mass index change, waist circumference change, or respective abdominal adipose tissue volumes. CONCLUSIONS Increasing accumulation of fat quantity and decreasing fat attenuation are associated with worsening of CVD risk factors beyond the associations with generalized adiposity, central adiposity, or respective adipose tissue volumes. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Lee, Jane J.; Pedley, Alison; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Lee, Jane J.; Pedley, Alison; Fox, Caroline S.] NHLBI, Populat Studies Branch, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; National Institutes of Health; or the U.S. Department of Health and Human Services. Drs. Pedley and Fox are employees of Merck & Company, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 45 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 4 PY 2016 VL 68 IS 14 BP 1509 EP 1521 DI 10.1016/j.jacc.2016.06.067 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DZ5XC UT WOS:000385934400003 PM 27687192 ER PT J AU O'Grady, GL Verschuuren, C Yuen, M Webster, R Menezes, M Fock, JM Pride, N Best, HA Damm, TB Turner, C Lek, M Engel, AG North, KN Clarke, NF MacArthur, DG Kamsteeg, EJ Cooper, ST AF O'Grady, Gina L. Verschuuren, Corien Yuen, Michaela Webster, Richard Menezes, Manoj Fock, Johanna M. Pride, Natalie Best, Heather A. Damm, Tatiana Benavides Turner, Christian Lek, Monkol Engel, Andrew G. North, Kathryn N. Clarke, Nigel F. MacArthur, Daniel G. Kamsteeg, Erik-Jan Cooper, Sandra T. TI Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome SO NEUROLOGY LA English DT Article ID MUTATIONS CAUSE; ELECTROMYOGRAPHY; DIAGNOSIS AB Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans. C1 [O'Grady, Gina L.; Yuen, Michaela; Pride, Natalie; Best, Heather A.; Damm, Tatiana Benavides; North, Kathryn N.; Clarke, Nigel F.; Cooper, Sandra T.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Webster, Richard; Menezes, Manoj] Childrens Hosp Westmead, Kids Res Inst, TY Dept Neurol, Sydney, NSW, Australia. [Turner, Christian] Childrens Hosp Westmead, Heart Ctr Children, Sydney, NSW, Australia. [O'Grady, Gina L.; Menezes, Manoj; Best, Heather A.; North, Kathryn N.; Clarke, Nigel F.; Cooper, Sandra T.] Univ Sydney, Fac Med, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Verschuuren, Corien] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 AB Groningen, Netherlands. [Fock, Johanna M.] Univ Groningen, Univ Med Ctr Groningen, Dept Child Neurol, NL-9700 AB Groningen, Netherlands. [Lek, Monkol; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; MacArthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Engel, Andrew G.] Mayo Clin, Dept Neurol, Rochester, MN USA. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia. [Kamsteeg, Erik-Jan] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. RP Cooper, ST (reprint author), Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia.; Cooper, ST (reprint author), Univ Sydney, Fac Med, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. EM Sandra.cooper@sydney.edu.au RI North, Kathryn/K-6476-2012 OI North, Kathryn/0000-0003-0841-8009 FU National Health and Medical Research Council of Australia [1022707, 1031893, 1080587, 1056285, 1048816]; National Human Genome Research Institute of the US National Institutes of Health [U54 HG003067]; National Institute of Health [NS6277] FX This work was supported by the National Health and Medical Research Council of Australia (grant numbers 1022707 to N.F.C. and K.N.N., 1031893 to N.F.C. and K.N.N., 1080587 to D.G.M., K.N.N., N.F.C., and S.T.C., 1056285 to G.L.O., and 1048816 to S.T.C.). Exome sequencing was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander). Work done in Dr. Engel's laboratory was supported by National Institute of Health (grant number NS6277). NR 21 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 4 PY 2016 VL 87 IS 14 BP 1442 EP 1448 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DZ2FC UT WOS:000385656700011 PM 27590285 ER PT J AU van Etten, ES Gurol, ME van der Grond, J Haan, J Viswanathan, A Schwab, KM Ayres, AM Algra, A Rosand, J van Buchem, MA Terwindt, GM Greenberg, SM Wermer, MJH AF van Etten, Ellis S. Gurol, M. Edip van der Grond, Jeroen Haan, Joost Viswanathan, Anand Schwab, Kristin M. Ayres, Alison M. Algra, Ale Rosand, Jonathan van Buchem, Mark A. Terwindt, Gisela M. Greenberg, Steven M. Wermer, Marieke J. H. TI Recurrent hemorrhage risk and mortality in hereditary and sporadic cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID DUTCH TYPE; INTRACEREBRAL HEMORRHAGE; HCHWA-D; CLINICAL-DIAGNOSIS; SPECTRUM; GENE AB Objective: To determine whether hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease model for the sporadic variant of amyloid angiopathy (sCAA), has a comparable recurrent intracerebral hemorrhage (ICH) risk and mortality after a first symptomatic ICH. Methods: We included patients with HCHWA-D from the Leiden University Medical Center and patients with sCAA from the Massachusetts General Hospital in a cohort study. Baseline characteristics, hemorrhage recurrence, and short-and long-term mortality were compared. Hazard ratios (HRs) adjusted for age and sex were calculated with Cox regression analyses. Results: We included 58 patients with HCHWA-D and 316 patients with sCAA. Patients with HCHWA-D had fewer cardiovascular risk factors (>= 1 risk factor 24% vs 70% in sCAA) and were younger at the time of presenting hemorrhage (mean age 54 vs 72 years in sCAA). Eight patients (14%) with HCHWA-D and 46 patients (15%) with sCAA died before 90 days. During a mean follow-up time of 5 +/- 4 years (total 1,550 person-years), the incidence rate of recurrent ICH in patients with HCHWA-D was 20.9 vs 8.9 per 100 person-years in sCAA. Patients with HCHWA-D had a long-term mortality of 8.2 vs 8.4 per 100 person-years in patients with sCAA. After adjustments, patients with HCHWA-D had a higher risk of recurrent ICH (HR 2.8; 95% confidence interval 1.6-4.9; p < 0.001) and a higher long-term mortality (HR 2.8; 95% confidence interval 1.5-5.2; p = 0.001). Conclusions: Patients with HCHWA-D have worse long-term prognosis after a first ICH than patients with sCAA. The absence of cardiovascular risk factors in most patients with HCHWA-D suggests that vascular amyloid is responsible for the recurrent hemorrhages. HCHWA-D is therefore a pure form of cerebral amyloid angiopathy with an accelerated clinical course and provides a good model to study the pathophysiology and future therapeutic interventions of amyloid-related hemorrhages. C1 [van Etten, Ellis S.; Haan, Joost; Terwindt, Gisela M.; Wermer, Marieke J. H.] Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. [van der Grond, Jeroen; van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RA Leiden, Netherlands. [Algra, Ale] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RA Leiden, Netherlands. [Haan, Joost] Alrijne Hosp, Dept Neurol, Leiderdorp, Netherlands. [Algra, Ale] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands. Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Gurol, M. Edip; Viswanathan, Anand; Schwab, Kristin M.; Ayres, Alison M.; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Stroke Res Ctr, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Rosand, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA USA. RP van Etten, ES (reprint author), Leiden Univ, Med Ctr, Dept Neurol, NL-2300 RA Leiden, Netherlands. EM e.s.van_etten@lumc.nl FU National Institute of Neurologic Disorders and Stroke [K23 NS083711, T32NS048005, R01 NS070834]; National Institute on Aging [R01AG26484] FX National Institute of Neurologic Disorders and Stroke (K23 NS083711, T32NS048005, R01 NS070834) and the National Institute on Aging (R01AG26484). Funding: J.R., S.M.G., A.V., M.E.G., M.J.H.W. NR 23 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 4 PY 2016 VL 87 IS 14 BP 1482 EP 1487 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DZ2FC UT WOS:000385656700016 PM 27590282 ER PT J AU Lauer, A van Veluw, SJ William, CM Charidimou, A Roongpiboonsopit, D Vashkevich, A Ayres, A Martinez-Ramirez, S Gurol, EM Biessels, GJ Frosch, M Greenberg, SM Viswanathan, A AF Lauer, Arne van Veluw, Susanne J. William, Christopher M. Charidimou, Andreas Roongpiboonsopit, Duangnapa Vashkevich, Anastasia Ayres, Alison Martinez-Ramirez, Sergi Gurol, Edip M. Biessels, Geert Jan Frosch, Matthew Greenberg, Steven M. Viswanathan, Anand TI Microbleeds on MRI are associated with microinfarcts on autopsy in cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID DISEASE AB Objectives: To identify in vivo MRI markers that might correlate with cerebral microinfarcts (CMIs) on autopsy in patients with cerebral amyloid angiopathy (CAA). Methods: We included patients with neuropathologic evidence of CAA on autopsy and available antemortem brain MRI. Clinical characteristics and in vivo MRI markers of CAA-related small vessel disease were recorded, including white matter hyperintensities, cerebral microbleeds, cortical superficial siderosis, and centrum semiovale perivascular spaces. In addition, the presence of intracerebral hemorrhage on MRI was assessed. Evaluation of the presence and number of CMIs was performed in 9 standard histology sections. Results: Of 49 analyzed patients with CAA, CMIs were present in 36.7%. The presence of >= 1 CMIs on autopsy was associated with higher numbers of microbleeds on antemortem MRI (median 8 [interquartile range 2.5-33.0] vs 1 [interquartile range 0-3], p = 0.003) and with the presence of intracerebral hemorrhage (44.4% vs 16.1%, p = 0.03). No associations between CMIs and other in vivo MRI markers of CAA were found. In a multivariable model adjusted for severe CAA pathology, higher numbers of microbleeds were independent predictors of the presence of CMIs on pathology. Conclusions: CMIs are a common finding at autopsy in patients with CAA. The strong association between MRI-observed microbleeds and CMIs at autopsy may suggest a shared underlying pathophysiologic mechanism between these lesions. C1 [Lauer, Arne; van Veluw, Susanne J.; Charidimou, Andreas; Roongpiboonsopit, Duangnapa; Vashkevich, Anastasia; Ayres, Alison; Martinez-Ramirez, Sergi; Gurol, Edip M.; Greenberg, Steven M.; Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA USA. [van Veluw, Susanne J.; Biessels, Geert Jan] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands. [William, Christopher M.] NYU, Sch Med, Dept Pathol, Langone Med Ctr, New York, NY USA. [Roongpiboonsopit, Duangnapa] Naresuan Univ, Fac Med, Dept Med, Phitsanulok, Thailand. [Frosch, Matthew] Harvard Med Sch, Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA USA. RP Lauer, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA USA. EM arne.lauer@gmx.de FU NIH [R01AG047975, R01AG026484, P50AG005134, K23AG02872605] FX This work was supported by the NIH (grants R01AG047975, R01AG026484, P50AG005134, K23AG02872605). NR 12 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 4 PY 2016 VL 87 IS 14 BP 1488 EP 1492 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DZ2FC UT WOS:000385656700017 PM 27613583 ER PT J AU Galan, JA Avruch, J AF Galan, Jacob A. Avruch, Joseph TI MST1/MST2 Protein Kinases: Regulation and Physiologic Roles SO BIOCHEMISTRY LA English DT Article ID HIPPO SIGNALING PATHWAY; CASPASE-MEDIATED ACTIVATION; TUMOR-SUPPRESSOR RASSF1A; CELL-CYCLE EXIT; PROMOTES APOPTOSIS; OXIDATIVE-STRESS; STRUCTURAL BASIS; FAMILY PROTEIN; MST1 KINASE; CENTROSOME DISJUNCTION AB The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with. the other polypeptides that: contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to, constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus: Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap l's control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2's physiologic programs and contributions to pathophysiology remains to be elucidated. C1 [Galan, Jacob A.; Avruch, Joseph] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Galan, Jacob A.; Avruch, Joseph] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Galan, Jacob A.; Avruch, Joseph] Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. [Galan, Jacob A.; Avruch, Joseph] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Avruch, J (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA.; Avruch, J (reprint author), Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA.; Avruch, J (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM avruch@molbio.mgh.harvard.edu FU National Institutes of Health [CA136567, DK017776, DK007028] FX This work was supported by National Institutes of Health Grants CA136567, DK017776, and DK007028. NR 152 TC 0 Z9 0 U1 6 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 4 PY 2016 VL 55 IS 39 BP 5507 EP 5519 DI 10.1021/acs.biochem.6b00763 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DY1GE UT WOS:000384842100002 PM 27618557 ER PT J AU Goroll, AH AF Goroll, Allan H. TI Primary Care "Provider" and Professional Identity Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Goroll, Allan H.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Goroll, AH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, 15 Parkman,St,Ste 645, Boston, MA 02114 USA. EM ahgoroll@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 4 PY 2016 VL 316 IS 13 BP 1412 EP 1412 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DX7TC UT WOS:000384591300029 PM 27701656 ER PT J AU Ledoux, WR Pai, S Shofer, JB Wang, YN AF Ledoux, William R. Pai, Shruti Shofer, Jane B. Wang, Yak-Nam TI The association between mechanical and biochemical/histological characteristics in diabetic and non-diabetic plantar soft tissue SO JOURNAL OF BIOMECHANICS LA English DT Article DE Foot; Diabetes; Subcutaneous; Ulceration; Plantar soft tissue; Adipose ID LOWER-EXTREMITY AMPUTATION; PERIPHERAL NEUROPATHY; HEEL-PAD; STEREOLOGICAL METHODS; CONNECTIVE-TISSUE; FOOT ULCERS; FAT PADS; MELLITUS; THICKNESS; STIFFNESS AB Diabetes, and the subsequent complication of lower limb ulcers leading to potential amputation, remains an important health care problem in United States, even with declining amputation rates. It has been well documented that diabetes can alter the mechanical properties (i.e., increased stiffness) of the plantar soft tissue, although this finding is not universal. Similarly, biochemical, and histological changes have been found in the plantar soft tissue, but, as with the mechanical changes, these findings are not consistent across all studies. Our group's work has demonstrated that diabetes increases plantar soft tissue modulus and increases elastic septal thickness. The purpose of the current study was to explore the association between mechanical, biochemical and histological properties. Using previously collected data, a linear mixed effects regression was conducted. The correlations were weak; of the 32 that were tested, only 3 (modulus to septal thickness when location was accounted for, energy loss to total collagen, and energy loss to collagen/elastin ratio) were statistically significant, none with an R-2 greater than 0.10. The main differences in the means were increased tissue stiffness and increased septal wall thickness, both trends were supported in the literature. However, as the correlations were weak, it is likely that another unexamined biochemical factor (perhaps collagen crosslinking) is associated with the mechanical tissue changes. Published by Elsevier Ltd. C1 [Ledoux, William R.; Pai, Shruti; Shofer, Jane B.; Wang, Yak-Nam] VA RR&D Ctr Excellence Limb Loss Prevent & Prosth, Seattle, WA 98108 USA. [Ledoux, William R.; Pai, Shruti] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Ledoux, William R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Wang, Yak-Nam] Univ Washington, Appl Phys Lab, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA Puget Sound, MS 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@uw.edu FU National Institutes of Health [1R01 DK75633-03]; Department of Veterans Affairs, MID Service grant [A4843C] FX This study was supported by the National Institutes of Health grant 1R01 DK75633-03 and the Department of Veterans Affairs, MID Service grant A4843C. The authors have no conflicts to report. NR 42 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD OCT 3 PY 2016 VL 49 IS 14 BP 3328 EP 3333 DI 10.1016/j.jbiomech.2016.08.021 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA EA9SG UT WOS:000386984400026 PM 27623704 ER PT J AU Lin, L Li, JS Kernkamp, WA Hosseini, A Kim, C Yin, P Wang, LX Tsai, TY Asnis, P Li, GA AF Lin, Lin Li, Jing-Sheng Kernkamp, Willem A. Hosseini, Ali Kim, ChangWan Yin, Peng Wang, Lianxin Tsai, Tsung-Yuan Asnis, Peter Li, Guoan TI Postoperative time dependent tibiofemoral articular cartilage contact kinematics during step-up after ACL reconstruction SO JOURNAL OF BIOMECHANICS LA English DT Article DE Anterior cruciate ligament reconstruction; Cartilage contact; Osteoarthritis; Biomechanics ID ANTERIOR CRUCIATE LIGAMENT; 3-DIMENSIONAL JOINT KINEMATICS; IN-VIVO KINEMATICS; KNEE OSTEOARTHRITIS; FEMORAL TUNNEL; STANCE PHASE; STAIR ASCENT; FOLLOW-UP; WALKING; GAIT AB This study was to investigate the in vivo tibiofemoral cartilage contact locations before and after anterior cruciate ligament (ACL) reconstruction at 6 and 36 months. Ten patients with unilateral ACL injury were included. A step-up motion was analyzed using a combined magnetic resonance modeling and dual fluoroscopic imaging techniques. The preoperative (i.e. ACL deficient and healthy contralateral) and postoperative cartilage contact locations at 6 and 36 months were analyzed. Similar patterns of the cartilage contact locations during the step-up motion were found for the preoperative and postoperative knee states as compared to the preoperative healthy contralateral side. At the end of step-up motion, the medial contact locations at postoperative 36 months were more anterior when compared to the preoperative healthy contralateral (p=0.02) and 6 months postoperative knee states (p=0.01). The changes of the cartilage contact locations at 36 months after ACL reconstruction compared to the healthy contralateral side were strongly correlated with the changes at 6 months postoperatively. This study showed that the tibiofemoral cartilage contact locations of the knee changes with time after ACL reconstruction, implying an ongoing recovery process within the 36 months after the surgery. There could be an association between "the short-term (6 months) and longer-term (36 months) contact kinematics after ACL reconstruction. Future studies need to investigate the intrinsic relationship between knee kinematics at different times after ACL reconstruction. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Lin, Lin; Li, Jing-Sheng; Kernkamp, Willem A.; Hosseini, Ali; Yin, Peng; Tsai, Tsung-Yuan; Asnis, Peter; Li, Guoan] Massachusetts Gen Hosp, Dept Orthoped Surg, Bioengn Lab, 55 Fruit St, Boston, MA 02114 USA. [Lin, Lin; Li, Jing-Sheng; Kernkamp, Willem A.; Hosseini, Ali; Yin, Peng; Tsai, Tsung-Yuan; Asnis, Peter; Li, Guoan] Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. [Lin, Lin] Peking Univ, Hosp 3, Inst Sports Med, North Garden Rd, Beijing 100191, Peoples R China. [Kim, ChangWan] Inje Univ, Coll Med, Busan Paik Hosp, Dept Orthoped Surg, 633-166 Gaegeum Dong, Busan 614735, South Korea. [Yin, Peng] Chinese Peoples Liberat Army Gen Hosp, Dept Orthopaed, 28 Fuxin Rd, Beijing 100853, Peoples R China. [Yin, Peng] Nankai Univ, Coll Med, 94 Weijin Rd, Tianjin 300071, Peoples R China. [Wang, Lianxin] Jilin Univ, China Japan Union Hosp, Dept Orthoped Surg, Changchun, Jilin Province, Peoples R China. RP Li, GA (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, Bioengn Lab, 55 Fruit St, Boston, MA 02114 USA.; Li, GA (reprint author), Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. EM gli1@partners.org FU National Institute of Health [R01AR055612]; China Scholarship Council [201406015009] FX This work was partially supported by National Institute of Health Grant (R01AR055612) and China Scholarship Council (201406015009). NR 40 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD OCT 3 PY 2016 VL 49 IS 14 BP 3509 EP 3515 DI 10.1016/j.jbiomech.2016.09.022 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA EA9SG UT WOS:000386984400050 PM 27720228 ER PT J AU Qin, Q Mei, SL Wu, Q Sun, HF Li, LY Taing, L Chen, SJ Li, FG Liu, T Zang, CZ Xu, H Chen, YW Meyer, CA Zhang, Y Brown, M Long, HW Liu, XS AF Qin, Qian Mei, Shenglin Wu, Qiu Sun, Hanfei Li, Lewyn Taing, Len Chen, Sujun Li, Fugen Liu, Tao Zang, Chongzhi Xu, Han Chen, Yiwen Meyer, Clifford A. Zhang, Yong Brown, Myles Long, Henry W. Liu, X. Shirley TI ChiLin: a comprehensive ChIP-seq and DNase-seq quality control and analysis pipeline SO BMC BIOINFORMATICS LA English DT Article DE ChIP-seq; DNase-seq; Quality atlas; Analysis pipeline ID HUMAN TRANSCRIPTION FACTORS; INTEGRATIVE ANALYSIS; REGULATORY ELEMENTS; RECEPTOR-BINDING; PROSTATE-CANCER; HUMAN GENOME; CHROMATIN; MOUSE; LANDSCAPE; VISUALIZATION AB Background: Transcription factor binding, histone modification, and chromatin accessibility studies are important approaches to understanding the biology of gene regulation. ChIP-seq and DNase-seq have become the standard techniques for studying protein-DNA interactions and chromatin accessibility respectively, and comprehensive quality control (QC) and analysis tools are critical to extracting the most value from these assay types. Although many analysis and QC tools have been reported, few combine ChIP-seq and DNase-seq data analysis and quality control in a unified framework with a comprehensive and unbiased reference of data quality metrics. Results: ChiLin is a computational pipeline that automates the quality control and data analyses of ChIP-seq and DNase-seq data. It is developed using a flexible and modular software framework that can be easily extended and modified. ChiLin is ideal for batch processing of many datasets and is well suited for large collaborative projects involving ChIP-seq and DNase-seq from different designs. ChiLin generates comprehensive quality control reports that include comparisons with historical data derived from over 23,677 public ChIP-seq and DNase-seq samples (11,265 datasets) from eight literature-based classified categories. To the best of our knowledge, this atlas represents the most comprehensive ChIP-seq and DNase-seq related quality metric resource currently available. These historical metrics provide useful heuristic quality references for experiment across all commonly used assay types. Using representative datasets, we demonstrate the versatility of the pipeline by applying it to different assay types of ChIP-seq data. The pipeline software is available open source at https://github.com/cfce/chilin. Conclusion: ChiLin is a scalable and powerful tool to process large batches of ChIP-seq and DNase-seq datasets. The analysis output and quality metrics have been structured into user-friendly directories and reports. We have successfully compiled 23,677 profiles into a comprehensive quality atlas with fine classification for users. C1 [Qin, Qian; Mei, Shenglin; Wu, Qiu; Sun, Hanfei; Chen, Sujun; Liu, X. Shirley] Shanghai Pulm Hosp, Shanghai Key Lab TB, Shanghai, Peoples R China. [Qin, Qian; Mei, Shenglin; Wu, Qiu; Sun, Hanfei; Chen, Sujun; Zhang, Yong; Liu, X. Shirley] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai, Peoples R China. [Taing, Len; Zang, Chongzhi; Xu, Han; Chen, Yiwen; Meyer, Clifford A.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Taing, Len; Zang, Chongzhi; Xu, Han; Chen, Yiwen; Meyer, Clifford A.; Liu, X. Shirley] Harvard Sch Publ Hlth, Boston, MA USA. [Li, Lewyn; Taing, Len; Li, Fugen; Brown, Myles; Long, Henry W.; Liu, X. Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Brown, Myles] Dana Farber Canc Inst, Div Mol & Cellular Oncol, Dept Med Oncol, Boston, MA 02115 USA. [Brown, Myles] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Brown, Myles] Harvard Med Sch, Boston, MA USA. [Liu, Tao] SUNY Buffalo, Dept Biochem, Buffalo, NY USA. RP Liu, XS (reprint author), Shanghai Pulm Hosp, Shanghai Key Lab TB, Shanghai, Peoples R China.; Long, HW; Liu, XS (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. EM henry_long@dfci.harvard.edu; xsliu@jimmy.harvard.edu RI Zhang, Yong/B-4838-2011 OI Zhang, Yong/0000-0001-6316-2734 FU National Natural Science Foundation of China [31329003]; National Institutes of Health [CA180980] FX This work was supported by National Natural Science Foundation of China [31329003] and National Institutes of Health [CA180980]. NR 52 TC 1 Z9 1 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2016 VL 17 AR 404 DI 10.1186/s12859-016-1274-4 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DY9NQ UT WOS:000385461400004 PM 27716038 ER PT J AU Yamamoto, KN Ishii, M Inoue, Y Hirokawa, F MacArthur, BD Nakamura, A Haeno, H Uchiyama, K AF Yamamoto, Kimiyo N. Ishii, Masatsugu Inoue, Yoshihiro Hirokawa, Fumitoshi MacArthur, Ben D. Nakamura, Akira Haeno, Hiroshi Uchiyama, Kazuhisa TI Prediction of postoperative liver regeneration from clinical information using a data-led mathematical model SO SCIENTIFIC REPORTS LA English DT Article ID MIDDLE HEPATIC VEIN; SURGICAL COMPLICATIONS; INDOCYANINE GREEN; HEPATECTOMY; METASTASIS; CANCER; CLASSIFICATION; EXPERIENCE; RESECTION; DONORS AB Although the capacity of the liver to recover its size after resection has enabled extensive liver resection, post-hepatectomy liver failure remains one of the most lethal complications of liver resection. Therefore, it is clinically important to discover reliable predictive factors after resection. In this study, we established a novel mathematical framework which described post-hepatectomy liver regeneration in each patient by incorporating quantitative clinical data. Using the model fitting to the liver volumes in series of computed tomography of 123 patients, we estimated liver regeneration rates. From the estimation, we found patients were divided into two groups: i) patients restored the liver to its original size (Group 1, n = 99); and ii) patients experienced a significant reduction in size (Group 2, n = 24). From discriminant analysis in 103 patients with full clinical variables, the prognosis of patients in terms of liver recovery was successfully predicted in 85-90% of patients. We further validated the accuracy of our model prediction using a validation cohort (prediction = 84-87%, n = 39). Our interdisciplinary approach provides qualitative and quantitative insights into the dynamics of liver regeneration. A key strength is to provide better prediction in patients who had been judged as acceptable for resection by current pragmatic criteria. C1 [Yamamoto, Kimiyo N.; Ishii, Masatsugu; Inoue, Yoshihiro; Hirokawa, Fumitoshi; Uchiyama, Kazuhisa] Osaka Med Coll Hosp, Dept Gen Surg, Osaka, Japan. [Yamamoto, Kimiyo N.; Ishii, Masatsugu; Inoue, Yoshihiro; Hirokawa, Fumitoshi; Uchiyama, Kazuhisa] Osaka Med Coll Hosp, Dept Surg Gastroenterol, Osaka, Japan. [Yamamoto, Kimiyo N.; Haeno, Hiroshi] Kyushu Univ, Dept Biol, Math Biol Lab, Fac Sci, Fukuoka, Japan. [MacArthur, Ben D.] Univ Southampton, Math Sci, Southampton SO17 1BJ, Hants, England. [MacArthur, Ben D.] Univ Southampton, Human Dev & Hlth, Fac Med, Southampton SO17 1BJ, Hants, England. [Nakamura, Akira] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Inoue, Y (reprint author), Osaka Med Coll Hosp, Dept Gen Surg, Osaka, Japan.; Inoue, Y (reprint author), Osaka Med Coll Hosp, Dept Surg Gastroenterol, Osaka, Japan. EM sur129@poh.osaka-med.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [26115006]; National Cancer Center Research and Development Fund [26-A-6] FX H.H. was supported by a Grant-in-Aid for Scientific Research on Innovative Areas "Stem Cell Aging and Disease" from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 26115006) and by the National Cancer Center Research and Development Fund (26-A-6). NR 34 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD OCT 3 PY 2016 VL 6 AR 34214 DI 10.1038/srep34214 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DX9ZV UT WOS:000384757200001 PM 27694914 ER PT J AU Koek, RJ Schwartz, HN Scully, S Langevin, JP Spangler, S Korotinsky, A Jou, K Leuchter, A AF Koek, Ralph J. Schwartz, Holly N. Scully, Stephenie Langevin, Jean-Philippe Spangler, Shana Korotinsky, Arkady Jou, Kevin Leuchter, Andrew TI Treatment-refractory posttraumatic stress disorder (TRPTSD): a review and framework for the future SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Post-traumatic stress disorder; Treatment-refractory; Psychopharmacology; Extinction; Neuromodulation ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; TRANSCRANIAL MAGNETIC STIMULATION; VENLAFAXINE EXTENDED-RELEASE; COGNITIVE-BEHAVIOR THERAPY; QUALITY-OF-LIFE; COMBAT-RELATED PTSD; MAJOR DEPRESSIVE DISORDER; TERM-FOLLOW-UP; ADJUNCTIVE RISPERIDONE TREATMENT AB Post-traumatic stress disorder (PTSD) is a serious psychiatric consequence of trauma that occurs in a proportion of individuals exposed to life-threatening events. Trauma-focused psychotherapy is often recommended as first choice for those who do not recover spontaneously. But many individuals require medications. In the US, only paroxetine (PRX) and sertraline (SRT) are FDA approved for PTSD. But response and remission rates with these medications are low, so numerous other pharmacologic interventions have been tried. To date, there has not been a systematic review of the data on what are the best next-step pharmacologic strategies for individuals who fail standard treatments. To that end, we review 168 published trials of medications other than PRX or SRT and provide a detailed analysis of the 88/168 studies that describe alternative pharmacologic interventions in patients refractory to other treatment. We also review clinical factors relevant to treatment-refractory PTSD; the neurobiology of extinction, as well as evidence-based psychotherapy and neuromodulation strategies for this condition. Published by Elsevier Inc. C1 [Koek, Ralph J.; Schwartz, Holly N.; Spangler, Shana; Korotinsky, Arkady; Jou, Kevin] VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Mental Hlth Serv, North Hill, CA USA. [Koek, Ralph J.; Korotinsky, Arkady; Jou, Kevin; Leuchter, Andrew] David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Scully, Stephenie] US Navy, Naval Med Ctr San Diego, San Diego, CA USA. [Langevin, Jean-Philippe] Greater VA Greater Los Angeles Healthcare Syst, Neurosurg Serv, 11301 Wilshire Blvd,Bldg 500,10H2, Los Angeles, CA 90073 USA. [Langevin, Jean-Philippe] David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA USA. [Spangler, Shana] VA Campus Toolkit, VA VITAL Program Director, North Hills, CA USA. [Leuchter, Andrew] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza, Los Angeles, CA 90024 USA. RP Koek, RJ (reprint author), 16111 Plummer St,116A-11, North Hills, CA 91343 USA. EM rkoek@ucla.edu; hollynschwartz@gmail.com; Stephenie.scully@gmail.com; Jean-philippe.langevin@va.gov; shana.spangler@va.gov; arkady.korotinsky@va.gov; kevin.jou@va.gov FU National Institutes of Health; Wyeth Pharmaceuticals; Novartis Pharmaceuticals; Seaside Therapeutics; Genentech; Shire Pharmaceuticals; Neuronetics; Eli Lilly and Company; Neurosigma; Aspect Medical Systems/Covidien; Shire FX This work was carried out without any research funding. AFL, within the past 5 years, has received research support from the National Institutes of Health, Wyeth Pharmaceuticals, Novartis Pharmaceuticals, Seaside Therapeutics, Genentech, Shire Pharmaceuticals, Neuronetics, Eli Lilly and Company, and Neurosigma. He has served as a consultant to NeoSync Inc., Brain Cells, Inc., Taisho Pharmaceuticals, Eli Lilly and Company, and Aspect Medical Systems/Covidien. He is Chief Scientific Officer of Brain Biomarker Analytics LLC (BBA). He owns stock options in NeoSync, Inc. and has equity interest in BBA. I.A.C., within the past 5 years, has received research support from Aspect Medical Systems/Covidien, National Institutes of Health, Neuronetics and Shire; he has been on the speakers' bureau for Neuronetics and the Medical Education Speakers Network; he has been an advisor/consultant/reviewer for Allergan, Covidien, Pfizer, Neuronetics, NeuroSigma, NIH (ITVS), US Department of Defense, US Department of Justice, VA (DSMB); his biomedical intellectual property is assigned to the Regents of the University of California, and he owns stock options in NeuroSigma. JPL Has filed a patent application for amygdala deep brain stimulation for post-traumatic stress disorder. None of the other authors have potential conflicts to declare. None of the authors have any conflicts to declare. NR 516 TC 4 Z9 4 U1 36 U2 72 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 EI 1878-4216 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD OCT 3 PY 2016 VL 70 BP 170 EP 218 DI 10.1016/j.pnpbp.2016.01.015 PG 49 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DP9YO UT WOS:000378854200020 PM 26854815 ER PT J AU Kajiwara, Y McKenzie, A Dorr, N Sosa, MAG Elder, G Schmeidler, J Dickstein, DL Bozdagi, O Zhang, B Buxbaum, JD AF Kajiwara, Yuji McKenzie, Andrew Dorr, Nate Sosa, Miguel A. Gama Elder, Gregory Schmeidler, James Dickstein, Dara L. Bozdagi, Ozlem Zhang, Bin Buxbaum, Joseph D. TI The human-specific CASP4 gene product contributes to Alzheimer-related synaptic and behavioural deficits SO HUMAN MOLECULAR GENETICS LA English DT Article ID BLOOD-BRAIN-BARRIER; MILD COGNITIVE IMPAIRMENT; AMYLOID BETA-PEPTIDE; MOUSE MODEL; INFLAMMASOME ACTIVATION; FUNCTIONAL DIFFERENCES; NLRP3 INFLAMMASOME; INSULIN-RESISTANCE; MICROGLIAL CELLS; COMMON VARIANTS AB Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Ab) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Ab levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD. C1 [Kajiwara, Yuji; Sosa, Miguel A. Gama; Elder, Gregory; Schmeidler, James; Bozdagi, Ozlem; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1668, New York, NY 10029 USA. [McKenzie, Andrew; Zhang, Bin; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [McKenzie, Andrew; Zhang, Bin] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Dorr, Nate; Sosa, Miguel A. Gama] Icahn Sch Med Mt Sinai, Gen Med Res Serv, New York, NY 10029 USA. [Elder, Gregory] James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY USA. [Elder, Gregory] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Dickstein, Dara L.; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Dickstein, Dara L.; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1668, New York, NY 10029 USA. EM Joseph.Buxbaum@mssm.edu FU National Institute on Aging [AG046170]; Icahn School of Medicine at Mount Sinai Alzheimer Disease Research Center [AG005138-28] FX This work was supported by the National Institute on Aging [AG046170, MPI, Dr. E Shadt, B Zhang and JD Buxbaum]; and the Icahn School of Medicine at Mount Sinai Alzheimer Disease Research Center [AG005138-28, Dr. Mary Sano, PI, Drs. O Bozdagi and JD Buxbaum, PL]. NR 89 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2016 VL 25 IS 19 BP 4315 EP 4327 DI 10.1093/hmg/ddw265 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EN1YZ UT WOS:000395807800014 PM 27516385 ER PT J AU Evans, DS Avery, CL Nalls, MA Li, G Barnard, J Smith, EN Tanaka, T Butler, AM Buxbaum, SG Alonso, A Arking, DE Berenson, GS Bis, JC Buyske, S Carty, CL Chen, W Chung, MK Cummings, SR Deo, R Eaton, CB Fox, ER Heckbert, SR Heiss, G Hindorff, LA Hsueh, WC Isaacs, A Jamshidi, Y Kerr, KF Liu, F Liu, YM Lohman, KK Magnani, JW Maher, JF Mehra, R Meng, YA Musani, SK Newton-Cheh, C North, KE Psaty, BM Redline, S Rotter, JI Schnabel, RB Schork, NJ Shohet, RV Singleton, AB Smith, JD Soliman, EZ Srinivasan, SR Taylor, HA Van Wagoner, DR Wilson, JG Young, T Zhang, ZM Zonderman, AB Evans, MK Ferrucci, L Murray, SS Tranah, GJ Whitsel, EA Reiner, AP Sotoodehnia, N AF Evans, Daniel S. Avery, Christy L. Nalls, Mike A. Li, Guo Barnard, John Smith, Erin N. Tanaka, Toshiko Butler, Anne M. Buxbaum, Sarah G. Alonso, Alvaro Arking, Dan E. Berenson, Gerald S. Bis, Joshua C. Buyske, Steven Carty, Cara L. Chen, Wei Chung, Mina K. Cummings, Steven R. Deo, Rajat Eaton, Charles B. Fox, Ervin R. Heckbert, Susan R. Heiss, Gerardo Hindorff, Lucia A. Hsueh, Wen-Chi Isaacs, Aaron Jamshidi, Yalda Kerr, Kathleen F. Liu, Felix Liu, Yongmei Lohman, Kurt K. Magnani, Jared W. Maher, Joseph F. Mehra, Reena Meng, Yan A. Musani, Solomon K. Newton-Cheh, Christopher North, Kari E. Psaty, Bruce M. Redline, Susan Rotter, Jerome I. Schnabel, Renate B. Schork, Nicholas J. Shohet, Ralph V. Singleton, Andrew B. Smith, Jonathan D. Soliman, Elsayed Z. Srinivasan, Sathanur R. Taylor, Herman A., Jr. Van Wagoner, David R. Wilson, James G. Young, Taylor Zhang, Zhu-Ming Zonderman, Alan B. Evans, Michele K. Ferrucci, Luigi Murray, Sarah S. Tranah, Gregory J. Whitsel, Eric A. Reiner, Alex P. Sotoodehnia, Nona CA CHARGE QRS Consortium TI Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID RESTING HEART-RATE; COMMON VARIANTS; PR INTERVAL; VENTRICULAR CONDUCTION; CARDIAC CONDUCTION; HUMAN-POPULATIONS; GENETIC-VARIATION; JACKSON HEART; METAANALYSIS; DESIGN AB The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 x 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 x 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 x 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 x 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 x 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved. C1 [Evans, Daniel S.; Cummings, Steven R.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Avery, Christy L.; Butler, Anne M.; Heiss, Gerardo; North, Kari E.; Whitsel, Eric A.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Li, Guo; Bis, Joshua C.; Heckbert, Susan R.; Psaty, Bruce M.; Sotoodehnia, Nona] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Barnard, John] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Smith, Erin N.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Rady Childrens Hosp, La Jolla, CA 92093 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Buxbaum, Sarah G.] Jackson State Univ, Ctr Excellence Minor Hlth & Hlth Dispar, Jackson, MS USA. [Buxbaum, Sarah G.] Jackson State Univ, Sch Publ Hlth Initiative, Dept Epidemiol & Biostat, Jackson, MS USA. [Alonso, Alvaro] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Berenson, Gerald S.] Tulane Univ, Dept Med & Cardiol, New Orleans, LA 70118 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Carty, Cara L.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Chung, Mina K.; Mehra, Reena] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Chung, Mina K.; Mehra, Reena; Van Wagoner, David R.] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH USA. [Chung, Mina K.; Mehra, Reena] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Epidemiol, Providence, RI 02912 USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Dept Med, Div Cardiovasc Dis, Jackson, MS 39216 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hindorff, Lucia A.] NHGRI, NIH, Off Populat Genom, Bethesda, MD 20892 USA. [Hsueh, Wen-Chi] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Isaacs, Aaron] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Isaacs, Aaron] Maastricht Univ, Dept Biochem, Maastricht Ctr Syst Biol MaCSBio, CARIM Sch Cardiovasc Dis, Maastricht, Netherlands. [Jamshidi, Yalda] St Georges Univ London, Inst Cardiovasc & Cell Sci, Cardiogenet Lab, London, England. [Kerr, Kathleen F.] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. [Liu, Felix] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Liu, Yongmei; Lohman, Kurt K.] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Magnani, Jared W.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Dept Med,Div Cardiol, Pittsburgh, PA USA. [Maher, Joseph F.; Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Meng, Yan A.; Newton-Cheh, Christopher; Young, Taylor] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA USA. [Musani, Solomon K.] Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Harvard Med Sch, Boston, MA 02114 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Redline, Susan] Harvard Med Sch, Brigham & Womens Hosp, Div Sleep Med, Dept Med, Boston, MA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg, Hamburg, Germany. [Schnabel, Renate B.] German Ctr Cardiovasc Res, Hamburg, Germany. [Schork, Nicholas J.] J Craig Venter Inst, San Diego, CA USA. [Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Ctr Cardiovasc Res, Honolulu, HI 96822 USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Soliman, Elsayed Z.; Zhang, Zhu-Ming] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Murray, Sarah S.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Whitsel, Eric A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. RP Evans, DS (reprint author), Mission Hall Global Hlth & Clinical Sci Bldg, San Francisco, CA 94158 USA.; Sotoodehnia, N (reprint author), Metropolitan Pk East Tower,1730 Minor Ave, Seattle, WA 98101 USA. EM devans@psg.ucsf.edu; nsotoo@u.washington.edu FU National Institutes of Health [R01 HL088456, R01 HL116747, R01 HL111089, R01 HL091244, K99 HL098458, 5T32CA009330-30, R01 ES017794, HHSN268200625226C, UL1RR025005, P20MD006899, U24AG051129, HHSN268200782096C]; Laughlin Family; German Research Foundation [SCHNA 1149/3-1]; National Heart, Lung, and Blood Institute (NHLBI)sponsored Candidate gene Association Resource (CARe) project; ARIC; JHS; MESA; CFS; Broad Institute of Harvard; MIT [N01-HC-65226]; Atherosclerosis Risk in Communities (ARIC):National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; Cleveland Family Study (CFS): Case Western Reserve University [NIH HL 46380, M01RR00080]; Jackson Heart Study (JHS) from the National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Minnesota [N01-HC95163]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; Health, Aging, and Body Composition Study (Health ABC): NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Center for Inherited Disease Research (CIDR); Intramural Research Program of the NIH, National Institute on Aging; Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): intramural research program of the National Institute on Aging; National Center for Minority Health and Health Disparities, National Institutes of Health; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; Women's Health Initiative (WHI): National Heart, Lung, and Blood Institute; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; NHLBI [N02-HL-64278]; Cardiovascular Health Study (CHS):NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114, HL085251]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Baltimore Longitudinal Study of Aging (BLSA): Intramural Research Program of the NIH; National Institute on Aging; MedStar Research Institute; Bogalusa Heart Study (BHS): National Institute of Environmental Health Science [R01ES021724]; National Institute on Aging [R01AG016592]; STSI/TSRI [U54 NS056883]; Scripps Genomic Medicine; National Human Genome Research Institute (NHGRI) [U01HG007416, U01HG007417, U01HG007397, U01HG007376, U01HG007419]; PAGE Coordinating Center [U01HG007419]; NIH [5R01HL090620, 5R01HL111314]; Fondation Leducq [CVD-07-03]; European North American Atrial Fibrillation Research Alliance FX This work was supported by the National Institutes of Health [R01 HL088456 to N.S., R01 HL116747 to N.S., R01 HL111089 to N.S., R01 HL091244 to N.S., K99 HL098458 to C.L.A., 5T32CA009330-30 to A.M.B., R01 ES017794 to E.A.W., P20MD006899 to S.G.B.,and U24AG051129 to D.S.E.], the Laughlin Family [to N.S.], and the German Research Foundation [SCHNA 1149/3-1 to R.B.S.].; As part of the National Heart, Lung, and Blood Institute (NHLBI)sponsored Candidate gene Association Resource (CARe) project, the ARIC, JHS, MESA, and CFS studies contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard and MIT (N01-HC-65226) to create a genotype/phenotype database for wide dissemination to the biomedical research community.; Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by GrantNumber UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080).; Jackson Heart Study (JHS): The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), and University of Virginia (subcontract to R01-HL-071205).; Health, Aging, and Body Composition Study (Health ABC): The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): The HANDLS study was in part supported by the intramural research program of the National Institute on Aging and the National Center for Minority Health and Health Disparities, National Institutes of Health. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (contract # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov).; Women's Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This manuscript was prepared in collaboration with investigators of the WHI, and has been reviewed and/or approved by the Women's Health Initiative (WHI). WHI investigators are listed at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20I nvestigator%20Short%20List.pdf. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278.; Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114, HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Baltimore Longitudinal Study of Aging (BLSA): The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute.; Bogalusa Heart Study (BHS): BHS is supported by grants R01ES021724 from National Institute of Environmental Health Science and R01AG016592 from the National Institute on Aging. Analysis performed at STSI/TSRI was supported by U54 NS056883 and Scripps Genomic Medicine. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, and general study coordination was provided by the PAGE Coordinating Center (U01HG007419). The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. Funding for the atrial tissue eQTL study was provided by NIH 5R01HL090620, NIH 5R01HL111314, Fondation Leducq CVD-07-03, European North American Atrial Fibrillation Research Alliance. NR 80 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2016 VL 25 IS 19 BP 4350 EP 4368 DI 10.1093/hmg/ddw284 PG 19 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EN1YZ UT WOS:000395807800017 PM 27577874 ER PT J AU Barbui, C Dua, T Kolappa, K Saraceno, B Saxena, S AF Barbui, Corrado Dua, Tarun Kolappa, Kavitha Saraceno, Benedetto Saxena, Shekhar TI Access to psychotropic medicines in low-resource settings SO LANCET PSYCHIATRY LA English DT Editorial Material C1 [Barbui, Corrado] Univ Verona, WHO Collaborating Ctr Res & Training Mental Hlth, Dept Neurosci Biomed & Movement Sci, Sect Psychiat, I-37134 Verona, Italy. [Dua, Tarun; Saxena, Shekhar] World Hlth Org, Dept Mental Hlth & Subst Abuse, Geneva, Switzerland. [Kolappa, Kavitha] Harvard Med Sch, Massachusetts Gen Hosp, McLean Psychiat Residency, Boston, MA USA. [Saraceno, Benedetto] Nova Univ Lisbon, Lisbon Inst Global Mental Hlth, Lisbon, Portugal. RP Barbui, C (reprint author), Univ Verona, WHO Collaborating Ctr Res & Training Mental Hlth, Dept Neurosci Biomed & Movement Sci, Sect Psychiat, I-37134 Verona, Italy. EM corrado.barbui@univr.it NR 12 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD OCT PY 2016 VL 3 IS 10 BP 913 EP 915 PG 4 WC Psychiatry SC Psychiatry GA EN9UE UT WOS:000396344300006 PM 27692258 ER PT J AU Bernstein, KD Goldberg, S Liebsch, NJ Schwab, J Hornicek, FJ Choy, E Cote, G Chen, YLE DeLaney, TF AF Bernstein, K. De Amorim Goldberg, S. Liebsch, N. J. Schwab, J. Hornicek, F. J. Choy, E. Cote, G. Chen, Y. L. E. DeLaney, T. F. TI Treatment Outcomes of Patients With Primary Chordomas Treated With Preoperative Radiation (Alone) Followed by Surgery SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 25-28, 2016 CL Boston, MA SP Amer Soc Radiat Oncol C1 [Bernstein, K. De Amorim; Goldberg, S.; Hornicek, F. J.; Cote, G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Liebsch, N. J.; Schwab, J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Choy, E.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Chen, Y. L. E.; DeLaney, T. F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2016 VL 96 IS 2 SU S MA 3745 BP E711 EP E712 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EB8QL UT WOS:000387655804324 ER EF