FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Pope, C North-Lee, B Davis, B AF Pope, Charlene North-Lee, Bertha Davis, Boyd TI Dropped Cues in Patient-Physician Interactions: How Discourse Analysis Finds Areas for Coaching SO INTERNATIONAL JOURNAL OF QUALITATIVE METHODS LA English DT Meeting Abstract C1 [Pope, Charlene; North-Lee, Bertha] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Davis, Boyd] Univ North Carolina Charlotte, Charlotte, NC USA. NR 0 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 1609-4069 J9 INT J QUAL METH JI Int. J. Qual. Meth. PD DEC PY 2017 VL 16 IS 1 PG 1 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA EL7CA UT WOS:000394777500099 ER PT J AU Denning, JT Turley, P AF Denning, Jeffrey T. Turley, Patrick TI Was That SMART? Institutional Financial Incentives and Field of Study SO JOURNAL OF HUMAN RESOURCES LA English DT Article ID REGRESSION DISCONTINUITY DESIGNS; COLLEGE MAJOR; EARNINGS; CHOICE; EDUCATION; LABOR AB We examine whether students respond to immediate financial incentives when choosing their college major. From 2006-2007 to 2010-2011, low-income students in technical or foreign language majors could receive up to $8,000 in SMART Grants. Since income-eligibility was determined using a strict threshold, we determine the causal impact of this grant on student major with a regression discontinuity design. Using administrative data from public universities in Texas, we determine that income-eligible students were 3.2 percentage points more likely than their ineligible peers to major in targeted fields. We measure a larger impact of 10.2 percentage points at Brigham Young University. C1 [Denning, Jeffrey T.] Brigham Young Univ, Econ, Provo, UT 84602 USA. [Turley, Patrick] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP Denning, JT (reprint author), Brigham Young Univ, Econ, Provo, UT 84602 USA. NR 35 TC 0 Z9 0 U1 5 U2 5 PU UNIV WISCONSIN PRESS PI MADISON PA JOURNAL DIVISION, 1930 MONROE ST, 3RD FL, MADISON, WI 53711 USA SN 0022-166X EI 1548-8004 J9 J HUM RESOUR JI J. Hum. Resour. PD WIN PY 2017 VL 52 IS 1 BP 152 EP 186 DI 10.3368/jhr.52.1.0414-6340R1 PG 35 WC Economics; Industrial Relations & Labor SC Business & Economics GA EO5DK UT WOS:000396713000005 ER PT J AU Alosco, ML Mez, J Kowall, NW Stein, TD Goldstein, LE Cantu, RC Katz, DI Solomon, TM Kiernan, PT Murphy, L Abdolmohammadi, B Daneshvar, D Montenigro, PH Nowinski, CJ Stern, RA Mckee, AC AF Alosco, Michael L. Mez, Jesse Kowall, Neil W. Stein, Thor D. Goldstein, Lee E. Cantu, Robert C. Katz, Douglas I. Solomon, Todd M. Kiernan, Patrick T. Murphy, Lauren Abdolmohammadi, Bobak Daneshvar, Daniel Montenigro, Philip H. Nowinski, Christopher J. Stern, Robert A. Mckee, Ann C. TI Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID 21ST-CENTURY BRAIN BANKING; ALZHEIMERS-DISEASE; COLUMBIA-UNIVERSITY; EDUCATION; INJURY; PATHOLOGY; DEMENTIA; SPECTRUM; CRITERIA AB This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE. C1 [Alosco, Michael L.; Mez, Jesse; Kowall, Neil W.; Stein, Thor D.; Goldstein, Lee E.; Cantu, Robert C.; Solomon, Todd M.; Kiernan, Patrick T.; Murphy, Lauren; Abdolmohammadi, Bobak; Daneshvar, Daniel; Montenigro, Philip H.; Nowinski, Christopher J.; Stern, Robert A.; Mckee, Ann C.] Boston Univ, Sch Med, Alzheimers Dis & CTE Ctr, Boston, MA 02118 USA. [Alosco, Michael L.; Mez, Jesse; Kowall, Neil W.; Stein, Thor D.; Goldstein, Lee E.; Katz, Douglas I.; Solomon, Todd M.; Kiernan, Patrick T.; Murphy, Lauren; Abdolmohammadi, Bobak; Daneshvar, Daniel; Montenigro, Philip H.; Stern, Robert A.; Mckee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Daneshvar, Daniel] North Shore Med Ctr, Dept Internal Med, Boston, MA USA. [Kowall, Neil W.; Stein, Thor D.; Mckee, Ann C.] VA Boston Healthcare Syst, US Dept Vet Affairs, Boston, MA 02130 USA. [Kowall, Neil W.; Stein, Thor D.; Mckee, Ann C.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Stein, Thor D.; Mckee, Ann C.] Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. [Goldstein, Lee E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Goldstein, Lee E.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Goldstein, Lee E.] Boston Univ, Coll Engn, Dept Biomed Engn, Boston, MA 02215 USA. [Goldstein, Lee E.] Boston Univ, Coll Engn, Dept Elect & Comp Engn, Boston, MA 02215 USA. [Cantu, Robert C.; Nowinski, Christopher J.] Concuss Legacy Fdn, Boston, MA USA. [Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA USA. [Katz, Douglas I.] Braintree Rehabil Hosp, Braintree, MA USA. [Montenigro, Philip H.; Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. RP Mckee, AC (reprint author), Boston Univ, Sch Med, Alzheimers Dis & CTE Ctr, Boston, MA 02118 USA.; Mckee, AC (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.; Mckee, AC (reprint author), VA Boston Healthcare Syst, US Dept Vet Affairs, Boston, MA 02130 USA.; Mckee, AC (reprint author), Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA.; Mckee, AC (reprint author), Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA. FU National Institute of Neurological Disorders and Stroke [1UO1NS086659-01, R01NS078337, R56NS078337]; Department of Defense [W81XWH-13-2-0064]; Department of Veterans Affairs; Veterans Affairs Biorepository [CSP 501]; National Institute of Aging Boston University Alzheimer's Disease Center [P30AG13846, 0572063345-5]; Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP) [13267017]; National Institute of Aging Boston University Framingham Heart Study [R01AG1649]; National Operating Committee on Standards for Athletic Equipment and the Concussion Legacy Foundation; Andlinger Foundation; WWE; NFL; National Institutes of Health [1F32NS096803-01]; Johnson & Johnson (New Brunswick, N.J.)/Janssen Research & Development, LLC (Raritan, N.J.); Rebiscan, Inc. (Cambridge, Mass.); Ivivi Health Sciences; Mackey-White Committee; NFL Players Association; Avid Radiopharmaceuticals, Inc. (Philadelphia); Athena Diagnostics/Quest Laboratories (Marlborough, Mass.); Amarantus BioScience Holdings, Inc. (San Francisco); Avanir Pharmaceuticals, Inc. (Aliso Viejo, Calif.) FX Supported by the National Institute of Neurological Disorders and Stroke (1UO1NS086659-01, R01NS078337, R56NS078337), the Department of Defense (W81XWH-13-2-0064), the Department of Veterans Affairs, the Veterans Affairs Biorepository (CSP 501), the National Institute of Aging Boston University Alzheimer's Disease Center (P30AG13846; supplement 0572063345-5), the Department of Defense Peer Reviewed Alzheimer's Research Program (DoD-PRARP #13267017), the National Institute of Aging Boston University Framingham Heart Study (R01AG1649), and the National Operating Committee on Standards for Athletic Equipment and the Concussion Legacy Foundation. This work was also supported by unrestricted gifts from the Andlinger Foundation, the WWE, and the NFL. Michael L. Alosco and research reported in this article are supported by the National Institutes of Health under grant 1F32NS096803-01.; Dr. Goldstein is a paid consultant to Johnson & Johnson (New Brunswick, N.J.)/Janssen Research & Development, LLC (Raritan, N.J.), and Rebiscan, Inc. (Cambridge, Mass.); and he has received funding from the WWE and Ivivi Health Sciences. Dr. Nowinski is a member of the Mackey-White Committee of the NFL Players Association and receives fees for speaking at educational programs. Dr. Stern has received research funding from the NFL, the NFL Players Association, and Avid Radiopharmaceuticals, Inc. (Philadelphia); he is a member of the Mackey-White Committee of the NFL Players Association; he is a paid consultant to Athena Diagnostics/Quest Laboratories (Marlborough, Mass.), Amarantus BioScience Holdings, Inc. (San Francisco), and Avanir Pharmaceuticals, Inc. (Aliso Viejo, Calif.); he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, Fla.), as well as compensation from expert legal opinion. Dr. McKee has received funding from the NFL, WWE, and is a member of the Mackey-White Committee of the NFL Players Association. All other authors report no financial relationships with commercial interests. NR 30 TC 0 Z9 0 U1 3 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2017 VL 29 IS 1 BP 6 EP 12 DI 10.1176/appi.neuropsych.16030043 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP0WO UT WOS:000397107600002 PM 27539377 ER PT J AU Salazar, R Dwivedi, AK Royall, DR AF Salazar, Ricardo Dwivedi, Alok Kumar Royall, Donald R. TI Cross-Ethnic Differences in the Severity of Neuropsychiatric Symptoms in Persons With Mild Cognitive Impairment and Alzheimer's Disease SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID BRIEF CLINICAL FORM; MEXICAN-AMERICANS; NPI-Q; DEMENTIA; HISPANICS; PREVALENCE; DEPRESSION; POPULATION; VALIDATION; INVENTORY AB In this cross-sectional study, we examined the neuropsychiatric profile of mild cognitive impairment (MCI) and Alzheimer's disease (AD) using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Data were available on 875 controls, 339 MCI cases, and 975 AD participants. Surprisingly, differences in neuropsychiatric symptom (NPS) severity by ethnicity in subjects with AD, but not with MCI, were found. More so, in Hispanics with AD, a higher frequency in most of the individual NPI-Q symptom items of the scale was observed, except for apathy. After adjustment for clinical features, some individual NPI-Q symptoms also showed an association with Hispanic ethnicity in the control group that nearly reached statistical significance. There may be cross-ethnic differences in the neuropsychiatric presentation of AD in Hispanics versus non-Hispanic whites. Future studies are needed to clarify the etiology of these differences, and to assess the need for ethnicity-specific treatment and care-giving interventions. C1 [Salazar, Ricardo] Texas Tech Univ Hlth Sci Ctr El Paso, Div Geriatr Psychiat & Behav Neurosci, Dept Psychiat, El Paso, TX 79905 USA. Texas Tech Univ Hlth Sci Ctr El Paso, Paul L Foster Sch Med, El Paso, TX 79905 USA. Texas Tech Univ Hlth Sci Ctr El Paso, Paul L Foster Sch Med, Dept Biomed Sci, Div Biostat & Epidemiol, El Paso, TX 79905 USA. Texas Tech Univ Hlth Sci Ctr El Paso, Biostat & Epidemiol Consulting Lab, El Paso, TX 79905 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat & Behav Med, San Antonio, TX 78229 USA. Univ Texas Hlth Sci Ctr San Antonio, Depts Med Family & Community Med, San Antonio, TX 78229 USA. South Texas Vet Hlth Care Syst, GRECC, San Antonio, TX USA. RP Salazar, R (reprint author), Texas Tech Univ Hlth Sci Ctr El Paso, Div Geriatr Psychiat & Behav Neurosci, Dept Psychiat, El Paso, TX 79905 USA. FU Texas Alzheimer's Research and Care Consortium (TARCC) - state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders FX This study was made possible by the Texas Alzheimer's Research and Care Consortium (TARCC) funded by the state of Texas through the Texas Council on Alzheimer's Disease and Related Disorders. NR 41 TC 0 Z9 0 U1 10 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2017 VL 29 IS 1 BP 13 EP 21 DI 10.1176/appi.neuropsych.15120423 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP0WO UT WOS:000397107600003 PM 27417070 ER PT J AU Lee, C Fan, YH Starr, JR Dogon, IL AF Lee, Cliff Fan, Yuehong Starr, Jacqueline R. Dogon, I. Leon TI Dentists' and dental students' attitudes, knowledge, preparedness, and willingness related to treatment of people living with HIV/AIDS in China SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article DE HIV stigma; access to care; attitude of health personnel; refusal to treat; China; dental education; dental ethics ID HIV-INFECTED PATIENTS; SELF-DISCLOSURE; ORAL LESIONS; HEALTH; CARE; BARRIERS; STIGMA; BLOOD AB Objectives: This study aims to assess the attitudes, knowledge, preparedness, and willingness of dentists and dental students to treat people-living-with-HIV/AIDS (PLWHA) in China, and to determine the factors associated with willingness to treat. Methods: We surveyed dentists and dental students in hospitals and dental schools in five regions in China with varying PLWHA prevalence. Survey questions covered demographics, as well as four categories regarding treating PLWHA: knowledge (scaled 0-1), attitude (scaled 1-4), preparedness (scaled 1-4), and willingness to treat (scaled 1-4). Composite scores for each category were calculated as weighted means. Confounder-adjusted regression analysis was performed to determine the factor(s) correlated with willingness to treat. Results: We collected 394 (84 percent) and 462 (90 percent) useable surveys from dentists and dental students respectively. Dentists' mean composite scores were 0.63 (poor knowledge), 2.1 (negative attitude), 2.8 (adequate preparedness), and 2.5 (neutral willingness). Students' mean composite scores were 0.64 (poor knowledge), 2.3 (negative attitude), 2.7 (adequate preparedness), and 2.6 (positive willingness). Forty-five percent of dentists and 59 percent of dental students had scores indicating positive willingness to treat. Attitude was the only factor consistently correlated with willingness to treat. Dentists and dental students scored low in all categories except for preparedness. Conclusion: It is imperative that knowledge of HIV/AIDS and attitudes toward PLWHA be further improved during dental training to increase the access to and effectiveness of dental care of PLWHA in China and to enhance their quality of life. C1 [Lee, Cliff; Fan, Yuehong] Harvard Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. [Starr, Jacqueline R.] Forsyth Inst, Cambridge, MA USA. [Starr, Jacqueline R.] Harvard Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA USA. [Dogon, I. Leon] Harvard Sch Dent Med, Dept Restorat Dent & Biomat Sci, Boston, MA USA. RP Lee, C; Fan, YH (reprint author), Harvard Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. EM cliff_lee@alumni.harvard.edu; yuehongfan@alumni.harvard.edu FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center [UL1 TR001102]; Harvard University FX This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. NR 30 TC 0 Z9 0 U1 7 U2 7 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4006 EI 1752-7325 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD WIN PY 2017 VL 77 IS 1 BP 30 EP 38 DI 10.1111/jphd.12168 PG 9 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA EN1JV UT WOS:000395767200005 PM 27427861 ER PT J AU Vella, D Ovchinnikov, D Martino, N Vega-Mayoral, V Dumcenco, D Kung, YC Antognazza, MR Kis, A Lanzani, G Mihailovic, D Gadermaier, C AF Vella, D. Ovchinnikov, D. Martino, N. Vega-Mayoral, V. Dumcenco, D. Kung, Y-C Antognazza, M-R Kis, A. Lanzani, G. Mihailovic, D. Gadermaier, C. TI Unconventional electroabsorption in monolayer MoS2 SO 2D MATERIALS LA English DT Article DE electroabsorption; electromodulation; monolayer MoS2; spectroscopy; excitons; trions ID TRANSITION-METAL DICHALCOGENIDES; STARK-EFFECT SPECTROSCOPY; FIELD-EFFECT TRANSISTORS; QUANTUM-WELL STRUCTURES; SINGLE-LAYER MOS2; OPTICAL MODULATORS; 2D SEMICONDUCTORS; ELECTRIC-FIELD; GRAPHENE; OPTOELECTRONICS AB Signal modulation in optoelectronics is obtained by modulation of either the refractive index or the absorbance by an electric field. However, electromodulators have not kept up with the miniaturization of other electronic and optical components. Here we show a strong transverse electroabsorption signal in a monolayer of the 2D semiconductor MoS2. The electroabsorption spectrum is dominated by an apparent linewidth broadening of around 15% at a modulated voltage of only V-pp = 0.5 V. Contrary to known variants of the Stark effect, the broadening increases linearly with the applied field strength and arises from a linear variation of the distance between the strongly overlapping exciton and trion resonances. The achievable modulation depths exceeding 0.1 dB nm(-1) bear the scope for extremely compact, ultrafast, energy-efficient electroabsorption modulators for integrated photonics, including on-chip optical communication. C1 [Vella, D.; Vega-Mayoral, V.; Mihailovic, D.; Gadermaier, C.] Jozef Stefan Inst, Dept Complex Matter, Jamova 39, Ljubljana 1000, Slovenia. [Vella, D.; Vega-Mayoral, V.; Mihailovic, D.; Gadermaier, C.] Jozef Stefan Int Postgrad Sch, Jamova 39, Ljubljana 1000, Slovenia. [Ovchinnikov, D.; Dumcenco, D.; Kung, Y-C; Kis, A.] Ecole Polytech Fed Lausanne, Inst Elect Engn, CH-1015 Lausanne, Switzerland. [Ovchinnikov, D.; Dumcenco, D.; Kung, Y-C; Kis, A.] Ecole Polytech Fed Lausanne, Inst Mat Sci & Engn, CH-1015 Lausanne, Switzerland. [Martino, N.] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. [Martino, N.] Harvard Med Sch, 65 Landsdowne St, Cambridge, MA 02139 USA. [Antognazza, M-R; Lanzani, G.] Italian Inst Technol, Ctr Nano Sci & Technol, Via Pascoli 70-3, I-20133 Milan, Italy. [Lanzani, G.] Politecn Milan, Dept Phys, P Leonardo da Vinci 32, I-20133 Milan, Italy. [Mihailovic, D.] Univ Ljubljana, Fac Math & Phys, Jadranska 19, Ljubljana 1000, Slovenia. [Mihailovic, D.] Ctr Excellence Nanosci & Nanotechnol, Jamova 39, Ljubljana 1000, Slovenia. RP Vella, D (reprint author), Jozef Stefan Inst, Dept Complex Matter, Jamova 39, Ljubljana 1000, Slovenia.; Vella, D (reprint author), Jozef Stefan Int Postgrad Sch, Jamova 39, Ljubljana 1000, Slovenia. EM daniele.vella@ijs.si; christoph.gadermaier@ijs.si RI Kis, Andras/A-4631-2011 OI Kis, Andras/0000-0002-3426-7702 FU Marie-Curie ITN 'MoWSeS' [317451]; European Union [318804]; Swiss SNF [147607]; EC under the Graphene Flagship [604391] FX We are grateful for the inspiring discussions with S Bertolazzi, M Caironi, Ya A Gerasimenko, V V Kabanov, D Neumaier, V Perebeinos, J Strle, and T Heine. Device fabrication was carried out in the EPFL Center for Micro/Nanotechnology (CMI). We thank Z Benes (CMI) for technical support with e-beam lithography. The research leading to these results has received funding from the Marie-Curie ITN 'MoWSeS' (grant no. 317451), the European Union's Seventh Framework Programme FP7/2007-2013 under Grant Agreement No. 318804 (SNM) and the Swiss SNF Sinergia Grant no. 147607. We acknowledge funding by the EC under the Graphene Flagship (grant agreement no. 604391). NR 44 TC 0 Z9 0 U1 2 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 2053-1583 J9 2D MATER JI 2D Mater. PD JUN PY 2017 VL 4 IS 2 AR 021005 DI 10.1088/2053-1583/aa5784 PG 9 WC Materials Science, Multidisciplinary SC Materials Science GA EM6WU UT WOS:000395454100001 ER PT J AU Seisen, T Jindal, T Karabon, P Sood, A Bellmunt, J Roupret, M Leow, JJ Vetterlein, MW Sun, M Alanee, S Choueiri, TK Trinh, QD Menon, M Abdollah, F AF Seisen, Thomas Jindal, Tarun Karabon, Patrick Sood, Akshay Bellmunt, Joaquim Roupret, Morgan Leow, Jeffrey J. Vetterlein, Malte W. Sun, Maxine Alanee, Shaheen Choueiri, Toni K. Quoc-Dien Trinh Menon, Mani Abdollah, Firas TI Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma SO EUROPEAN UROLOGY LA English DT Letter DE Urothelial carcinoma; Ureteral neoplasms; Ureter; Renal pelvis; Drug therapy; Propensity score; Survival ID LOCAL TREATMENT; SURVIVAL; OUTCOMES; CANCER AB Given the growing body of evidence supporting the benefit of primary tumor control for a wide range of metastatic malignancies, we hypothesized that chemotherapy plus radical nephroureterectomy (RNU) is associated with an overall survival (OS) benefit compared to chemotherapy alone for metastatic upper tract urothelial carcinoma (mUTUC). Within the National Cancer Data Base (2004-2012), we identified 398 (38.4%) and 637 (61.6%) patients who received chemotherapy plus RNU and chemotherapy alone, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves showed that 3-yr OS was 16.2% (95% confidence interval [CI] 12.120.3) for chemotherapy plus RNU and 6.4% (95% CI 4.1-8.7) for chemotherapy alone (p < 0.001). In IPTW-adjusted Cox regression analysis, chemotherapy plus RNU was associated with a significant OS benefit (hazard ratio 0.70, 95% CI 0.61-0.80; p < 0.001). Despite the usual biases related to the observational study design, our findings show a net OS benefit for fit patients who received chemotherapy plus RNU for mUTUC relative to their counterparts treated with chemotherapy alone. Patient summary: We examined the role of radical nephroureterectomy in addition to systemic chemotherapy for metastatic upper tract urothelial carcinoma. We found that such treatment may be associated with an overall survival benefit compared to chemotherapy alone in fit patients. (C) 2016 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Seisen, Thomas; Jindal, Tarun; Karabon, Patrick; Sood, Akshay; Vetterlein, Malte W.; Alanee, Shaheen; Menon, Mani; Abdollah, Firas] Vattikuti Urol Inst, Henry Ford Hlth, Ctr Outcomes Res Analyt & Evaluat, Detroit, MI USA. [Bellmunt, Joaquim; Choueiri, Toni K.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Roupret, Morgan] Pierre & Marie Curie Univ, Pitie Salpetriere Hosp, AP HP, Dept Urol, Paris, France. [Leow, Jeffrey J.; Sun, Maxine; Quoc-Dien Trinh] Harvard Med Sch, Brigham & Womens Hosp, Div Urol Surg, Boston, MA USA. [Leow, Jeffrey J.; Sun, Maxine; Quoc-Dien Trinh] Harvard Med Sch, Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA USA. RP Abdollah, F (reprint author), Henry Ford Hosp, Vattikuti Urol Inst, 2799 West Grand Blvd, Detroit, MI 48202 USA. EM firas.abdollah@gmail.com FU Pierre Fabre; Astellas Pharma; Pfizer; Merck; Genentech; Novartis; Millennium Pharmaceuticals; Sanofi; Sanofi Pasteur; IPSEN; Takeda Pharmaceuticals; Bayer AG; GlaxoSmithKline; Bristol-Myers Squibb; Eisai; Prometheus Labs; Foundation Medicine Research; Cerulean Pharma; AstraZeneca; Peloton; Exelixis; TRACON Pharmaceuticals; Peloton Therapeutics; GenomeDx Biosciences FX Firas Abdollah certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas Seisen, Tarun Jindal, Patrick Karabon, Akshay Sood, Jeffrey J. Leow, Malte W. Vetterlein, Maxine Sun, Quoc-Dien Trinh, and Mani Menon have nothing to disclose. Joaquim Bellmunt has received consulting/advisory fees from Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, and Novartis; institutional research funding from Millennium Pharmaceuticals and Sanofi; and travel/accommodation expenses from Pfizer and MSD Oncology. Morgan Roupret has received consulting/advisory fees from Sanofi Pasteur and IPSEN. Shaheen Alanee has received consulting/advisory fees from Takeda Pharmaceuticals. Toni K. Choueirin has received honoraria from the National Comprehensive Cancer Network and UpToDate; consulting/advisory fees from Pfizer, Bayer AG, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Genentech, Eisai, Prometheus Labs, Foundation Medicine Research, Cerulean Pharma, AstraZeneca, and Peloton; and institutional funding from Pfizer, Novartis, Merck, Exelixis, TRACON Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, and Genentech. Firas Abdollah has received consulting/advisory fees from GenomeDx Biosciences. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2017 VL 71 IS 5 BP 714 EP 718 DI 10.1016/j.eururo.2016.11.012 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA EQ0PO UT WOS:000397773300020 PM 27912971 ER PT J AU Gray, PJ Lin, CC Cooperberg, MR Jemal, A Efstathiou, JA AF Gray, Phillip J. Lin, Chun Chieh Cooperberg, Matthew R. Jemal, Ahmedin Efstathiou, Jason A. TI Temporal Trends and the Impact of Race, Insurance, and Socioeconomic Status in the Management of Localized Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Localized; Androgen deprivation therapy; Practice patterns ID ANDROGEN-DEPRIVATION THERAPY; ACTIVE SURVEILLANCE; DATA-BASE; LOW-RISK; RADICAL PROSTATECTOMY; MORTALITY OUTCOMES; UNITED-STATES; RADIOTHERAPY; MEN; COHORT AB Background: Numerous management options exist for patients with prostate cancer; however, recent trends and their influencing factors are not well described. Objective: To describe modern patterns of care and factors associated with management choice using the National Cancer Database. Design, setting, and participants: Patients with localized prostate cancer diagnosed between 2004 and 2012 were included and grouped according to National Comprehensive Cancer Network guidelines into low, intermediate, or high risk. Outcome measurements and statistical analysis: Trend analyses and multivariate logistic regression was used to identify factors associated with management. Results and limitations: There were 598 640 patients who met the study criteria; 36.3% were classified as low risk, 43.8% intermediate risk, and 20.0% high risk. Over the study period, among low-risk patients, observation increased from 9.2% to 21.3%, while radical prostatectomy (RP) increased from 29.5% to 51.1% (p < 0.001 for both). In contrast, external beam radiotherapy decreased from 24.3% to 14.5%, while brachytherapy decreased from 31.7% to 11.1%. A similar pattern was seen for patients with intermediate-risk or high-risk disease. Among high-risk patients, RP increased from 25.1% to 43.4% replacing external beam radiotherapy as the dominant therapy. On multivariate analysis, racial minorities, the uninsured, and low-income patients were less likely to receive RP. Low-risk patients in similar subgroups were significantly more likely to be observed. Limitations include potential miscoding or misclassification of variables. Conclusions: Patterns of care in localized prostate cancer are changing rapidly. While use of observation is increasing in low-risk groups, the use of RP is increasing across all risk groups with a concomitant decline in use of radiotherapy. Socioeconomic factors appear to influence management choice. Patient summary: In this report we identify a recent significant increase in the use of radical prostatectomy for prostate cancer patients. Socioeconomic factors such as race, insurance type, and income may affect treatments offered to and received by patients. (C) 2016 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Gray, Phillip J.] Hallmark Hlth Canc Ctr, CHEM Canc Radiat Oncol, 48 Montvale Ave, Stoneham, MA 02180 USA. [Lin, Chun Chieh; Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res Program, Atlanta, GA 30329 USA. [Cooperberg, Matthew R.] Univ Calif San Francisco, Dept Urol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Gray, PJ (reprint author), Hallmark Hlth Canc Ctr, CHEM Canc Radiat Oncol, 48 Montvale Ave, Stoneham, MA 02180 USA. EM pjgraymd@gmail.com FU American Cancer Society FX American Cancer Society intramural research funding assisted with the collection of the data. NR 30 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2017 VL 71 IS 5 BP 729 EP 737 DI 10.1016/j.eururo.2016.08.047 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EQ0PO UT WOS:000397773300024 PM 27597241 ER PT J AU Kishan, AU Shaikh, T Wang, PC Reiter, RE Said, J Raghavan, G Nickols, NG Aronson, WJ Sadeghi, A Kamrava, M Demanes, DJ Steinberg, ML Horwitz, EM Kupelian, PA King, CR AF Kishan, Amar U. Shaikh, Talha Wang, Pin-Chieh Reiter, Robert E. Said, Jonathan Raghavan, Govind Nickols, Nicholas G. Aronson, William J. Sadeghi, Ahmad Kamrava, Mitchell Demanes, David Jeffrey Steinberg, Michael L. Horwitz, Eric M. Kupelian, Patrick A. King, Christopher R. TI Clinical Outcomes for Patients with Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis SO EUROPEAN UROLOGY LA English DT Article DE Gleason 9; Gleason 10; Radiotherapy; Radical prostatectomy ID ANDROGEN-DEPRIVATION THERAPY; ISUP CONSENSUS CONFERENCE; INTERNATIONAL-SOCIETY; RANDOMIZED-TRIALS; RADIATION-THERAPY; BEAM RADIOTHERAPY; HORMONAL-THERAPY; SHORT-TERM; CANCER; CARCINOMA AB Background: The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons. Objective: To compare outcomes of patientswithGS 9-10 CaP following EBRT, extremely-dose escalatedradiotherapy(as exemplifiedbyEBRT + brachytherapy[EBRT + BT]), andRP. Design, setting, participants: Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT + BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy. Outcome measurements and statistical analysis: Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasisfree survival, cancer-specific survival (CSS), and overall survival (OS). Results and limitations: The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT + BT patients (1.2% and 16.1%, p < 0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT + BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p = 0.0005) or RP (79.1% and 61.5%, p < 0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts. Conclusions: Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP. Patient summary: While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to bemade and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patientswith very aggressive cancers (defined asGleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival. (C) 2016 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Kishan, Amar U.; Wang, Pin-Chieh; Raghavan, Govind; Nickols, Nicholas G.; Kamrava, Mitchell; Demanes, David Jeffrey; Steinberg, Michael L.; Kupelian, Patrick A.; King, Christopher R.] Univ Calif Los Angeles, Dept Radiat Oncol, Los Angeles, CA 90024 USA. [Shaikh, Talha; Horwitz, Eric M.] Fox Chase Canc Ctr, Dept Radiat Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Reiter, Robert E.; Aronson, William J.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Said, Jonathan] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. [Nickols, Nicholas G.; Sadeghi, Ahmad] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Radiat Oncol, Los Angeles, CA USA. [Aronson, William J.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Urol, Los Angeles, CA USA. RP Kishan, AU (reprint author), Dept Radiat Oncol, Suite B265,200 Med Plaza, Los Angeles, CA 90095 USA. EM aukishan@mednet.ucla.edu NR 34 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD MAY PY 2017 VL 71 IS 5 BP 766 EP 773 DI 10.1016/j.eururo.2016.06.046 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EQ0PO UT WOS:000397773300031 PM 27452951 ER PT J AU Abdallah, CG AF Abdallah, Chadi G. TI What's the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID ANTIDEPRESSANT; KETAMINE; METABOLITES; DEPRESSION; RECEPTORS C1 [Abdallah, Chadi G.] US Dept Vet Affairs, Natl Ctr PTSD, Clin Neurosci Div, West Haven, CT USA. [Abdallah, Chadi G.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Abdallah, CG (reprint author), Yale Univ, Sch Med, VA Natl Ctr PTSD, Dept Psychiat,Clin Neurosci Div, 950 Campbell Ave,151E, West Haven, CT 06516 USA. EM chadi.abdallah@yale.edu FU U.S. Department of Veterans Affairs; National Center for PTSD; Patterson Trust Award; National Institute of Mental Health [K23MH101498] FX This work was supported by the U. S. Department of Veterans Affairs, National Center for PTSD, the Patterson Trust Award, and the National Institute of Mental Health (Grant No. K23MH101498). The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the Department of Veterans Affairs or other sponsoring institutions. NR 10 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2017 VL 81 IS 8 BP E61 EP E63 DI 10.1016/j.biopsych.2017.01.002 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3SA UT WOS:000397300800002 PM 28317551 ER PT J AU Naggie, S Marks, KM Hughes, M Fierer, DS Macbrayne, C Kim, A Hollabaugh, K Roa, J Symonds, B Brainard, DM McHutchison, JG Peters, MG Kiser, JJ Chung, R AF Naggie, Susanna Marks, Kristen M. Hughes, Michael Fierer, Daniel S. Macbrayne, Christine Kim, Arthur Hollabaugh, Kimberly Roa, Jhoanna Symonds, Bill Brainard, Diana M. McHutchison, John G. Peters, Marion G. Kiser, Jennifer J. Chung, Raymond CA ACTG A5327 Study Team TI Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis; human immunodeficiency virus; direct-acting antivirals; early infection; interferon-free ID ADHERENCE; OUTCOMES; PEOPLE; TRIAL; MEN AB Background. Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods. The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants. Results. Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment. Conclusion. Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear. C1 [Naggie, Susanna] Duke Univ, Med Ctr, Durham, NC USA. [Marks, Kristen M.] Weill Cornell, New York, NY USA. [Hughes, Michael] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Fierer, Daniel S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Macbrayne, Christine; Kiser, Jennifer J.] Univ Colorado, Aurora, CO USA. [Kim, Arthur; Chung, Raymond] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hollabaugh, Kimberly; Roa, Jhoanna] Social & Sci Syst Inc, Silver Spring, MD USA. [Symonds, Bill] Roivant, New York, NY USA. [Brainard, Diana M.; McHutchison, John G.] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Peters, Marion G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Naggie, S (reprint author), 2400 Pratt St,Rm 0311 Terrace Level, Durham, NC 27705 USA. EM susanna.naggie@duke.edu FU National Institute of Allergy and Infectious Diseases of the (NIH) [UM1 AI068634, UM1 AI068636, UM1 AI106701]; Center for AIDS Research and Gilead Sciences; National Institutes of Health [R01 DA040499] FX This work was supported by the National Institute of Allergy and Infectious Diseases of the (NIH; UM1 AI068634, UM1 AI068636, and UM1 AI106701). The research was also been supported, in part, by a grant(s) funded by the Center for AIDS Research and Gilead Sciences. J. K. was supported by the National Institutes of Health [R01 DA040499]. NR 29 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 APR 15 PY 2017 VL 64 IS 8 BP 1035 EP 1042 DI 10.1093/cid/cix025 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800006 ER PT J AU Branda, JA Strle, K Nigrovic, LE Lantos, PM Lepore, TJ Damle, NS Ferraro, MJ Steere, AC AF Branda, John A. Strle, Klemen Nigrovic, Lise E. Lantos, Paul M. Lepore, Timothy J. Damle, Nitin S. Ferraro, Mary Jane Steere, Allen C. TI Evaluation of Modified 2-Tiered Serodiagnostic Testing Algorithms for Early Lyme Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Lyme; Borrelia burgdorferi; VlsE; C6; serology ID BORRELIA-BURGDORFERI; ERYTHEMA MIGRANS; ENZYME-IMMUNOASSAY; ANTIBODY-RESPONSES; COST-EFFECTIVENESS; IGM IMMUNOBLOTS; UNITED-STATES; SKIN-LESIONS; PEPTIDE; VLSE AB Background. The conventional 2-tiered serologic testing protocol for Lyme disease (LD), an enzyme immunoassay (EIA) followed by immunoglobulin M and immunoglobulin G Western blots, performs well in late-stage LD but is insensitive in patients with erythema migrans (EM), the most common manifestation of the illness. Western blots are also complex, difficult to interpret, and relatively expensive. In an effort to improve test performance and simplify testing in early LD, we evaluated several modified 2-tiered testing (MTTT) protocols, which use 2 assays designed as first-tier tests sequentially, without the need of Western blots. Methods. The MTTT protocols included (1) a whole-cell sonicate (WCS) EIA followed by a C6 EIA; (2) a WCS EIA followed by a VlsE chemiluminescence immunoassay (CLIA); and (3) a variable major protein-like sequence, expressed (VlsE) CLIA followed by a C6 EIA. Sensitivity was determined using serum from 55 patients with erythema migrans; specificity was determined using serum from 50 patients with other illnesses and 1227 healthy subjects. Results. Sensitivity of the various MTTT protocols in patients with acute erythema migrans ranged from 36% (95% confidence interval [CI], 25%-50%) to 54% (95% CI, 42%-67%), compared with 25% (95% CI, 16%-38%) using the conventional protocol (P =.003-0.3). Among control subjects, the 3 MTTT protocols were similarly specific (99.3%-99.5%) compared with conventional 2-tiered testing (99.5% specificity; P =.6-1.0). Conclusions. Although there were minor differences in sensitivity and specificity among MTTT protocols, each provides comparable or greater sensitivity in acute EM, and similar specificity compared with conventional 2-tiered testing, obviating the need for Western blots. C1 [Branda, John A.; Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Strle, Klemen; Ferraro, Mary Jane; Steere, Allen C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Nigrovic, Lise E.] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Lantos, Paul M.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Lantos, Paul M.] Duke Univ, Sch Med, Dept Pediat, Durham, NC USA. [Lepore, Timothy J.] Nantucket Cottage Hosp, Nantucket, MA USA. [Damle, Nitin S.] South Cty Internal Med, Wakefield, RI USA. [Damle, Nitin S.] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. RP Branda, JA (reprint author), Massachusetts Gen Hosp, Clin Microbiol Lab, GRB 526, Boston, MA 02114 USA. EM branda.john@mgh.harvard.edu FU DiaSorin, Inc; Bay Area Lyme Foundation FX This work was supported by research grants from DiaSorin, Inc, and the Bay Area Lyme Foundation to J. A. B. NR 29 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 APR 15 PY 2017 VL 64 IS 8 BP 1074 EP 1080 DI 10.1093/cid/cix043 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800011 ER PT J AU Dugast, AS Arnold, K Lofano, G Moore, S Hoffner, M Simek, M Poignard, P Seaman, M Suscovich, TJ Pereyra, F Walker, BD Lauffenburger, D Kwon, DS Keele, BF Alter, G AF Dugast, Anne-Sophie Arnold, Kelly Lofano, Giuseppe Moore, Sarah Hoffner, Michelle Simek, Melissa Poignard, Pascal Seaman, Michael Suscovich, Todd J. Pereyra, Florencia Walker, Bruce D. Lauffenburger, Doug Kwon, Douglas S. Keele, Brandon F. Alter, Galit TI Virus-driven Inflammation Is Associated With the Development of bNAbs in Spontaneous Controllers of HIV SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE neutralizing antibodies; inflammation; HIV vaccine ID REACTIVE HIV-1-NEUTRALIZING ACTIVITY; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; DISEASE PROGRESSION; FOUNDER VIRUS; INFECTION; BROAD; INDIVIDUALS; THERAPY; VIREMIA AB Background. Understanding the mechanism(s) by which broadly neutralizing antibodies (bNAbs) emerge naturally following infection is crucial for the development of a protective vaccine against human immunodeficiency virus (HIV). Although previous studies have implicated high viremia and associated immune activation as potential drivers for the development of bNAbs, here we sought to unlink the effect of these 2 parameters by evaluating the key inflammatory predictors of bNAb development in HIV-infected individuals who spontaneously control HIV in the absence of antiretroviral therapy ("controllers"). Methods. The breadth of antibody-mediated neutralization against 11 tier 2 or 3 viruses was assessed in 163 clade B spontaneous controllers of HIV. Plasma levels of 17 cytokines were screened in the same set of subjects. The relationship of the inflammatory signature was assessed in the context of viral blips or viral RNA levels in peripheral blood or gastrointestinal biopsies from aviremic controllers (< 50 copies RNA/mL) and in the context of viral sequence diversity analysis in the plasma of viremic controllers (< 50-2000 copies RNA/mL). Results. A unique inflammatory profile, including high plasma levels of CXCL13, sCD40L, IP10, RANTES, and TNF alpha, was observed in HIV controllers who developed bNAbs. Interestingly, viral load and tissue viremia, but not intermittent viral blips, were associated with these cytokine profiles. However, viral diversity was not significantly associated with increased breadth in controllers. Conclusion. These results suggest that low antigenic diversity in the setting of a unique inflammatory profile associated with antigen persistence may be linked to the evolution of neutralizing antibody breadth. C1 [Dugast, Anne-Sophie; Lofano, Giuseppe; Moore, Sarah; Hoffner, Michelle; Suscovich, Todd J.; Pereyra, Florencia; Walker, Bruce D.; Kwon, Douglas S.; Alter, Galit] Ragon Inst Massachusetts Gen Hosp Hardvard Univ &, Cambridge, MA USA. [Arnold, Kelly; Lauffenburger, Doug] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Simek, Melissa; Poignard, Pascal] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Poignard, Pascal] Int AIDS Vaccine Initiat, New York, NY USA. [Seaman, Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Keele, Brandon F.] Leidos Biomed Res Inc, Frederick Natl Lab, AIDS & Canc Virus Program, Frederick, MD USA. RP Alter, G (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. EM galter@PARTNERS.ORG FU Bill and Melinda Gates Foundation CAVD [OPP1066973, OPP1032817]; National Cancer Institute, National Institutes of Health [HHSN261200800001E, R01 AI080289, R01 A102660-01, R37 AI080289-06A1]; Ragon Institute of MGH, MIT, and Harvard; IAVI; USAID; Ministry of Foreign Affairs of the Netherlands; Bill and Melinda Gates Foundation FX This work was supported by the Bill and Melinda Gates Foundation CAVD (OPP1066973: Development of broadly neutralizing antibodies in HIV infection and following immunization and OPP1032817: Leveraging Antibody Effector Function), the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E, R01 AI080289, R01 A102660-01 and R37 AI080289-06A1 and the Ragon Institute of MGH, MIT, and Harvard. This work was partially funded by IAVI with the generous support of USAID, Ministry of Foreign Affairs of the Netherlands, and the Bill and Melinda Gates Foundation; a full list of IAVI donors is available at www.iavi.org. NR 38 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 APR 15 PY 2017 VL 64 IS 8 BP 1098 EP 1104 DI 10.1093/cid/cix057 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800015 ER PT J AU Strymish, J Gupte, G Afable, MK Gupta, K Kim, EJ Vimalananda, V Simon, SR Orlander, JD AF Strymish, Judith Gupte, Gouri Afable, Melissa K. Gupta, Kalpana Kim, Eun Ji Vimalananda, Varsha Simon, Steven R. Orlander, Jay D. TI Electronic Consultations (E-consults): Advancing Infectious Disease Care in a Large Veterans Affairs Healthcare System SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE electronic consultations (e-consults); telemedicine; consultation ID IMPACT AB The impact of e-consults on total consultative services was evaluated. After implementing infectious diseases e-consults within an electronically integrated healthcare system, consultation volume increased. As compared with face-to-face consultations, e-consults were more often related to antimicrobial guidance and were requested by off-site providers. E-consults increased the breadth and volume of total consults. C1 [Strymish, Judith; Gupta, Kalpana; Simon, Steven R.; Orlander, Jay D.] VA Boston Healthcare Syst, Dept Med, West Roxbury, MA 02132 USA. [Strymish, Judith; Simon, Steven R.] Harvard Med Sch, Boston, MA USA. [Gupte, Gouri; Afable, Melissa K.] Boston Univ, Sch Publ Hlth, Dept Hlth Law Policy & Management, Boston, MA USA. [Kim, Eun Ji; Vimalananda, Varsha] Edith Nourse Rogers Mem Vet Affairs Med Ctr, CHOIR, Bedford, MA USA. [Gupta, Kalpana; Kim, Eun Ji; Vimalananda, Varsha; Orlander, Jay D.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Simon, Steven R.] Brigham & Womens Hosp, Div Gen Med & Primary Care, 75 Francis St, Boston, MA 02115 USA. RP Strymish, J (reprint author), VA Boston Healthcare Syst, Dept Med, West Roxbury, MA 02132 USA. EM Judith.strymish@va.gov NR 12 TC 1 Z9 1 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 APR 15 PY 2017 VL 64 IS 8 BP 1123 EP 1125 DI 10.1093/cid/cix058 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800019 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 Diffuse F-18-FDG accumulation in the subarachnoid space detected by PET/CT in a patient with subarachnoid hemorrhage and hyperglycemia SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Editorial Material C1 [Fu, Zhanli; Liu, Meng; Li, Ziao] Peking Univ, Hosp 1, Beijing 100034, Peoples R China. [Zhang, Jin] Beijing Univ Chinese Med, Dongzhimen Hosp, Beijing 100007, Peoples R China. [Li, Qian] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Fu, ZL (reprint author), Peking Univ, Hosp 1, Beijing 100034, Peoples R China. EM fuzhanli2002@163.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD APR PY 2017 VL 44 IS 4 BP 732 EP 733 DI 10.1007/s00259-016-3610-3 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM0CF UT WOS:000394985700020 PM 28064344 ER PT J AU Montgomery, AE Cusack, M Szymkowiak, D Fargo, J O'Toole, T AF Montgomery, Ann Elizabeth Cusack, Meagan Szymkowiak, Dorota Fargo, Jamison O'Toole, Thomas TI Factors contributing to eviction from permanent supportive housing: Lessons from HUD-VASH SO EVALUATION AND PROGRAM PLANNING LA English DT Article DE Eviction; Permanent supportive housing; Substance use disorder; Acute care; Veterans ID CHRONICALLY HOMELESS INDIVIDUALS; INDEPENDENT LIVING PROGRAMS; SEVERE ALCOHOL-PROBLEMS; SERIOUS MENTAL-ILLNESS; 1ST; PROJECT; EXPANSION; OUTCOMES; PEOPLE; CARE AB Introduction: Eviction from housing is associated with several negative outcomes, further exacerbated among high-need populations requiring financial and supportive services to maintain housing stability. This study investigated risk and protective factors both characteristics and precipitating events of tenant eviction informing permanent supportive housing (PSH) programs' efforts to identify tenants at risk and intervene. Methods: Using administrative data for a cohort of 20,146 Veterans participating in PSH, this study assessed differences in Veterans who exited the program due to eviction and Veterans Who exited because they accomplished their goals. A series of logistic regressions identified patterns of health services use that may signal imminent eviction. Results: Veterans with a drug use disorder and those who received inpatient, emergency, or outpatient care related to mental/behavioral health and substance use conditions proximal to program exit had greater risk for eviction. Receipt of outpatient primary medical care and supportive services was generally protective against eviction. The likelihood of eviction was greatest for Veterans with acute care use within 30 days of exit. Discussion: PSH providers may use these correlates of eviction to identify Veterans in need of an intervention to prevent eviction. Future work should focus on operationalizing these findings and identifying appropriate interventions. Published by Elsevier Ltd. C1 [Montgomery, Ann Elizabeth; Cusack, Meagan; Szymkowiak, Dorota; Fargo, Jamison; O'Toole, Thomas] US Dept Vet Affairs, Natl Ctr Homelessness Vet, Philadelphia, PA USA. [Montgomery, Ann Elizabeth] Birmingham VA Med Ctr, Hlth Serv Res, Birmingham, AL USA. [Montgomery, Ann Elizabeth] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Fargo, Jamison] Utah State Univ, Coll Educ & Human Serv, Logan, UT 84322 USA. [O'Toole, Thomas] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Cusack, Meagan] 4100 Chester Ave,Suite 202, Philadelphia, PA 19104 USA. [Szymkowiak, Dorota] 4100 Chester Ave,Suite 201, Philadelphia, PA 19104 USA. [Fargo, Jamison] 2810 Old Main Hill, Logan, UT 84322 USA. [O'Toole, Thomas] 830 Chalkstone Ave, Providence, RI 02908 USA. RP Montgomery, AE (reprint author), RPHB 227M,1720 2nd Ave South, Birmingham, AL 35294 USA. EM ann.montgomery2@va.gov; meagan.cusack@va.gov; dorota.szymkowiak@va.gov; jamison.fargo@usu.edu; thomas.o'toole@va.gov FU U.S. Department of Veterans Affairs (VA); National Center on Homelessness Among Veterans; U.S. Department of Housing and Urban Development (HUD); Office of Policy Development and Research FX Research for this paper was supported by the U.S. Department of Veterans Affairs (VA), National Center on Homelessness Among Veterans and the U.S. Department of Housing and Urban Development (HUD), Office of Policy Development and Research. The authors wish to express their gratitude to Brent Roberts of the VA Center on Health Equity Research and Promotion and Todd Manning of the Veterans Health Administration Support Service Center for their assistance with data management. The contents of this paper do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 44 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 0149-7189 EI 1873-7870 J9 EVAL PROGRAM PLANN JI Eval. Program Plan. PD APR PY 2017 VL 61 BP 55 EP 63 DI 10.1016/j.evalprogplan.2016.11.014 PG 9 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA EM3MZ UT WOS:000395220600006 PM 27940343 ER PT J AU Levingston, CA Young, MRI AF Levingston, Corinne A. Young, M. Rita I. TI Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD-1 antibodies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cytokines; head and neck cancer; HNSCC; immunotherapy; PD-1; premalignant oral lesions; T cell ID SQUAMOUS-CELL CARCINOMA; REGULATORY T-CELLS; ADVANCED MELANOMA; IMMUNE REACTIVITY; ENDOTHELIAL-CELLS; OVARIAN-CANCER; NEGATIVE HEAD; LUNG-CANCER; NECK-CANCER; OPEN-LABEL AB A carcinogen-induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD-1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL-2 and the inflammatory cytokines IL-6, IL-17 and TNF-a by spleen cells of lesion-bearing mice that were treated with PD-1 antibody for 1 week compared to cytokine production by spleen cells of lesion-bearing mice treated with control antibody. Production of IFN-c increased at 3 weeks of PD-1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD-1 antibody-treated mice. Flow cytometric analysis for IFN-c-expressing cells showed shifts in CD4(+) 1 cells expressing IFN-c consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD-1 antibody- treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD-1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD-1 antibody-treated mice progressed to the same degree as in control antibody-treated mice. Overall, these results show an early beneficial response to PD-1 antibody treatment, which then fails with continued treatment and lesion progression. C1 [Levingston, Corinne A.; Young, M. Rita I.] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC USA. [Young, M. Rita I.] Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Med Univ South Carolina, Dept Otolaryngol, 114 Doughty St, Charleston, SC 29425 USA. EM Youngmr@musc.edu FU Merck Investigator Studies Program [52353]; The Clinical Sciences Research and Development Program of the Department of Veterans Affairs [I01-CX000851] FX Grant sponsors: Merck Investigator Studies Program; Grant sponsors: ID#52353; Grant sponsors: The Clinical Sciences Research and Development Program of the Department of Veterans Affairs; Grant number: Grant number: NR 46 TC 0 Z9 0 U1 1 U2 1 PU WILEY 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 APR PY 2017 VL 140 IS 7 BP 1609 EP 1619 DI 10.1002/ijc.30543 PG 11 WC Oncology SC Oncology GA EM2WT UT WOS:000395177200015 PM 27914100 ER PT J AU Charvet, CJ Hof, PR Raghanti, MA Van der Kouwe, AJ Sherwood, CC Takahashi, E AF Charvet, Christine J. Hof, Patrick R. Raghanti, Mary Ann Van der Kouwe, Andre J. Sherwood, Chet C. Takahashi, Emi TI Combining diffusion magnetic resonance tractography with stereology highlights increased cross-cortical integration in primates SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE cortex; evolution; connections; RRID:SCR_001905; RRID:SCR_002526; RRID:SCR_004817; RRID:SCR_012324 ID CORTICOCORTICAL FIBER-CONNECTIONS; VISUAL-CORTEX; CAT CEREBRUM; RHESUS-MONKEY; OPTICAL FRACTIONATOR; MACAQUE MONKEY; TOTAL NUMBER; BRAIN; PROJECTIONS; NEOCORTEX AB The isocortex of primates is disproportionately expanded relative to many other mammals, yet little is known about what the expansion of the isocortex entails for differences in cellular composition and connectivity patterns in primates. Across the depth of the isocortex, neurons exhibit stereotypical patterns of projections. Upper-layer neurons (i.e., layers II-IV) project within and across cortical areas, whereas many lower-layer pyramidal neurons (i.e., layers V-VI) favor connections to subcortical regions. To identify evolutionary changes in connectivity patterns, we quantified upper (i.e., layers II-IV)- and lower (i.e., layers V-VI)-layer neuron numbers in primates and other mammals such as rodents and carnivores. We also used MR tractography based on high-angular resolution diffusion imaging and diffusion spectrum imaging to compare anterior-to-posterior corticocortical tracts between primates and other mammals. We found that primates possess disproportionately more upper-layer neurons as well as an expansion of anterior-to-posterior corticocortical tracts compared with other mammals. Taken together, these findings demonstrate that primates deviate from other mammals in exhibiting increased cross-cortical connectivity. J. Comp. Neurol. 525:1075-1093, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Charvet, Christine J.; Takahashi, Emi] Harvard Med Sch, Boston Childrens Hosp, Div Newborn Med, Dept Med, Boston, MA 02115 USA. [Charvet, Christine J.; Sherwood, Chet C.] George Washington Univ, Dept Anthropol, Washington, DC 20052 USA. [Charvet, Christine J.; Sherwood, Chet C.] George Washington Univ, Ctr Adv Study Human Paleobiol, Washington, DC 20052 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Raghanti, Mary Ann] Kent State Univ, Dept Anthropol, Kent, OH 44240 USA. [Raghanti, Mary Ann] Kent State Univ, Sch Biomed Sci, Kent, OH 44240 USA. [Van der Kouwe, Andre J.; Takahashi, Emi] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Res, Charlestown, MA 02129 USA. [Van der Kouwe, Andre J.; Takahashi, Emi] Harvard Med Sch, Charlestown, MA 02129 USA. RP Charvet, CJ (reprint author), Cornell Univ, Dept Mol Biol & Genet, 349 Biotechnol Bldg, Ithaca, NY 14853 USA. EM charvetcj@gmail.com FU National Institutes of Health [R01 HD078561, R21 HD069001, R03 NS091587]; James S. McDonnell Foundation [220020293] FX fGrant sponsor: National Institutes of Health; Grant numbers: R01 HD078561 (to E.T.); R21 HD069001 (to E.T.); R03 NS091587 (to E.T.); Grant sponsor: James S. McDonnell Foundation; Grant number: 220020293 (to C.C.S.). NR 54 TC 0 Z9 0 U1 2 U2 2 PU WILEY 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 APR 1 PY 2017 VL 525 IS 5 BP 1075 EP 1093 DI 10.1002/cne.24115 PG 19 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA EL4FW UT WOS:000394578100002 PM 27615357 ER PT J AU Haller, CS Bosma, CM Kapur, K Zafonte, R Langer, EJ AF Haller, Chiara S. Bosma, Colin M. Kapur, Kush Zafonte, Ross Langer, Ellen J. TI Mindful creativity matters: trajectories of reported functioning after severe traumatic brain injury as a function of mindful creativity in patients' relatives: a multilevel analysis SO QUALITY OF LIFE RESEARCH LA English DT Article DE Mindfulness; Creativity; Severe traumatic brain injury; Functioning of the patient; Association with the relative ID SELF; DEPRESSION; PERSONALITY; COMPETENCE; PREDICTORS; THERAPISTS; STYLE AB The objective of the present investigation was to examine the association of mindful creativity with the trajectory of recovery (emotional, interpersonal, cognitive, and total functioning) of patients with severe TBI. This was drawn from a subsample of an adult prospective cohort study on severe TBI in Switzerland; patients and their relatives were assessed at 3, 6, and 12 months (patients N = 176, relatives N = 176). Predictor measures were assessed using Mindful Creativity Scale-short form and time (trajectory of functioning of the patient over time). Outcome measures were assessed using Patient Competency Rating Scale for Neuro-rehabilitation (PCRS-NR; measuring emotional, interpersonal, cognitive, and total functioning post-injury). All measures were assessed at each time point. Mixed linear models were run separately for ages > 50 and ae50 (i.e., bimodal distribution). Patients' mindful creativity showed no significant association with patients' functioning across time in any of the models. In all age groups, interpersonal functioning decreased across time (slope(> 50) = -4.66, p = .037; slope(ae50) = -7.19, p = .007). Interestingly, in age group ae50, interpersonal functioning increased when looking at relative mindful creativity by time (slope = 1.69, p = .005). Additionally, relatives mindful creativity was significantly associated with patients' functioning in age group ae50: (a) patients' total functioning (slope = 0.18, p = .03) and (b) cognitive functioning (slope = 0.72, p = .020). Relatives' mindful creativity was significantly associated with patients' functioning after severe TBI. Implications for treatment and future research are discussed. C1 [Haller, Chiara S.; Bosma, Colin M.; Langer, Ellen J.] Harvard Univ, Dept Psychol, 33 Kirland St, Cambridge, MA 02138 USA. [Haller, Chiara S.] Massachusetts Mental Hlth Ctr, Div Publ Psychiat, 75 Fenwood Rd, Boston, MA 02115 USA. [Kapur, Kush] Harvard Med Sch, Boston, MA 02115 USA. [Kapur, Kush] Boston Childrens Hosp, Clin Res Ctr, 21 Autumn St, Boston, MA 02115 USA. [Kapur, Kush] Boston Childrens Hosp, Dept Neurol, 21 Autumn St, Boston, MA 02115 USA. [Zafonte, Ross] Harvard Med Sch, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Massachusetts Gen Hosp, Cambridge, MA USA. RP Haller, CS (reprint author), Harvard Univ, Dept Psychol, 33 Kirland St, Cambridge, MA 02138 USA.; Haller, CS (reprint author), Massachusetts Mental Hlth Ctr, Div Publ Psychiat, 75 Fenwood Rd, Boston, MA 02115 USA. EM haller@fas.harvard.edu FU PEBITA team FX Many thanks to the PEBITA team for their passion and support (www.pebita.ch). Profound thanks to all the participants. NR 53 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD APR PY 2017 VL 26 IS 4 BP 893 EP 902 DI 10.1007/s11136-016-1416-1 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EN5RL UT WOS:000396063100009 PM 27663903 ER PT J AU Kohler, RE Tomlinson, J Chilunjika, TE Young, S Hosseinipour, M Lee, CN AF Kohler, Racquel E. Tomlinson, Jared Chilunjika, Tiyamike Eletima Young, Sven Hosseinipour, Mina Lee, Clara N. TI "Life is at a standstill" Quality of life after lower extremity trauma in Malawi SO QUALITY OF LIFE RESEARCH LA English DT Article DE Quality of life; Injury; Trauma; Lower extremity; Malawi; Africa ID INJURIES AB Low- and middle-income countries face a disproportionate burden of death and disability from injuries, many of which are due to road traffic accidents or falls. Lower extremity injuries in particular have implications not only for physical disabilities affecting work and school performance, but also for quality of life (QOL) of the individual. This qualitative study explores the psychosocial impact and QOL changes due to lower extremity injuries among trauma patients in central Malawi. We transcribed and translated interviews with 20 patients who received care for a trauma to the lower extremity at a tertiary hospital in Lilongwe. We used NVivo to organize and thematically analyze the data. Participants reported limitations in physical functioning, activities of daily living, social roles, and vocational and social activities. Limited mobility led to unplanned long-term disruptions in work, personal financial loss, and household economic hardship. As a result, psychological distress, fears and worries about recovery, and poor perceptions of health and QOL were common. Several contextual factors influenced patient outcomes including socioeconomic status, religious beliefs, social networks, local landscape, housing structures, and transportation accessibility. Lower extremity trauma led to physical suffering and ongoing social and economic costs among Malawians. Injuries affecting mobility have broad QOL and economic consequences for patients and affected family members. Interventions are needed to improve post-injury recovery and QOL. Better access to trauma surgery and social and welfare support services for people living with disabling conditions are needed to alleviate the consequences of injuries. C1 [Kohler, Racquel E.] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Tomlinson, Jared; Chilunjika, Tiyamike Eletima; Young, Sven] Kamuzu Cent Hosp, Dept Surg, Lilongwe, Malawi. [Young, Sven] Haukeland Hosp, Dept Orthopaed Surg, Bergen, Norway. [Hosseinipour, Mina] Univ N Carolina, Dept Med, UNC Project, Lilongwe, Malawi. [Lee, Clara N.] Univ N Carolina, Dept Surg, Chapel Hill, NC USA. [Lee, Clara N.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Lee, Clara N.] Univ N Carolina, Cecil Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. RP Kohler, RE (reprint author), Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Racquel_kohler@dfci.harvard.edu FU UNC Cancer Care Quality Training Program [R25 CA116339]; Dana-Farber/Harvard Cancer Prevention Fellowship [3R25 CA057711] FX The authors would like to thank the surgery and orthopedic departments at Kamuzu Central Hospital and UNC Project Malawi for their assistance with this study. REK was supported by UNC Cancer Care Quality Training Program (R25 CA116339) and the Dana-Farber/Harvard Cancer Prevention Fellowship (3R25 CA057711). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD APR PY 2017 VL 26 IS 4 BP 1027 EP 1035 DI 10.1007/s11136-016-1431-2 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EN5RL UT WOS:000396063100021 PM 27771822 ER PT J AU Maeda, Y Kim, H Kettner, N Kim, J Cina, S Malatesta, C Gerber, J McManus, C Ong-Sutherland, R Mezzacappa, P Libby, A Mawla, I Morse, LR Kaptchuk, TJ Audette, J Napadow, V AF Maeda, Yumi Kim, Hyungjun Kettner, Norman Kim, Jieun Cina, Stephen Malatesta, Cristina Gerber, Jessica McManus, Claire Ong-Sutherland, Rebecca Mezzacappa, Pia Libby, Alexandra Mawla, Ishtiaq Morse, Leslie R. Kaptchuk, Ted J. Audette, Joseph Napadow, Vitaly TI Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture SO BRAIN LA English DT Article DE carpal tunnel syndrome; nerve conduction studies; neuropathic pain; entrapment neuropathy; neuromuscular disease; imaging ID RANDOMIZED-CONTROLLED-TRIAL; WHITE-MATTER PLASTICITY; CORTICAL PLASTICITY; GENERAL-POPULATION; HIGH-RESOLUTION; BRAIN; PAIN; NERVE; DIFFUSION; PLACEBO AB Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 +/- 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro-acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i. e. median sensory nerve conduction latency) and in the brain (i. e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 +/- 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome. C1 [Maeda, Yumi; Kim, Hyungjun; Kim, Jieun; Cina, Stephen; Gerber, Jessica; Mezzacappa, Pia; Libby, Alexandra; Mawla, Ishtiaq; Napadow, Vitaly] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Maeda, Yumi; Kettner, Norman; Napadow, Vitaly] Logan Univ, Dept Radiol, Chesterfield, MO 63017 USA. [Kim, Hyungjun; Kim, Jieun] Korean Inst Oriental Med, Div Clin Res, Daejeon 34054, South Korea. [Malatesta, Cristina; McManus, Claire; Ong-Sutherland, Rebecca] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Medford, MA 02155 USA. [Morse, Leslie R.] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Audette, Joseph] Atrium Hlth, Harvard Vanguard Med Associates, Dept Pain Med, Boston, MA 02215 USA. RP Napadow, V (reprint author), Martinos Ctr Biomed Imaging, 2301 149 Thirteenth St, Charlestown, MA 02129 USA. EM vitaly@nmr.mgh.harvard.edu FU National Center for Complementary and Integrative Health (NCCIH); U.S. National Institutes of Health (NIH) [R01-AT004714, R01-AT004714-02S1, P01-AT006663, K24-AT004095]; Korean Institute of Oriental Medicine (KIOM) [C16210]; National Center for Research Resources (NCRR) NIH [P41-RR14075, S10-RR021110, S10-RR023043] FX This research was supported by the National Center for Complementary and Integrative Health (NCCIH), U.S. National Institutes of Health (NIH) (R01-AT004714, R01-AT004714-02S1, P01-AT006663, K24-AT004095), Korean Institute of Oriental Medicine (KIOM) (C16210), as well as the National Center for Research Resources (NCRR) NIH (P41-RR14075, S10-RR021110, S10-RR023043) NR 59 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD APR PY 2017 VL 140 BP 914 EP 927 DI 10.1093/brain/awx015 PN 4 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP3ZE UT WOS:000397319400016 ER PT J AU Dummer, R Schadendorf, D Ascierto, PA Arance, A Dutriaux, C Di Giacomo, AM Rutkowski, P Del Vecchio, M Gutzmer, R Mandala, M Thomas, L Demidov, L Garbe, C Hogg, D Liszkay, G Queirolo, P Wasserman, E Ford, J Weill, M Sirulnik, LA Jehl, V Bozon, V Long, GV Flaherty, K AF Dummer, Reinhard Schadendorf, Dirk Ascierto, Paolo A. Arance, Ana Dutriaux, Caroline Di Giacomo, Anna Maria Rutkowski, Piotr Del Vecchio, Michele Gutzmer, Ralf Mandala, Mario Thomas, Luc Demidov, Lev Garbe, Claus Hogg, David Liszkay, Gabriella Queirolo, Paola Wasserman, Ernesto Ford, James Weill, Marine Sirulnik, L. Andres Jehl, Valentine Bozon, Viviana Long, Georgina V. Flaherty, Keith TI Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID BRAF-MUTATED MELANOMA; MEK INHIBITION; METASTATIC MELANOMA; CUTANEOUS MELANOMA; IMPROVED SURVIVAL; VEMURAFENIB; SELUMETINIB; DABRAFENIB; MUTATIONS; DOCETAXEL AB Background There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. Methods NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2: 1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m 2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. Findings Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1.7 months (IQR 1.4-4.1). Median progression-free survival was 2.8 months (95% CI 2.8-3.6) in the binimetinib group and 1.5 months (1.5-1.7) in the dacarbazine group (hazard ratio 0.62 [95% CI 0.47-0.80]; one-sided p< 0.001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. Interpretation Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. C1 [Dummer, Reinhard] Univ Zurich Hosp, Skin Canc Ctr, Dept Dermatol, CH-8091 Zurich, Switzerland. [Schadendorf, Dirk] Univ Hosp Essen, Dept Dermatol, Essen, Germany. [Schadendorf, Dirk] German Canc Consortium, Heidelberg, Germany. [Ascierto, Paolo A.] Ist Nazl Tumori Fdn Pascale, Melanoma Unit, Canc Immunotherapy & Innovat Therapies, Via Mariano Semmola, Naples, Italy. [Arance, Ana] Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain. [Dutriaux, Caroline] Hop St Andre, Ctr Hosp Univ Bordeaux, Dept Oncol Dermatol, Bordeaux, France. [Di Giacomo, Anna Maria] Univ Hosp Siena, Med Oncol & Immunotherapy, Viale Bracci, Siena, Italy. [Rutkowski, Piotr] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Del Vecchio, Michele] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Via Giacomo Venezian, Milan, Italy. [Gutzmer, Ralf] Hannover Med Sch, Skin Canc Ctr Hannover, Dept Dermatol & Allergy, Hannover, Germany. [Mandala, Mario] Papa Giovanni XXIII Canc Ctr Hosp, Dept Haematol & Oncol, Bergamo, Italy. [Thomas, Luc] Univ Lyon 1, Lyons Canc Res Ctr, Ctr Hosp Lyon Sud, Dept Dermatol, Pierre Benite, France. [Demidov, Lev] Minist Hlth, NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Garbe, Claus] Univ Hosp Tuebingen, Dept Dermatol, Tubingen, Germany. [Hogg, David] Princess Margaret Hosp, Univ Hlth Network, Dept Med, Toronto, ON, Canada. [Liszkay, Gabriella] Natl Inst Oncol, Dept Dermatol, Budapest, Hungary. [Queirolo, Paola] IRCCS San Martino Largo Rosanna Benzi, Inst Canc Res, Dept Med Oncol, Genoa, Italy. [Wasserman, Ernesto; Ford, James; Sirulnik, L. Andres] Novartis Pharmaceut, One Hlth Plaza, E Hanover, NJ USA. [Weill, Marine; Jehl, Valentine] Novartis Pharma AG, Basel, Switzerland. [Bozon, Viviana] Array BioPharma, Boulder, CO USA. [Long, Georgina V.] Univ Sydney, Royal North Shore Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [Long, Georgina V.] Univ Sydney, Mater Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [Flaherty, Keith] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. RP Dummer, R (reprint author), Univ Zurich Hosp, Skin Canc Ctr, Dept Dermatol, CH-8091 Zurich, Switzerland. EM reinhard.dummer@usz.ch FU Array BioPharma; Novartis Pharmaceuticals Corporation FX Array BioPharma and Novartis Pharmaceuticals Corporation. NR 34 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2017 VL 18 IS 4 BP 435 EP 445 DI 10.1016/S1470-2045(17)30180-8 PG 11 WC Oncology SC Oncology GA EQ0LF UT WOS:000397762000032 PM 28284557 ER PT J AU Cavo, M Terpos, E Nanni, C Moreau, P Lentzsch, S Zweegman, S Hillengass, J Engelhardt, M Usmani, SZ Vesole, DH San-Miguel, J Kumar, SK Richardson, PG Mikhael, JR da Costa, FL Dimopoulos, MA Zingaretti, C Abildgaard, N Goldschmidt, H Orlowski, RZ Chng, WJ Einsele, H Lonial, S Barlogie, B Anderson, KC Rajkumar, SV Durie, BGM Zamagni, E AF Cavo, Michele Terpos, Evangelos Nanni, Cristina Moreau, Philippe Lentzsch, Suzanne Zweegman, Sonja Hillengass, Jens Engelhardt, Monika Usmani, Saad Z. Vesole, David H. San-Miguel, Jesus Kumar, Shaji K. Richardson, Paul G. Mikhael, Joseph R. da Costa, Fernando Leal Dimopoulos, Meletios-Athanassios Zingaretti, Chiara Abildgaard, Niels Goldschmidt, Hartmut Orlowski, Robert Z. Chng, Wee Joo Einsele, Hermann Lonial, Sagar Barlogie, Bart Anderson, Kenneth C. Rajkumar, S. Vincent Durie, Brian G. M. Zamagni, Elena TI Role of F-18-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group SO LANCET ONCOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; WHOLE-BODY MRI; FDG-PET/CT; BONE-DISEASE; SOLITARY PLASMACYTOMA; COMPUTED-TOMOGRAPHY; IMAGING TECHNIQUES; EXTRAMEDULLARY DISEASE; CLINICAL-PARAMETERS; RESPONSE ASSESSMENT AB The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of (18)fluorodeoxyglucose (F-18-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. F-18-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of F-18-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of F-18-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. F-18-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity. C1 [Cavo, Michele; Zamagni, Elena] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Terpos, Evangelos] Univ Athens, Sch Med, Dept Clin Therapeut, Athens, Greece. [Nanni, Cristina] Azienda Osped Univ Bologna, Nucl Med, Bologna, Italy. [Moreau, Philippe] Univ Hosp Nantes, Dept Haematol, Nantes, France. [Lentzsch, Suzanne] Columbia Univ, Med Ctr, New York, NY USA. [Zweegman, Sonja] Vrije Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands. [Hillengass, Jens; Goldschmidt, Hartmut] Univ Heidelberg Hosp, Dept Internal Med 5, Heidelberg, Germany. [Engelhardt, Monika] Univ Freiburg, Fac Med, Dept Med Hematol Oncol & Stem Cell Transplantat, Med Ctr, Freiburg, Germany. [Usmani, Saad Z.] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Vesole, David H.] Hackensack UMC, John Theurer Canc Ctr, Hackensack, NJ USA. [San-Miguel, Jesus] Univ Navarra Clin, CIMA, IDISNA, Pamplona, Spain. [Kumar, Shaji K.; Rajkumar, S. Vincent] Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA. [Richardson, Paul G.; Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Mikhael, Joseph R.] Mayo Clin, Div Hematol & Oncol, Phoenix, AZ USA. [da Costa, Fernando Leal] Inst Portugues Oncol Francisco Gentil, Dept Hematol, Myeloma Clin, Lisbon, Portugal. [Dimopoulos, Meletios-Athanassios] Univ Athens, Sch Med, Dept Clin Therapeut, Athens, Greece. [Zingaretti, Chiara] IRST IRCCS, Biostat & Clin Trial Unit, Meldola, Italy. [Abildgaard, Niels] Odense Univ Hosp, Dept Hematol, Odense, Denmark. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chng, Wee Joo] Natl Univ Hlth Syst, Natl Univ Canc Inst, Singapore, Singapore. [Einsele, Hermann] Univ Hosp Wurzburg, Dept Internal Med 2, Wurzburg, Germany. [Lonial, Sagar] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA. [Barlogie, Bart] Mt Sinai Canc Inst, Tisch Canc Inst, Multiple Myeloma Program, New York, NY USA. [Durie, Brian G. M.] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. RP Cavo, M (reprint author), Univ Bologna, Sch Med, S Orsola Malpighi Hosp, Seragnoli Inst Hematol,Dept Expt Diagnost & Speci, I-40138 Bologna, Italy. EM michele.cavo@unibo.it 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2017 VL 18 IS 4 BP E206 EP E217 PG 12 WC Oncology SC Oncology GA EQ0LF UT WOS:000397762000011 PM 28368259 ER PT J AU Zou, T Awad, MM AF Zou, T. Awad, M. M. TI More valuable than platinum: first-line pembrolizumab in advanced stage non-small-cell lung cancer SO ANNALS OF ONCOLOGY LA English DT Editorial Material ID PD-1 BLOCKADE; RESISTANCE; MUTATIONS; MELANOMA C1 [Zou, T.; Awad, M. M.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. RP Awad, MM (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. EM mark_awad@dfci.harvard.edu NR 17 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 685 EP 687 DI 10.1093/annonc/mdx083 PG 4 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100006 ER PT J AU Hui, R Garon, EB Goldman, JW Leighl, NB Hellmann, MD Patnaik, A Gandhi, L Eder, JP Ahn, MJ Horn, L Felip, E Carcereny, E Rangwala, R Lubiniecki, GM Zhang, J Emancipator, K Roach, C Rizvi, NA AF Hui, R. Garon, E. B. Goldman, J. W. Leighl, N. B. Hellmann, M. D. Patnaik, A. Gandhi, L. Eder, J. P. Ahn, M-J Horn, L. Felip, E. Carcereny, E. Rangwala, R. Lubiniecki, G. M. Zhang, J. Emancipator, K. Roach, C. Rizvi, N. A. TI Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial SO ANNALS OF ONCOLOGY LA English DT Article DE pembrolizumab; non-small cell lung cancer; immunotherapy; anti-PD-1 ID PROGRAMMED DEATH LIGAND-1; PD-1 BLOCKADE; OPEN-LABEL; CHEMOTHERAPY; NIVOLUMAB; IMMUNOHISTOCHEMISTRY; RESISTANCE; DOCETAXEL AB Background: Pembrolizumab improved survival as first-and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (>= 1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received >= 1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS >= 50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS<1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS >= 50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS >= 50%. C1 [Hui, R.] Westmead Hosp, Med Oncol, Sydney, NSW, Australia. [Hui, R.] Univ Sydney, Sydney, NSW, Australia. [Garon, E. B.; Goldman, J. W.] Univ Calif Los Angeles, David Geffen Sch Med, Hematol Oncol, Santa Monica, CA USA. [Leighl, N. B.] Princess Margaret Canc Ctr, Dept Med, Toronto, ON, Canada. [Hellmann, M. D.] Mem Sloan Kettering Canc Ctr, Hematol Oncol, 1275 York Ave, New York, NY 10021 USA. [Hellmann, M. D.] Weill Cornell Med Coll, New York, NY USA. [Patnaik, A.] South Texas Accelerated Res Therapeut, Oncol & Hematol Clin Res, San Antonio, TX USA. [Gandhi, L.] Dana Farber Canc Inst, Hematol Oncol, Boston, MA 02115 USA. [Eder, J. P.] Yale Univ, Med Oncol, New Haven, CT USA. [Ahn, M-J] Sungkyunkwan Univ, Samsung Med Ctr, Hematol & Oncol, Sch Med, Seoul, South Korea. [Horn, L.] Vanderbilt Ingram Canc Ctr, Thorac Oncol, Nashville, TN USA. [Felip, E.] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Med Oncol, Barcelona, Spain. [Carcereny, E.] Catalan Inst Oncol Badalona, Med Oncol, Badalona, Spain. [Rangwala, R.; Lubiniecki, G. M.; Zhang, J.; Emancipator, K.] Merck & Co Inc, Med Oncol, Kenilworth, NJ USA. [Roach, C.] Dako, Compan Diagnost, Carpinteria, CA USA. [Rizvi, N. A.] Columbia Univ, Thorac Oncol, New York, NY USA. [Gandhi, L.] NYU, Laura & Isaac Perlmutter Canc Ctr, Langone Med Ctr, New York, NY USA. RP Hui, R (reprint author), Univ Sydney, Westmead Hosp, Crown Princess Mary Canc Ctr, Dept Med Oncol, Westmead, NSW 2145, Australia. EM rina.hui@sydney.edu.au FU Merck & Co., Inc., Kenilworth, NJ; Merck Co., Inc. FX This study was supported by Merck & Co., Inc., Kenilworth, NJ. Editorial assistance was provided by Tricia Brown and Jennifer M. Kulak, PhD (ApotheCom, Yardley, PA) and was funded by Merck & Co., Inc. No grant numbers apply. NR 24 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 874 EP 881 DI 10.1093/annonc/mdx008 PG 8 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100034 ER PT J AU Dittrich, C Stiefel, F Kiss, A Dizon, DS AF Dittrich, C. Stiefel, F. Kiss, A. Dizon, D. S. TI Reply to the letter to the editor 'Integrating communication as a core skill in the global curriculum for medical oncology' by Horlait et al. SO ANNALS OF ONCOLOGY LA English DT Letter C1 [Dittrich, C.] Kaiser Franz Josef Spital, Ctr Oncol & Haematol, Vienna, Austria. [Dittrich, C.] Appl Canc Res Inst Translat Res, Vienna, Austria. [Stiefel, F.] Univ Hosp Lausanne CHUV, Dept Psychiat, Psychiat Liaison Serv, Lausanne, Switzerland. [Kiss, A.] Univ Basel Hosp, Psychosomat Div, Dept Internal Med, Basel, Switzerland. [Dizon, D. S.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Gynecol Oncol, Boston, MA USA. RP Dittrich, C (reprint author), Kaiser Franz Josef Spital, Ctr Oncol & Haematol, Vienna, Austria.; Dittrich, C (reprint author), Appl Canc Res Inst Translat Res, Vienna, Austria. EM education@esmo.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 905 EP 906 DI 10.1093/annonc/mdw679 PG 3 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100042 ER PT J AU Robinson, TN Berian, JR AF Robinson, Thomas N. Berian, Julia R. TI Incorporating Patient-centered Outcomes Into Surgical Care SO ANNALS OF SURGERY LA English DT Editorial Material ID DELIRIUM C1 [Robinson, Thomas N.] Denver VA Med Ctr, Dept Surg, Denver, CO USA. [Berian, Julia R.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. RP Robinson, TN (reprint author), 1055 Clermont St 112, Denver, CO 80220 USA. EM thomas.robinson@ucdenver.edu FU John A. Hartford Foundation; University of Chicago; American College of Surgeons FX Dr Berian's position as the James C. Thompson Geriatric Surgery Clinical Scholar in Residence at the American College of Surgeons is supported by a grant from the John A. Hartford Foundation. Additional support for Dr Berian's position as the American College of Surgeons Clinical Scholar in Residence was provided by the University of Chicago and the American College of Surgeons. NR 6 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD APR PY 2017 VL 265 IS 4 BP 654 EP 655 DI 10.1097/SLA.0000000000002038 PG 2 WC Surgery SC Surgery GA EN4PQ UT WOS:000395989800004 PM 27735822 ER PT J AU Lillemoe, KD AF Lillemoe, Keith D. TI Annals of Surgery Looks at The Opioid Crisis SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Lillemoe, Keith D.] Massachusetts Gen Hosp, White 506,55 Fruit St, Boston, MA 02114 USA. RP Lillemoe, KD (reprint author), Massachusetts Gen Hosp, White 506,55 Fruit St, Boston, MA 02114 USA. EM klillemoe@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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD APR PY 2017 VL 265 IS 4 BP 692 EP 692 PG 1 WC Surgery SC Surgery GA EN4PQ UT WOS:000395989800011 PM 28121681 ER PT J AU Cauley, CE Anderson, G Haynes, AB Menendez, M Bateman, BT Ladha, K AF Cauley, Christy E. Anderson, Geoffrey Haynes, Alex B. Menendez, Mariano Bateman, Brian T. Ladha, Karim TI Predictors of In-hospital Postoperative Opioid Overdose After Major Elective Operations A Nationally Representative Cohort Study SO ANNALS OF SURGERY LA English DT Article DE opioid-related disorders; overdose; pain management; perioperative care; surgery ID RESPIRATORY DEPRESSION; PAIN MANAGEMENT; EVENTS; RISK; ANALGESIA; MORPHINE; SAFETY AB Objective: The aim of this study was to describe national trends and outcomes of in-hospital postoperative opioid overdose (OD) and identify predictors of postoperative OD. Summary of Background Data: In 2000, the Joint Commission recommended making pain the 5th vital sign, increasing the focus on postoperative pain control. However, the benefits of pain management must be weighed against the potentially lethal risk of opioid OD. Methods: This is a retrospective multi-institutional cohort study of patients undergoing 1 of 6 major elective inpatient operation from 2002 to 2011 using the Nationwide Inpatient Sample, an approximately 20% representative sample of all United States hospital admissions. Patients with postoperative OD were identified using ICD-9 codes for poisoning from opioids or adverse effects from opioids. Multivariate logistic regression was used to identify independent predictors. Results: Among 11,317,958 patients, 9458 (0.1%) had a postoperative OD; this frequency doubled over the study period from 0.6 to 1.1 overdoses per 1000 cases. Patients with postoperative OD died more frequently during their hospitalization (1.7% vs 0.4%, P < 0.001). Substance abuse history was the strongest predictor of OD (odds ratio = 14.8; 95% confidence interval: 12.7-17.2). Gender, age, income, geographic location, operation type, and certain comorbid diseases also predicted OD (P < 0.05). Hospital variables, including teaching status, size, and urban/rural location, did not predict postoperative OD. Conclusions: Postoperative OD is a rare, but potentially lethal complication, with increasing incidence. Postoperative monitoring and treatment safety interventions should be thoughtfully employed to target high-risk patients and avoid this potentially fatal complication. C1 [Cauley, Christy E.; Anderson, Geoffrey; Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Menendez, Mariano] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, Austin, TX 78712 USA. [Bateman, Brian T.; Ladha, Karim] Massachusetts Gen Hosp, Dept Anesthesia, Crit Care & Pain Med, Boston, MA 02114 USA. [Ladha, Karim] Univ Toronto, Toronto Gen Hosp, Dept Anesthesia, Toronto, ON M5S 1A1, Canada. RP Cauley, CE (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM ccauley@partners.org FU National Cancer Institute at the NIH grant [R25CA092203] FX This work was supported by the National Cancer Institute at the NIH grant R25CA092203to CEC. NR 23 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD APR PY 2017 VL 265 IS 4 BP 702 EP 708 DI 10.1097/SLA.0000000000001945 PG 7 WC Surgery SC Surgery GA EN4PQ UT WOS:000395989800014 PM 28267693 ER PT J AU Kaafarani, HMA Weil, E Wakeman, S Ring, D AF Kaafarani, Haytham M. A. Weil, Eric Wakeman, Sarah Ring, David TI The Opioid Epidemic and New Legislation in Massachusetts: Time For a Culture Change in Surgery? SO ANNALS OF SURGERY LA English DT Article ID PAIN INTENSITY; SATISFACTION C1 [Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Kaafarani, Haytham M. A.; Weil, Eric; Wakeman, Sarah] Harvard Med Sch, Boston, MA USA. [Weil, Eric; Wakeman, Sarah] Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Austin, TX USA. RP Kaafarani, HMA (reprint author), Massachusetts Gen Hosp & Harvard Med Sch, 165 Cambridge St Suite 810, Boston, MA 02114 USA. EM hkaafarani@partners.org NR 6 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD APR PY 2017 VL 265 IS 4 BP 731 EP 733 DI 10.1097/SLA.0000000000002083 PG 3 WC Surgery SC Surgery GA EN4PQ UT WOS:000395989800019 PM 27849666 ER PT J AU Kim, SJ Chen, ZL Essani, AB Elshabrawy, HA Volin, MV Fantuzzi, G McInnes, IB Baker, JF Finn, P Kondos, G Volkov, S Swedler, W Arami, S Sweiss, N Shahrara, S AF Kim, Seung-jae Chen, Zhenlong Essani, Abdul B. Elshabrawy, Hatem A. Volin, Michael V. Fantuzzi, Giamila McInnes, Iain B. Baker, Joshua F. Finn, Patricia Kondos, George Volkov, Suncica Swedler, William Arami, Shiva Sweiss, Nadera Shahrara, Shiva TI Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID BODY-MASS INDEX; COLLAGEN-INDUCED ARTHRITIS; OF-RHEUMATOLOGY CRITERIA; ADIPOSE-TISSUE; INTERLEUKIN-8 PRODUCTION; INSULIN-RESISTANCE; INNATE IMMUNITY; IN-VITRO; CLASSIFICATION; OSTEOARTHRITIS AB Objective Studies were performed to uncover the significance of obesity in rheumatoid arthritis (RA) and preclinical models. Methods Preclinical arthritis models were used to examine the impact of obesity on disease onset and remission. Conditioned media from RA adipose tissues were used to investigate the mechanism contributing to joint neutrophil influx and M1 macrophage differentiation observed in early and remission phases of arthritis. Results We report that mice fed with high fat diet (HFD) have an earlier onset of collagen-induced arthritis (CIA) compared with mice on regular diet. However, the differences in CIA joint swelling between the two diet groups are lost once disease is established. We found that early arthritis triggered by obesity is due to elevated joint MIP2/interleukin-8 levels detected in CIA as well as in the RA and mouse adipose tissues and the effect of this chemokine on neutrophil recruitment. Although active disease progression is similarly affected in both diet groups, arthritis resolution is accelerated in lean mice while joint inflammation is sustained in obese mice. We document that HFD can prolong toll-like receptor (TLR) 4-induced arthritis by increasing joint monocyte migration and further remodelling the recruited cells into M1 macrophages. Consistently, we show that adipose condition media can transform RA and wild-type naive myeloid cells into M1 macrophages; however, this function is impaired by TLR4 blockade or deficiency. Conclusions We conclude that despite established disease being unaffected by obesity, the early and the resolution phases of RA are impacted by obesity through different mechanisms. C1 [Volin, Michael V.] Univ Illinois, Dept Med, Div Rheumatol, 840 S Woods St,Bldg CSB,Room 1113-1114, Chicago, IL 60612 USA. [Kim, Seung-jae; Chen, Zhenlong; Essani, Abdul B.; Elshabrawy, Hatem A.; Swedler, William; Arami, Shiva; Sweiss, Nadera; Shahrara, Shiva] Jesse Brown VA Med Ctr, Div Rheumatol, Chicago, IL USA. [Kim, Seung-jae; Chen, Zhenlong; Essani, Abdul B.; Elshabrawy, Hatem A.; Volkov, Suncica; Swedler, William; Arami, Shiva; Shahrara, Shiva] Midwestern Univ, Dept Microbiol & Immunol, Downers Grove, IL 60515 USA. [Fantuzzi, Giamila] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL USA. [McInnes, Iain B.] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland. [Baker, Joshua F.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Baker, Joshua F.] Hosp Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Finn, Patricia] Univ Illinois, Div Med, Div Pulm, Chicago, IL USA. [Kondos, George] Univ Illinois, Div Med, Div Cardiol, Chicago, IL USA. RP Shahrara, S (reprint author), Univ Illinois, Dept Med, Div Rheumatol, 840 S Woods St,Bldg CSB,Room 1113-1114, Chicago, IL 60612 USA. EM shahrara@uic.edu FU Department of Veteran's Affairs MERIT Award [1I01BX002286]; National Institutes of Health [AR055240, AR065778]; Within Our Reach from the ACR; Department of Defense [PR093477]; Arthritis Foundation Innovative award; VA clinical science research and development; VA Career Development Award [IK2 CX000955] FX This work was supported in part by awards from Department of Veteran's Affairs MERIT Award 1I01BX002286, the National Institutes of Health AR055240 and AR065778, grant from Within Our Reach from the ACR, funding provided by Department of Defense PR093477 and Arthritis Foundation Innovative award. JFB efforts were funded by VA clinical science research and development as well as VA Career Development Award IK2 CX000955. NR 54 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 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2017 VL 76 IS 4 AR UNSP 731 DI 10.1136/annrheumdis-2016-209206 PG 9 WC Rheumatology SC Rheumatology GA EO7FH UT WOS:000396856100019 ER PT J AU Singh, JA Uhlig, T AF Singh, Jasvinder A. Uhlig, Till TI Chasing crystals out of the body: will treat to serum urate target for gout help us get there? SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Editorial Material ID QUALITY-OF-LIFE; LOWERING THERAPY; ALLOPURINOL; CARE; HYPERURICEMIA; FEBUXOSTAT; ADHERENCE; RECOMMENDATIONS; PRODUCTIVITY; MANAGEMENT C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Uhlig, Till] Diakonhjemmet Hosp, Dept Rheumatol, Natl Advisory Unit Rehabil Rheumatol, Oslo, Norway. [Uhlig, Till] Univ Oslo, Fac Med, Oslo, Norway. RP Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU Takeda; Savient; Regeneron; Merz; Iroko; Bioiberica; Crealta; Allergan pharmaceuticals; WebMD; UBM LLC; American College of Rheumatology; Horizon pharmaceuticals; AstraZeneca; Novartis; Sobi FX JAS has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, Merz, Iroko, Bioiberica, Crealta and Allergan pharmaceuticals, WebMD, UBM LLC and the American College of Rheumatology. JAS serves as the principal investigator for an investigator-initiated study funded by Horizon pharmaceuticals through a grant to DINORA, a 501 (c) (3) entity. JAS is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology's (ACR) Annual Meeting Planning Committee (AMPC); Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and a member of the Veterans Affairs Rheumatology Field Advisory Committee. TU has received honorarium or consultant fees from AstraZeneca, Novartis and Sobi. NR 34 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 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2017 VL 76 IS 4 DI 10.1136/annrheumdis-2016-210436 PG 3 WC Rheumatology SC Rheumatology GA EO7FH UT WOS:000396856100003 ER PT J AU Zhu, L Fan, XL Wang, BJ Liu, LW Yan, XJ Zhou, L Zeng, Y Poznansky, MC Wang, LL Chen, HB Du, YN AF Zhu, Lu Fan, Xingliang Wang, Bingjie Liu, Longwei Yan, Xiaojun Zhou, Lyu Zeng, Yang Poznansky, Mark C. Wang, Lili Chen, Huabiao Du, Yanan TI Biornechanically primed liver microtumor array as a high-throughput mechanopharmacological screening platform for stromareprogrammed combinatorial therapy SO BIOMATERIALS LA English DT Article DE Microtumor array; Mechanopharmacology; Thermal-sensitive materials; Stroma reprogramming; Vitamin D combinatorial therapy ID TUMOR STROMA; CANCER PROGRESSION; EXTRACELLULAR-MATRIX; CELL-ADHESION; IN-VITRO; METASTASIS; STIFFNESS; GROWTH; 3D; MICROENVIRONMENT AB Recent breakthrough in stroma-reprogrammed combinatorial therapy (SRCT) for pancreatic tumor opens a new route for improving conventional chemotherapeutic efficacy, which utilizes VDR ligand to reprogram activated stromal cells in stiffened microenvironment, leading to reduced 'barrier effects' and increased tissue-infiltration of the chemotherapy drug. As a novel therapeutic strategy and mechanism of action, the progress of SRCT relies on tailored in vitro drug assessment platforms to further optimize its efficacy and extend to applications in other tumor types. Here, a high-throughput mechanopharmacological drug screening platform for SRCT was established based on biomechanically primed hepatic stromal stellate cells to recapitulate state-specific liver microtumors with barrier effects. Fifteen generic chemotherapy drugs co-administered with VDR ligand were screened to obtain optimal SRCT formulations (e.g. carboplatin + calcipotriol), which efficacy was successfully verified in xenograft tumor models. Overall, this platform provides a powerful tool for discovery and optimization of tissue-specific SRCT and realizes 'mechanopharmacology' to translate insights of stromal mechanobiology to pharmaceutical applications. (C) 2017 Elsevier Ltd. All rights reserved. C1 [Zhu, Lu; Fan, Xingliang; Wang, Bingjie; Liu, Longwei; Yan, Xiaojun; Zhou, Lyu; Du, Yanan] Tsinghua Univ, Dept Biomed Engn, Sch Med, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 100084, Peoples R China. [Zhu, Lu] Acad Mil Med Sci, Inst Med Equipment, Tianjin 300161, Peoples R China. [Zeng, Yang; Poznansky, Mark C.; Chen, Huabiao] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Boston, MA 02114 USA. [Zeng, Yang; Poznansky, Mark C.; Chen, Huabiao] Harvard Med Sch, Boston, MA 02114 USA. [Wang, Lili] Acad Mil Med Sci, Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. RP Du, YN (reprint author), Tsinghua Univ, Dept Biomed Engn, Sch Med, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing 100084, Peoples R China. EM duyanan@tsinghua.edu.cn FU National Natural Science Foundation of China [51461165302, 11372243, 31671036]; State Key Laboratory of Toxicology and Medical Countermeasures (Academy of Military Medical Science) [TMC201509] FX We thank all Du-lab members for general help. This work is financially supported by the National Natural Science Foundation of China (Grant No: 51461165302,11372243, 31671036), and State Key Laboratory of Toxicology and Medical Countermeasures (Academy of Military Medical Science) (Grant No: TMC201509). NR 45 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 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD APR PY 2017 VL 124 BP 12 EP 24 DI 10.1016/j.biomaterials.2017.01.030 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EN4CS UT WOS:000395956000002 PM 28182873 ER PT J AU Morris, MD Shiboski, S Bruneau, J Hahn, JA Hellard, M Prins, M Cox, AL Dore, G Grebely, J Kim, AY Lauer, GM Lloyd, A Rice, T Shoukry, N Maher, L Page, K AF Morris, Meghan D. Shiboski, Stephen Bruneau, Julie Hahn, Judith A. Hellard, Margaret Prins, Maria Cox, Andrea L. Dore, Gregory Grebely, Jason Kim, Arthur Y. Lauer, Georg M. Lloyd, Andrew Rice, Thomas Shoukry, Naglaa Maher, Lisa Page, Kimberly CA InC3 TI Geographic Differences in Temporal Incidence Trends of Hepatitis C Virus Infection Among People Who Inject Drugs: The InC3 Collaboration SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis C virus ( HCV); incidence trends; epidemiology; people who inject drugs; harm reduction strategies ID OPIATE SUBSTITUTION THERAPY; NEEDLE EXCHANGE PROGRAMS; SYRINGE EXCHANGE; HCV INFECTION; HIV-INFECTION; SAN-FRANCISCO; USERS; COHORT; RISK; METAANALYSIS AB Background. We determined temporal trends (1985-2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne). Methods. Using population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985-2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar- time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk. Results. Among 1391 initially HCV-negative participants followed prospectively (1644.5 person-years of observation [PYO]), 371 HCV incident infections resulted in an overall incidence of 22.6 per 100 PYO (95% confidence interval [CI], 20.4-25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 [95% CI,.8-. 9]) in the multivariable model. Conclusions. Differences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America. C1 [Morris, Meghan D.; Shiboski, Stephen; Rice, Thomas] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bruneau, Julie; Shoukry, Naglaa] Univ Montreal, Ctr Hosp Univ Montreal CRCHUM, Quebec City, PQ, Canada. [Hahn, Judith A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Hellard, Margaret] Burnet Inst, Melbourne, Vic, Australia. [Prins, Maria] Acad Med Ctr, Dept Publ Hlth & Epidemiol Infect Dis, Amsterdam, Netherlands. [Cox, Andrea L.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Dore, Gregory; Grebely, Jason; Lloyd, Andrew; Maher, Lisa] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Kim, Arthur Y.; Lauer, Georg M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lloyd, Andrew] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Page, Kimberly] Univ New Mexico Hlth Ctr, Dept Internal Med, Albuquerque, NM USA. RP Morris, MD (reprint author), 550 16th St, San Francisco, CA 94158 USA. EM meghanmorris@ucsf.edu FU National Institutes of Health (NIH); National Institute on Drug Abuse (NIDA) [R01DA599901]; NIH/NIDA [K01DA037802]; NIH National Center for Advancing Translational Sciences [KL2TR000143]; The Netherlands National Institute for Public Health; Environment to the Amsterdam Cohort Study; Baltimore Before and After Study [NIH U19 AI088791]; BAHSTION Boston Acute HCV Study; Transmission, Immunity and Outcomes Network [NIH U19 AI066345]; Sydney HITS-c - UNSW Hepatitis C Vaccine Initiative and NHMRC Project [630483]; Melbourne Networks/MIX National Health and Medical Research Council, Australia (NHMRC) Project [331312, 545891]; Victorian Operational Infrastructure Support Programme (Department of Health, Victoria, Australia); Montreal HepCo-the Canadian Institutes of Health Research [MOP-103138, MOP-106468]; San Francisco (UFO) [NIH/NIDA R01 DA016017] FX This work was supported by the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA) (R01DA599901). M. D. M. is supported by an NIH/NIDA career development award (K01DA037802) and the NIH National Center for Advancing Translational Sciences (KL2TR000143). Research support for the individual cohorts include The Netherlands National Institute for Public Health and the Environment to the Amsterdam Cohort Study; Baltimore Before and After Study (NIH U19 AI088791); BAHSTION Boston Acute HCV Study: Transmission, Immunity and Outcomes Network (NIH U19 AI066345); Sydney HITS-c - UNSW Hepatitis C Vaccine Initiative and NHMRC Project (grant number 630483); Melbourne Networks/MIX National Health and Medical Research Council, Australia (NHMRC) Project (grant numbers 331312 and 545891) and the Victorian Operational Infrastructure Support Programme (Department of Health, Victoria, Australia); Montreal HepCo-the Canadian Institutes of Health Research (MOP-103138 and MOP-106468); San Francisco (UFO) (NIH/NIDA R01 DA016017). NR 39 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 APR 1 PY 2017 VL 64 IS 7 BP 860 EP 869 DI 10.1093/cid/ciw869 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600010 PM 28362947 ER PT J AU Kadri, SS Swihart, BJ Bonne, SL Hohmann, SF Hennessy, LV Louras, P Evans, HL Rhee, C Suffredini, AF Hooper, DC Follmann, DA Bulger, EM Danner, RL AF Kadri, Sameer S. Swihart, Bruce J. Bonne, Stephanie L. Hohmann, Samuel F. Hennessy, Laura V. Louras, Peter Evans, Heather L. Rhee, Chanu Suffredini, Anthony F. Hooper, David C. Follmann, Dean A. Bulger, Eileen M. Danner, Robert L. TI Impact of Intravenous Immunoglobulin on Survival in Necrotizing Fasciitis With Vasopressor- Dependent Shock: A Propensity Score- Matched Analysis From 130 US Hospitals SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE intravenous immunoglobulin; toxic shock; necrotizing fasciitis ID SOFT-TISSUE INFECTIONS; A STREPTOCOCCAL INFECTIONS; POLYSPECIFIC IMMUNOGLOBULIN; STAPHYLOCOCCUS-AUREUS; THERAPY; MANAGEMENT; DISEASE; SUPERANTIGENS; SURVEILLANCE; PATHOGENESIS AB Background. Shock frequently complicates necrotizing fasciitis (NF) caused by group A Streptococcus (GAS) or Staphylococcus aureus. Intravenous immunoglobulin (IVIG) is sometimes administered for presumptive toxic shock syndrome (TSS), but its frequency of use and efficacy are unclear. Methods. Adult patients with NF and vasopressor-dependent shock undergoing surgical debridement from 2010 to 2014 were identified at 130 US hospitals. IVIG cases were propensity-matched and risk-adjusted. The primary outcome was in-hospital mortality and the secondary outcome was median length of stay (LOS). Results. Of 4127 cases of debrided NF with shock at 121 centers, only 164 patients (4%) at 61 centers received IVIG. IVIG subjects were younger with lower comorbidity indices, but higher illness severity. Clindamycin and vasopressor intensity were higher among IVIG cases, as was coding for TSS and GAS. In-hospital mortality did not differ between matched IVIG and non-IVIG groups (crude mortality, 27.3% vs 23.6%; adjusted odds ratio, 1.00 [95% confidence interval,.55-1.83]; P =.99). Early IVIG (= 2 days) did not alter this effect (P =.99). Among patients coded for TSS, GAS, and/or S. aureus, IVIG use was still unusual (59/868 [6.8%]) and lacked benefit (P =.63). Median LOS was similar between IVIG and non-IVIG groups (26 [ 13-49] vs 26 [11-43]; P =.84). Positive predictive values for identifying true NF and debridement among IVIG cases using our algorithms were 97% and 89%, respectively, based on records review at 4 hospitals. Conclusions. Adjunctive IVIG was administered infrequently in NF with shock and had no apparent impact on mortality or hospital LOS beyond that achieved with debridement and antibiotics. C1 [Kadri, Sameer S.; Suffredini, Anthony F.; Danner, Robert L.] Natl Inst Hlth Clin Ctr, Crit Care Med Dept, 10 Ctr Dr B10,2C145, Bethesda, MD 20892 USA. [Kadri, Sameer S.; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. [Swihart, Bruce J.; Follmann, Dean A.] NIAID, Biostat Res Branch, Bethesda, MD USA. [Bonne, Stephanie L.] Barnes Jewish Hosp, Dept Gen Surg, St Louis, MO USA. [Hohmann, Samuel F.] Vizient, Irving, TX USA. [Hohmann, Samuel F.] Rush Univ, Dept Hlth Syst Management, Chicago, IL USA. [Hennessy, Laura V.; Louras, Peter; Evans, Heather L.; Bulger, Eileen M.] Harborview Med Ctr, Dept Surg, Seattle, WA USA. [Rhee, Chanu] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Rhee, Chanu] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Kadri, SS (reprint author), Natl Inst Hlth Clin Ctr, Crit Care Med Dept, 10 Ctr Dr B10,2C145, Bethesda, MD 20892 USA.; Kadri, SS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. EM sameer.kadri@nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. NR 31 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 APR 1 PY 2017 VL 64 IS 7 BP 877 EP 885 DI 10.1093/cid/ciw871 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600012 PM 28034881 ER PT J AU Strle, K Sulka, KB Pianta, A Crowley, JT Arvikar, SL Anselmo, A Sadreyev, R Steere, AC AF Strle, Klemen Sulka, Katherine B. Pianta, Annalisa Crowley, Jameson T. Arvikar, Sheila L. Anselmo, Anthony Sadreyev, Ruslan Steere, Allen C. TI Helper 17 Cell Cytokine Responses in Lyme Disease Correlate With Borrelia burgdorferi Antibodies During Early Infection and With Autoantibodies Late in the Illness in Patients With Antibiotic-Refractory Lyme Arthritis SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Lyme disease; erythema migrans; Lyme arthritis; T (H) 17; antibodies ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; GROWTH-FACTOR; T(H)17 CELLS; AUTOANTIGEN; INFLAMMATION; PREVENTION; GENOTYPE; TARGET; FLUID AB Background. Control of Lyme disease is attributed predominantly to innate and adaptive T-helper 1 cell (T(H)1) immune responses, whereas the role of T-helper 17 cell (T(H)17) responses is less clear. Here we characterized these inflammatory responses in patients with erythema migrans (EM) or Lyme arthritis (LA) to elucidate their role early and late in the infection. Methods. Levels of 21 cytokines and chemokines, representative of innate, T(H)1, and T(H)17 immune responses, were assessed by Luminex in acute and convalescent sera from 91 EM patients, in serum and synovial fluid from 141 LA patients, and in serum from 57 healthy subjects. Antibodies to Borrelia burgdorferi or autoantigens were measured by enzyme-linked immunosorbent assay. Results. Compared with healthy subjects, EM patients had significantly higher levels of innate, T(H)1, and T(H)17-associated mediators (P <= .05) in serum. In these patients, the levels of inflammatory mediators, particularly T(H)17-associated cytokines, correlated directly with B. burgdorferi immunoglobulin G antibodies (P <= .02), suggesting a beneficial role for these responses in control of early infection. Late in the disease, in patients with LA, innate and T(H)1-associated mediators were often > 10-fold higher in synovial fluid than serum. In contrast, the levels of T(H)17-associated mediators were more variable, but correlated strongly with autoantibodies to endothelial cell growth factor, matrix metalloproteinase 10, and apolipoprotein B-100 in joints of patients with antibiotic-refractory LA, implying a shift in T(H)17 responses toward an autoimmune phenotype. Conclusions. Patients with Lyme disease often develop pronounced T(H)17 immune responses that may help control early infection. However, late in the disease, excessive T(H)17 responses may be disadvantageous by contributing to autoimmune responses associated with antibiotic-refractory LA. C1 [Strle, Klemen; Sulka, Katherine B.; Pianta, Annalisa; Crowley, Jameson T.; Arvikar, Sheila L.; Steere, Allen C.] Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Anselmo, Anthony; Sadreyev, Ruslan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA USA. RP Strle, K (reprint author), Massachusetts Gen Hosp, 55 Fruit St,CNY149/8301, Boston, MA 02114 USA. EM kstrle@mgh.harvard.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [K01AR062098]; Massachusetts General Hospital Executive Committee on Research (ECOR) Interim Support Fund [2016A050303]; National Institute of Allergy and Infectious Diseases, NIH [R01 A1-110175] FX This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) (K01AR062098) and the Massachusetts General Hospital Executive Committee on Research (ECOR) Interim Support Fund ( award number 2016A050303) to K. S.; and the National Institute of Allergy and Infectious Diseases, NIH (award number R01 A1-110175) to A. C. S. NR 40 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 APR 1 PY 2017 VL 64 IS 7 BP 930 EP 938 DI 10.1093/cid/cix002 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600020 PM 28077518 ER PT J AU Munshi, MN AF Munshi, Medha N. TI Cognitive Dysfunction in Older Adults With Diabetes: What a Clinician Needs to Know SO DIABETES CARE LA English DT Article ID TIGHT GLYCEMIC CONTROL; SELF-MANAGEMENT; RISK-FACTORS; SEVERE HYPOGLYCEMIA; POSITION STATEMENT; SCREENING TOOL; ACCORD-MIND; FOLLOW-UP; MELLITUS; DEMENTIA AB One of the challenges of managing older adults with diabetes is the individualization of care in people with multiple comorbid conditions. Although macrovascular and microvascular complications of diabetes are well recognized, there is a lack of awareness regarding other conditions such as cognitive dysfunction, depression, and physical disabilities. Cognitive dysfunction is of particular importance because of its impact on self-care and quality of life. In this Perspective, I discuss common and practical questions faced by clinicians managing diabetes in older adults who also have cognitive dysfunction. C1 [Munshi, Medha N.] Harvard Med Sch, Joslin Diabet Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Munshi, MN (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. EM mmunshi@bidmc.harvard.edu NR 54 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2017 VL 40 IS 4 BP 461 EP 467 DI 10.2337/dc16-1229 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0UZ UT WOS:000397103500013 PM 28325796 ER PT J AU Choi, YJ Jia, HM Gross, T Weinger, K Stone, PW Smaldone, AM AF Choi, Yoon Jeong Jia, Haomiao Gross, Tal Weinger, Katie Stone, Patricia W. Smaldone, Arlene M. TI The Impact of Medicare Part D on the Proportion of Out-of-Pocket Prescription Drug Costs Among Older Adults With Diabetes SO DIABETES CARE LA English DT Article ID COVERAGE; BENEFICIARIES; EXPENDITURES; NONADHERENCE; MEDICATIONS; SENIORS; BURDEN AB OBJECTIVE The purpose of this study was to evaluate the impact of Medicare Part D on reducing the financial burden of prescription drugs in older adults with diabetes. RESEARCH DESIGN AND METHODS Using Medical Expenditure Panel Survey data (2000-2011), interrupted time series and difference-in-difference analyses were used to examine out-of-pocket costs for prescription drugs in 4,664 Medicare beneficiaries (>= 65 years of age) compared with 2,938 younger, non-Medicare adults (50-60 years) with diabetes and to estimate the causal effects of Medicare Part D. RESULTS Part D enrollment of Medicare beneficiaries with diabetes gradually increased from 45.7% (2006) to 52.4% (2011). Compared with years 2000-2005, out-of-pocket pharmacy costs decreased by 13.5% (SE 2.1) for all Medicare beneficiaries with diabetes following Part D implementation; on average, Part D beneficiaries had 5.3% (0.8) lower costs compared with those without Part D. Compared with a younger group with diabetes, out-of-pocket pharmacy costs decreased by 19.4% (1.7) for Medicare beneficiaries after Part D. Part D beneficiaries with diabetes who experienced the coverage gap decreased from 60.1% (2006) to 40.9% (2011) over this period. CONCLUSIONS These findings demonstrate that although Medicare Part D has been effective in reducing the out-of-pocket cost burden of prescription drugs, approximately two out of five Part D beneficiaries with diabetes experienced the coverage gap in 2011. Future research is needed to examine the impact of Affordable Care Act provisions to close the coverage gap on the cost burden of prescription drugs for Medicare beneficiaries with diabetes. C1 [Choi, Yoon Jeong] Seoul Natl Univ, Coll Nursing, Res Inst Nursing Sci, Seoul, South Korea. [Jia, Haomiao; Gross, Tal; Stone, Patricia W.; Smaldone, Arlene M.] Columbia Univ, New York, NY USA. [Weinger, Katie] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. RP Choi, YJ (reprint author), Seoul Natl Univ, Coll Nursing, Res Inst Nursing Sci, Seoul, South Korea. EM yc2654@caa.columbia.edu FU Columbia University School of Nursing Center for Health Policy; Sigma Theta Tau International Honor Society of Nursing Alpha Zeta Chapter FX This study was supported by the Columbia University School of Nursing Center for Health Policy and Sigma Theta Tau International Honor Society of Nursing Alpha Zeta Chapter. NR 31 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2017 VL 40 IS 4 BP 502 EP 508 DI 10.2337/dc16-0902 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0UZ UT WOS:000397103500018 PM 27803119 ER PT J AU Aleppo, G Ruedy, KJ Riddlesworth, TD Kruger, DF Peters, AL Hirsch, I Bergenstal, RM Toschi, E Ahmann, AJ Shah, VN Rickels, MR Bode, BW Philis-Tsimikas, A Pop-Busui, R Rodriguez, H Eyth, E Bhargava, A Kollman, C Beck, RW AF Aleppo, Grazia Ruedy, Katrina J. Riddlesworth, Tonya D. Kruger, Davida F. Peters, Anne L. Hirsch, Irl Bergenstal, Richard M. Toschi, Elena Ahmann, Andrew J. Shah, Viral N. Rickels, Michael R. Bode, Bruce W. Philis-Tsimikas, Athena Pop-Busui, Rodica Rodriguez, Henry Eyth, Emily Bhargava, Anuj Kollman, Craig Beck, Roy W. CA REPLACE BG Study Group TI REPLACE-BG: A Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults With Well-Controlled Type 1 Diabetes SO DIABETES CARE LA English DT Article ID HYPOGLYCEMIA; ACCURACY; SYSTEM AB OBJECTIVE To determine whether the use of continuous glucose monitoring (CGM) without confirmatory blood glucose monitoring (BGM) measurements is as safe and effective as using CGM adjunctive to BGM in adults with well-controlled type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS A randomized noninferiority clinical trial was conducted at 14 sites in the T1D Exchange Clinic Network. Participants were >= 18 years of age (mean 44 6 14 years), had T1D for >= 1 year (mean duration 24 6 12 years), used an insulin pump, and had an HbA(1c) <= 9.0% (<= 75 mmol/mL) (mean 7.0 +/- 6 0.7% [53 +/- 7.7 mmol/mol]); prestudy, 47% were CGM users. Participants were randomly assigned 2: 1 to the CGM-only (n = 149) or CGM+BGM (n = 77) group. The primary outcome was time in range (70-180 mg/dL) over the 26-week trial, with a prespecified noninferiority limit of 7.5%. RESULTS CGMuse averaged 6.7 +/- 0.5 and 6.8 +/- 0.4 days/week in the CGM-only andCGM+BGM groups, respectively, over the 26-week trial. BGM tests per day (including the two required daily for CGM calibration) averaged 2.8 +/- 0.9 and 5.4 +/- 1.4 in the two groups, respectively (P < 0.001). Mean time in 70-180 mg/dL was 63 +/- 13% at both baseline and 26 weeks in the CGM-only group and 65 +/- 13% and 65 +/- 11% in the CGM+BGM group (adjusted difference 0%; one-sided 95% CI -2%). No severe hypoglycemic events occurred in the CGM-only group, and one occurred in the CGM+BGM group. CONCLUSIONS Use of CGM without regular use of confirmatory BGM is as safe and effective as using CGM with BGM in adults with well-controlled T1D at low risk for severe hypoglycemia. C1 [Aleppo, Grazia] Northwestern Univ, Chicago, IL USA. [Ruedy, Katrina J.; Riddlesworth, Tonya D.; Kollman, Craig; Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Kruger, Davida F.] Henry Ford Hlth Syst, Detroit, MI USA. [Peters, Anne L.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Hirsch, Irl] Univ Washington, Sch Med, Seattle, WA USA. [Bergenstal, Richard M.] Pk Nicollet Int Diabet Ctr, Minneapolis, MN USA. [Toschi, Elena] Joslin Diabet Ctr, Boston, MA USA. [Ahmann, Andrew J.] Oregon Hlth & Sci Univ, Harold Schnitzer Diabet Hlth Ctr, Portland, OR USA. [Shah, Viral N.] Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Rickels, Michael R.] Univ Penn, Perelman Sch Med, Philadelphia, PA USA. [Bode, Bruce W.] Atlanta Diabet Associates, Atlanta, GA USA. [Philis-Tsimikas, Athena] Scripps Whittier Diabet Inst, La Jolla, CA USA. [Pop-Busui, Rodica] Univ Michigan, Ann Arbor, MI USA. [Rodriguez, Henry; Eyth, Emily] Univ South, Tampa, FL USA. [Bhargava, Anuj] Iowa Diabet & Endocrinol Res Ctr, Des Moines, IA USA. RP Riddlesworth, TD (reprint author), Jaeb Ctr Hlth Res, Tampa, FL USA. EM t1dstats5@jaeb.org FU Leona M. and Harry B. Helmsley Charitable Trust FX Funding was provided by the Leona M. and Harry B. Helmsley Charitable Trust. Dexcom provided the CGM systems used in the trial. NR 23 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 40 IS 4 BP 538 EP 545 DI 10.2337/dc16-2482 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0UZ UT WOS:000397103500023 PM 28209654 ER PT J AU Shah, R Murthy, V Pacold, M Danielson, K Tanriverdi, K Larson, MG Hanspers, K Pico, A Mick, E Reis, J de Ferranti, S Freinkman, E Levy, D Hoffmann, U Osganian, S Das, S Freedman, JE AF Shah, Ravi Murthy, Venkatesh Pacold, Michael Danielson, Kirsty Tanriverdi, Kahraman Larson, Martin G. Hanspers, Kristina Pico, Alexander Mick, Eric Reis, Jared de Ferranti, Sarah Freinkman, Elizaveta Levy, Daniel Hoffmann, Udo Osganian, Stavroula Das, Saumya Freedman, Jane E. TI Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes SO DIABETES CARE LA English DT Article ID NONALCOHOLIC FATTY LIVER; CIRCULATING MICRORNAS; CARDIOVASCULAR-DISEASE; ADIPOSE-TISSUE; OBESITY; SURGERY; PROTEIN; RISK; NETWORKS; MIR-122 AB OBJECTIVE Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort. RESEARCH DESIGN AND METHODS We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico. RESULTS The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m(2); participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m(2). In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase). CONCLUSIONS These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR. C1 [Shah, Ravi; Danielson, Kirsty; Das, Saumya] Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Boston, MA USA. [Murthy, Venkatesh] Univ Michigan, Dept Med & Radiol, Ann Arbor, MI USA. [Pacold, Michael; de Ferranti, Sarah] MIT, Whitehead Inst, Metabol Core, Boston, MA USA. [Tanriverdi, Kahraman; Mick, Eric; Freedman, Jane E.] Univ Massachusetts, Worcester, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hanspers, Kristina; Pico, Alexander] Gladstone Inst, San Francisco, CA USA. [Reis, Jared; Levy, Daniel] NHLBI, Div Cardiovasc, Bethesda, MD USA. [Freinkman, Elizaveta] Boston Childrens Hosp, Dept Med & Cardiol, Prevent Cardiol, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Osganian, Stavroula] Boston Childrens Hosp, Div Gen Pediat, Boston, MA USA. RP Shah, R (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Boston, MA USA.; Murthy, V (reprint author), Univ Michigan, Dept Med & Radiol, Ann Arbor, MI USA. EM rvshah@partners.org; vlmurthy@med.umich.edu FU American Heart Association [14FTF19940000]; Harvard Catalyst [UL1-TR-001102]; Thrasher Research Fund; National Institutes of Health [K23-HL-127099, N01-HC-25195]; National Institutes of Health Common Fund Extracellular RNA Communication Consortium [UH3-TR-900921, UH3-TR-000901]; Milton Foundation; New Balance Foundation Obesity Prevention Center at Boston Children's Hospital; Boston Children's Hospital FX This work was supported by the American Heart Association (14FTF19940000 to R.S.), the Harvard Catalyst (UL1-TR-001102), the Thrasher Research Fund (to R.S.), the National Institutes of Health (K23-HL-127099), the National Institutes of Health Common Fund Extracellular RNA Communication Consortium (UH3-TR-900921 to J.E.F. and UH3-TR-000901 to S.D.), the Milton Foundation, New Balance Foundation Obesity Prevention Center at Boston Children's Hospital, and Boston Children's Hospital (for the POOL study to S.O.). The FHS is funded by National Institutes of Health contract N01-HC-25195. NR 38 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 40 IS 4 BP 546 EP 553 DI 10.2337/dc16-1354 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0UZ UT WOS:000397103500024 PM 28183786 ER PT J AU Klebanoff, MJ Corey, KE Chhatwal, J Kaplan, LM Chung, RT Hur, C AF Klebanoff, Matthew J. Corey, Kathleen E. Chhatwal, Jagpreet Kaplan, Lee M. Chung, Raymond T. Hur, Chin TI Bariatric Surgery for Nonalcoholic Steatohepatitis: A Clinical and Cost-Effectiveness Analysis SO HEPATOLOGY LA English DT Article ID FATTY LIVER-DISEASE; VITAMIN-E SUPPLEMENTATION; LIFE-STYLE INTERVENTION; CHRONIC HEPATITIS-C; QUALITY-OF-LIFE; WEIGHT-LOSS; REDUCES FEATURES; UTILITY ANALYSIS; MORBIDLY OBESE; UNITED-STATES AB Nonalcoholic steatohepatitis (NASH) affects 2%-3% of the US population and is expected to become the leading indication for liver transplantation in the next decade. Bariatric surgery may be an effective but expensive treatment for NASH. Using a state-transition model, our analysis assessed the effectiveness and cost-effectiveness of surgery to manage NASH. We simulated the benefits and harms of laparoscopic Roux-en-Y gastric bypass surgery in patients defined by weight class (overweight, mild obesity, moderate obesity, and severe obesity) and fibrosis stage (F0-F3). Comparators included intensive lifestyle intervention (ILI) and no treatment. Quality-adjusted life years (QALYs), costs, and incremental costeffectiveness ratios were calculated. Our results showed that surgery and ILI in obese patients (with F0-F3) increased QALYs by 0.678-2.152 and 0.452-0.618, respectively, compared with no treatment. Incremental cost-effectiveness ratios for surgery in all F0-F3 patients with mild, moderate, or severe obesity were $ 48,836/ QALY, $ 24,949/ QALY, and $ 19,222/ QALY, respectively. In overweight patients (with F0-F3), surgery increased QALYs by 0.050-0.824 and ILI increased QALYs by 0.031-0.164. In overweight patients, it was cost-effective to reserve treatment only for F3 patients; the incremental cost-effectiveness ratios for providing surgery or ILI only to F3 patients were $ 30,484/ QALY and $ 25,367/ QALY, respectively. Conclusions: Surgery was both effective and cost-effective for obese patients with NASH, regardless of fibrosis stage; in overweight patients, surgery increased QALYs for all patients regardless of fibrosis stage, but was cost-effective only for patients with F3 fibrosis; our results highlight the promise of bariatric surgery for treating NASH and underscore the need for clinical trials in this area. C1 [Klebanoff, Matthew J.; Corey, Kathleen E.; Chhatwal, Jagpreet; Kaplan, Lee M.; Chung, Raymond T.; Hur, Chin] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Klebanoff, Matthew J.; Chhatwal, Jagpreet; Hur, Chin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Klebanoff, Matthew J.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Corey, Kathleen E.; Chhatwal, Jagpreet; Kaplan, Lee M.; Chung, Raymond T.; Hur, Chin] Harvard Med Sch, Boston, MA USA. RP Corey, KE (reprint author), Massachusetts Gen Hosp, Blake 4,55 Fruit St, Boston, MA 02114 USA. EM kcorey@partners.org FU Gilead FX Dr. Chhatwal consults, advises, and received grants from Gilead. He advises Merck. Dr. Kaplan consults and advises Ethicon. He consults for Medtronic. NR 50 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2017 VL 65 IS 4 BP 1156 EP 1164 DI 10.1002/hep.28958 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3SS UT WOS:000397302600009 PM 27880977 ER PT J AU Li, B Li, TW Wang, BB Dou, RX Zhang, J Liu, JS Liu, XS AF Li, Bo Li, Taiwen Wang, Binbin Dou, Ruoxu Zhang, Jian Liu, Jun S. Liu, X. Shirley TI Ultrasensitive detection of TCR hypervariable-region sequences in solid-tissue RNA-seq data SO NATURE GENETICS LA English DT Letter C1 [Li, Bo; Zhang, Jian; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Li, Bo; Liu, Jun S.; Liu, X. Shirley] Harvard Univ, Dept Stat, Cambridge, MA USA. [Li, Taiwen] Sichuan Univ, West China Hosp Stomalol, State Key Lab Oral Dis, Chengdu, Peoples R China. [Wang, Binbin; Liu, X. Shirley] Tongji Univ, Sch Life Sci & Technol, Shanghai, Peoples R China. [Dou, Ruoxu] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou, Guangdong, Peoples R China. RP Liu, XS (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. EM xsliu@jimmy.harvard.edu FU NCI [1U01 CA180980]; National Natural Science Foundation of China [31329003, 31601077, 81321002] FX We acknowledge the following funding sources for supporting our work: NCI grant 1U01 CA180980 and National Natural Science Foundation of China grants 31329003 (to X.S.L.), 31601077 (to R.D.) and 81321002 (to T.L.). NR 9 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 49 IS 4 BP 482 EP 483 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA EP8CO UT WOS:000397603700006 PM 28358132 ER PT J AU Kosmicki, JA Samocha, KE Howrigan, DP Sanders, SJ Slowikowski, K Lek, M Karczewski, KJ Cutler, DJ Devlin, B Roeder, K Buxbaum, JD Neale, BM MacArthur, DG Wall, DP Robinson, EB Daly, MJ AF Kosmicki, Jack A. Samocha, Kaitlin E. Howrigan, Daniel P. Sanders, Stephan J. Slowikowski, Kamil Lek, Monkol Karczewski, Konrad J. Cutler, David J. Devlin, Bernie Roeder, Kathryn Buxbaum, Joseph D. Neale, Benjamin M. MacArthur, Daniel G. Wall, Dennis P. Robinson, Elise B. Daly, Mark J. TI Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples SO NATURE GENETICS LA English DT Article ID AUTISM SPECTRUM DISORDERS; CONGENITAL HEART-DISEASE; INTELLECTUAL DISABILITY; GENETIC RISK; GENERAL-POPULATION; MUTATIONS; SCHIZOPHRENIA; PATTERNS; SIBLINGS; RARE AB Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that similar to 1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation. C1 [Kosmicki, Jack A.; Samocha, Kaitlin E.; Howrigan, Daniel P.; Lek, Monkol; Karczewski, Konrad J.; Neale, Benjamin M.; MacArthur, Daniel G.; Robinson, Elise B.; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, ATGU, Boston, MA USA. [Kosmicki, Jack A.; Samocha, Kaitlin E.; Howrigan, Daniel P.; Slowikowski, Kamil; Lek, Monkol; Karczewski, Konrad J.; Neale, Benjamin M.; MacArthur, Daniel G.; Robinson, Elise B.; Daly, Mark J.] Harvard Med Sch, Boston, MA USA. [Kosmicki, Jack A.; Samocha, Kaitlin E.; Howrigan, Daniel P.; Slowikowski, Kamil; Lek, Monkol; Karczewski, Konrad J.; Neale, Benjamin M.; MacArthur, Daniel G.; Robinson, Elise B.; Daly, Mark J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Kosmicki, Jack A.; Samocha, Kaitlin E.; Howrigan, Daniel P.; Neale, Benjamin M.; Robinson, Elise B.; Daly, Mark J.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Kosmicki, Jack A.; Slowikowski, Kamil] Harvard Univ, Program Bioinformat & Integrat Genom, Cambridge, MA USA. [Kosmicki, Jack A.; Samocha, Kaitlin E.] Harvard Med Sch, Program Genet & Genom Biol & Biomed Sci, Boston, MA USA. [Sanders, Stephan J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Slowikowski, Kamil] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA USA. [Slowikowski, Kamil] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA USA. [Slowikowski, Kamil] Partners Ctr Personalized Genet Med, Boston, MA USA. [Cutler, David J.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Wall, Dennis P.] Stanford Univ, Dept Pediat Syst Med, Stanford, CA USA. [Wall, Dennis P.] Stanford Univ, Dept Biomed Data Sci, Stanford, CA USA. [Wall, Dennis P.] Stanford Univ, Dept Psychiat, Stanford, CA USA. RP Daly, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, ATGU, Boston, MA USA.; Daly, MJ (reprint author), Harvard Med Sch, Boston, MA USA.; Daly, MJ (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.; Daly, MJ (reprint author), Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. EM mjdaly@atgu.mgh.harvard.edu FU NIH [U01MH100233, U01MH100209, U01MH100229, U01MH100239, R56MH097849, R01 MH097849]; Simons Foundation Autism Research initiative [SFARI 342292]; Simons Foundation Autism Research initiative from the Simons Center for the Social Brain at MIT; National Institutes of Health [U54DK105566, R01 GM104371]; National Institutes of Mental Health [1K01MH099286]; NARSAD [22379]; [T32 HG002295/HG/NHGRI] FX We thank all of the members of the ATGU and the laboratory of D.P.W. for assistance in this endeavor. We thank the families who took part in the Simons Simplex Collection study and the Simons Variation in Individuals Project, as well as the clinicians who collected data at each of the study sites. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data tor comparison. A full list of contributing groups can be found on the ExAC website (see URLs). We also greatly thank A. Byrnes, R. Fine, D. Fronk, A. Martin, C. Nichols, N. Radd, K. Satterstrom, and E. Wigdor for their insightful contributions. Finally, we acknowledge G.A. Barnard for inspiring us to write in a inure conversational tone similar to that in his seminal. 1947 paper (Biometrika 34, 123-138, 1947). This work was supported by NIH grants U01MH100233, U01MH100209, U01MH100229, and U01MH100239 to the Autism Sequencing Consortium (ASC), and R56MH097849 and R01 MH097849 to the Population based Autism Genetics and Environment Study (PAGES). M.J.D., J.A.K., and K.E.S. Were supported by grants from the Simons Foundation Autism Research initiative (SFARI 342292 and a subaward from the Simons Center for the Social Brain at MIT). M.L. and D.G.M's work on the ExAC project was funded by U54DK105566 and R01 GM104371 from the National Institutes of Health. K.S. was funded by T32 HG002295/HG/NHGRI. E.B.R. was funded by National Institutes of Mental Health Grant 1K01MH099286 and NARSAD Young Investigator grant 22379. NR 42 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 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2017 VL 49 IS 4 BP 504 EP + DI 10.1038/ng.3789 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EP8CO UT WOS:000397603700013 PM 28191890 ER PT J AU Canver, MC Lessard, S Pinello, L Wu, YX Ilboudo, Y Stern, EN Needleman, AJ Galacteros, F Brugnara, C Kutlar, A McKenzie, C Reid, M Chen, DD Das, PP Cole, MA Zeng, J Kurita, R Nakamura, Y Yuan, GC Lettre, G Bauer, DE Orkin, SH AF Canver, Matthew C. Lessard, Samuel Pinello, Luca Wu, Yuxuan Ilboudo, Yann Stern, Emily N. Needleman, Austen J. Galacteros, Frederic Brugnara, Carlo Kutlar, Abdullah McKenzie, Colin Reid, Marvin Chen, Diane D. Das, Partha Pratim Cole, Mitchel A. Zeng, Jing Kurita, Ryo Nakamura, Yukio Yuan, Guo-Cheng Lettre, Guillaume Bauer, Daniel E. Orkin, Stuart H. TI Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FETAL-HEMOGLOBIN LEVELS; RED-BLOOD-CELL; INTERGENIC VARIANTS; AFRICAN-AMERICANS; GENETIC-VARIATION; CRISPR-CAS9; BCL11A; HBS1L-MYB; DNA AB Cas9-mediated, high-throughput, saturating in situ mutagenesis permits fine-mapping of function across genomic segments. Disease-and trait-associated variants identified in genome-wide association studies largely cluster at regulatory loci. Here we demonstrate the use of multiple designer nucleases and variant-aware library design to interrogate trait-associated regulatory DNA at high resolution. We developed a computational tool for the creation of saturating-mutagenesis libraries with single or multiple nucleases with incorporation of variants. We applied this methodology to the HBS1L-MYB intergenic region, which is associated with red-blood-cell traits, including fetal hemoglobin levels. This approach identified putative regulatory elements that control MYB expression. Analysis of genomic copy number highlighted potential false-positive regions, thus emphasizing the importance of off-target analysis in the design of saturating-mutagenesis experiments. Together, these data establish a widely applicable high-throughput and high-resolution methodology to identify minimal functional sequences within large disease-and trait-associated regions. C1 [Canver, Matthew C.; Wu, Yuxuan; Stern, Emily N.; Needleman, Austen J.; Chen, Diane D.; Das, Partha Pratim; Cole, Mitchel A.; Zeng, Jing; Bauer, Daniel E.; Orkin, Stuart H.] Boston Childrens Hosp, Dana Farber Canc Inst, Harvard Stem Cell Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Canver, Matthew C.; Wu, Yuxuan; Stern, Emily N.; Needleman, Austen J.; Chen, Diane D.; Das, Partha Pratim; Cole, Mitchel A.; Zeng, Jing; Bauer, Daniel E.; Orkin, Stuart H.] Harvard Stem Cell Inst, Harvard Med Sch, Dept Pediat, Boston, MA 02138 USA. [Lessard, Samuel; Ilboudo, Yann; Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Pinello, Luca] Massachusetts Gen Hosp, Harvard Med Sch, Dept Mol Pathol, Boston, MA USA. [Galacteros, Frederic] AP HP, Hop Henri Mondor, IMRB U955, UPeC,Red Cell Genet Dis Unit, Creteil, France. [Brugnara, Carlo] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA. [Kutlar, Abdullah] Augusta Univ, Sickle Cell Ctr, Dept Med, Augusta, GA USA. [McKenzie, Colin; Reid, Marvin] Univ West Indies, Caribbean Inst Hlth Res, Kingston, Jamaica. [Kurita, Ryo] Japanese Red Cross Soc, Cent Blood Inst, Dept Res & Dev, Tokyo, Japan. [Nakamura, Yukio] RIKEN BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki, Japan. [Nakamura, Yukio] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Yuan, Guo-Cheng] Harvard T H Chan Sch Publ Hlth, Boston, MA USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Bauer, DE; Orkin, SH (reprint author), Boston Childrens Hosp, Dana Farber Canc Inst, Harvard Stem Cell Inst, Div Hematol Oncol, Boston, MA 02115 USA.; Bauer, DE; Orkin, SH (reprint author), Harvard Stem Cell Inst, Harvard Med Sch, Dept Pediat, Boston, MA 02138 USA.; Orkin, SH (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA. EM Daniel.Bauer@childrens.harvard.edu; Stuart_Orkin@dfci.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [F30DK103359-01A1]; National Human Genome Research institute (NHGRI) Career Development Award [K99HG008399]; Canadian Institutes of Health Research Banting Doctoral Scholarship; Hematology Opportunities for the Next Generation at Research Scientists (HONORS) Award from the American Society of Hematology; National Heart, Lung, and Blood Institute (NHLBI) [R01HL119099]; Canada Research Program; Montreal Heart Institute Foundation; Canadian Institute of Health Research [MOP123382]; NIDDK [K08DK093705, R03DK109232, P30DK049216]; NHLBI [DP2OD022716, P01HL032262]; Burroughs Wellcome Fund; Doris Duke Charitable Foundation Innovzitions in Clinical Research Award; ASH Scholar Award; Charles H. Hood Foundation Child Health Research Award; Cooley's Anemia Foundation Fellowship FX We thank Z.Ilerbert, M. Berkeley, and M. Vangala (Dana -Farber Cancer Institute Molecular Biology Core Facility) for sequencing, F. Lu at the HHMI Sequencing facility, and members at the Hematologic Neoplasia How Cytometry and the Flow Cytometry Core facilities at the Dana -Farber Cancer institute for cell -sorting. We also thank J. Docnch, M. Haeussler, J.-P. Coneordct, R. Barrett, V. Sankaran, and J. Xu for helpful discussions. M.C.C. is supported by a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) award (F30DK103359-01A1). L.P. is supported by a National Human Genome Research institute (NHGRI) Career Development Award (K99HG008399). S.L. is funded by a Canadian Institutes of Health Research Banting Doctoral Scholarship. E.N.S. is supported by a Hematology Opportunities for the Next Generation at Research Scientists (HONORS) Award from the American Society of Hematology. G.C.Y. is supported by awards from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL119099). G.L. is funded by the Canada Research Program, the Montreal Heart Institute Foundation, and the Canadian Institute of Health Research (MOP123382). A portion of the DNA genotyping was performed as part of the Biogen Sickle Cell Disease Consortium. D.E.B. is supported by NIDDK (K08DK093705, R03DK109232), NHLBI (DP2OD022716), the Burroughs Wellcome Fund, a Doris Duke Charitable Foundation Innovzitions in Clinical Research Award, an ASH Scholar Award, a Charles H. Hood Foundation Child Health Research Award, and a Cooley's Anemia Foundation Fellowship. S.H.O. is supported by an award from the NHLBI (P01HL032262) and an award from the NIDDK (P30DK049216, Center of Excellence in Molecular Hematology). NR 52 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 49 IS 4 BP 625 EP + DI 10.1038/ng.3793 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EP8CO UT WOS:000397603700028 PM 28218758 ER PT J AU Swirski, FK Nahrendorf, M AF Swirski, Filip K. Nahrendorf, Matthias TI Old, caffeinated, and healthy SO NATURE REVIEWS CARDIOLOGY LA English DT Editorial Material ID ATHEROSCLEROSIS C1 [Swirski, Filip K.; Nahrendorf, Matthias] Harvard Med Sch, Massachusetts Gen Hosp, Dept Imaging, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. RP Swirski, FK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Imaging, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu FU NHLBI; MGH Research Scholar programme FX The authors acknowledge funding from the NHLBI and the MGH Research Scholar programme. NR 6 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD APR PY 2017 VL 14 IS 4 DI 10.1038/nrcardio.2017.22 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP3WF UT WOS:000397311700003 PM 28250451 ER PT J AU Woolf, TM Gurumurthy, CB Boyce, F Kmiec, EB AF Woolf, Tod M. Gurumurthy, Channabasavaiah B. Boyce, Frederick Kmiec, Eric B. TI To cleave or not to cleave: therapeutic gene editing with and without programmable nucleases SO NATURE REVIEWS DRUG DISCOVERY LA English DT Letter ID REPAIR; OLIGONUCLEOTIDES; DNA C1 [Woolf, Tod M.] ETAGEN Pharma Inc, Cambridge, MA 01239 USA. [Gurumurthy, Channabasavaiah B.] Univ Nebraska Med Ctr, Mouse Engn Core Facil, Omaha, NE 68198 USA. [Boyce, Frederick] Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Kmiec, Eric B.] Helen F Graham Canc Ctr & Res Inst, Gene Editing Inst Translat Canc Res, Newark, DE 19713 USA. RP Woolf, TM (reprint author), ETAGEN Pharma Inc, Cambridge, MA 01239 USA. EM tw@etagenpharma.com NR 13 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 16 IS 4 DI 10.1038/nrd.2017.42 PG 3 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA EP8AS UT WOS:000397598900018 PM 28303022 ER PT J AU Chawla, LS Bellomo, R Bihorac, A Goldstein, SL Siew, ED Bagshaw, SM Bittleman, D Cruz, D Endre, Z Fitzgerald, RL Forni, L Kane-Gill, SL Hoste, E Koyner, J Liu, KD Macedo, E Mehta, R Murray, P Nadim, M Ostermann, M Palevsky, PM Pannu, N Rosner, M Wald, R Zarbock, A Ronco, C Kellum, JA AF Chawla, Lakhmir S. Bellomo, Rinaldo Bihorac, Azra Goldstein, Stuart L. Siew, Edward D. Bagshaw, Sean M. Bittleman, David Cruz, Dinna Endre, Zoltan Fitzgerald, Robert L. Forni, Lui Kane-Gill, Sandra L. Hoste, Eric Koyner, Jay Liu, Kathleen D. Macedo, Etienne Mehta, Ravindra Murray, Patrick Nadim, Mitra Ostermann, Marlies Palevsky, Paul M. Pannu, Neesh Rosner, Mitchell Wald, Ron Zarbock, Alexander Ronco, Claudio Kellum, John A. TI Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup SO NATURE REVIEWS NEPHROLOGY LA English DT Article ID CRITICALLY-ILL PATIENTS; GLOMERULAR-FILTRATION-RATE; ACUTE TUBULAR-NECROSIS; GELATINASE-ASSOCIATED LIPOCALIN; ANGIOTENSIN RECEPTOR BLOCKERS; REPLACEMENT THERAPY MODALITY; INJURY REQUIRING DIALYSIS; SERUM CREATININE LEVEL; LONG-TERM SURVIVAL; CARDIAC-SURGERY AB Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD. C1 [Chawla, Lakhmir S.] Vet Affairs Med Ctr, Dept Med, 50 Irving St, Washington, DC 20310 USA. [Bellomo, Rinaldo] Monash Univ, Australian & New Zealand Intens Care Res Ctr, Clayton, Vic 3800, Australia. [Bihorac, Azra] Univ Florida, Dept Med, Gainesville, FL 32611 USA. [Goldstein, Stuart L.] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Siew, Edward D.] Vanderbilt Univ, Sch Med, Div Nephrol & Hypertens, Nashville, TN USA. [Bagshaw, Sean M.] Univ Alberta, Fac Med & Dent, Div Crit Care Med, Edmonton, AB T6G 2M7, Canada. [Bittleman, David] Univ Calif San Diego, Dept Med, San Diego, CA USA. [Cruz, Dinna] Univ Calif San Diego, UCSD Med Ctr, San Diego, CA USA. [Endre, Zoltan] Univ New South Wales, Prince Wales Hosp, Dept Nephrol, Kensington, NSW, Australia. [Endre, Zoltan] Univ New South Wales, Sch Clin, Kensington, NSW, Australia. [Forni, Lui] Surrey Cty Hosp, Surrey, England. [Kane-Gill, Sandra L.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA 15260 USA. [Hoste, Eric] Univ Ghent, Ghent Univ Hosp, Intens Care Unit, Ghent, Belgium. [Koyner, Jay] Univ Chicago, Dept Med, Chicago, IL USA. [Liu, Kathleen D.] Univ Calif San Francisco, Dept Med & Anesthesia, Divi Nephrol & Crit Care, San Francisco, CA 94143 USA. [Murray, Patrick] Uni Coll Dublin, UCD Hlth Sci Ctr, Dublin, Ireland. [Nadim, Mitra] Univ Southern California, Keck Sch Med, Dept Med, Div Nephrol, Los Angeles, CA USA. [Ostermann, Marlies] Guys & St Thomas NHS Fdn Hosp, Dept Intens Care, Westminster, England. [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Palevsky, Paul M.] Univ Pittsburgh, Renal Electrolyte Div, Pittsburgh, PA USA. [Pannu, Neesh] Univ Alberta, Fac Med & Dent, Div Crit Care Med, Edmonton, AB T6G 2M7, Canada. [Rosner, Mitchell] Univ Virginia, Div Nephrol, Charlottesville, VA 22903 USA. [Wald, Ron] St Michaels Hosp, Div Nephrol, Toronto, ON, Canada. [Wald, Ron] Univ Toronto, Toronto, ON, Canada. [Zarbock, Alexander] Univ Hosp Munster, Munster, Germany. [Ronco, Claudio] San Bortolo Hosp, Int Renal Res Inst Vicenza, Dept Nephrol, Dept Dialysis & Transplantat, Vicenza, Italy. [Kellum, John A.] Univ Pittsburgh, Ctr Crit Care Nephrol, Dept Crit Care Med, Pittsburgh, PA USA. RP Chawla, LS (reprint author), Vet Affairs Med Ctr, Dept Med, 50 Irving St, Washington, DC 20310 USA. EM minkchawla@gmail.com FU Baxter Medical; Astute Medical; INC; Society of Critical Care Medicine; Gambro Renal Products; VitaFlo; Mallinckrodt; Baxter Healthcare; Bellco; AM Pharma; La Jolla Pharmaceuticals; Relypsa; Fresenius-Kabi; iSAEC; Fresenius Medical Care; Baxter; Fresenius FX L.S.C. has received consulting fees from Astute Medical, Nxstage Medical and Bard Medical. R.B has received research support from Baxter Medical. A.B. has received research support from Astute Medical, INC and the Society of Critical Care Medicine. S.L.G. has received grants from Gambro Renal Products, VitaFlo, Mallinckrodt, and Alexion; grants and personal fees from Baxter Healthcare, Astute Medical, Bellco, AM Pharma, and La Jolla Pharmaceuticals; and personal fees from Bioporto, Akebia, Otsuka, Kaneka, and MediBeacon, all outside the submitted work. S.M.B. has received consulting fees from Baxter and La Jolla Pharmaceuticals. L.F. has received receiving consulting fees from Fresenius, Astute Medical, Eras Pharma, Baxter, and Ortho Clinical. E.H. has received speaker's fees from Alexion and a research grant from Bellco. J.K. has received consulting fees from Nxstage Medical, Astute Medical, Sphingotec and Pfizer. E.M. has received research funding from Relypsa and Fresenius-Kabi. R.M. has received consulting fees from Eli Lilly, Spectral, Keryx, Baxter, Ardea, AM Pharma, GSK, CSL Behring, Grifols, Astute Inc. Fresenius-Kabi, Quark, Ferring Research, Ionis Pharmaceuticals, Johnsons and Johnson and DURECT, and has received research support from iSAEC, Relypsa, Fresenius-Kabi and Fresenius. M.O. has received speaker honoraria and research funding from Fresenius Medical Care, and payment for advisory services from Baxter/Gambro. P.M.P has received consulting fees from Durect and Baxter. R.W. has received consulting fees from Durect and MedBeacon and unrestricted research support from Baxter. A.Z. has received unrestricted research grants from Fresenius and Astute Medical and lecture fees from Fresenius, Braun, Astute Medical, and Astellas. C.R. has received consulting fees from Astute, Asahi, GE and Baxter. J.A.K. has received consulting fees from Astute Medical, Atoc Bio, Astellas, Bard Medical, Baxter Medical, Bioporto, Grifols, Medibeacon and Nxstage Medical. E.D.S., D.B., D.C., Z.E., R.L.F., S.L.K.-G., K.D.L., P.M, M.N., N.P. and M.R. declare no competing interests. NR 152 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 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD APR PY 2017 VL 13 IS 4 BP 241 EP 257 DI 10.1038/nrneph.2017.2 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA EP3QN UT WOS:000397296900007 PM 28239173 ER PT J AU Aarsland, D Creese, B Politis, M Chaudhuri, KR Ffytche, DH Weintraub, D Ballard, C AF Aarsland, Dag Creese, Byron Politis, Marios Chaudhuri, K. Ray Ffytche, Dominic H. Weintraub, Daniel Ballard, Clive TI Cognitive decline in Parkinson disease SO NATURE REVIEWS NEUROLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; DEEP BRAIN-STIMULATION; LEWY BODY DEMENTIA; CEREBROSPINAL-FLUID BIOMARKERS; CLINICAL DIAGNOSTIC-CRITERIA; FACTOR G196A POLYMORPHISM; 5-YEAR FOLLOW-UP; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; AMYLOID-BETA AB Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition-or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-beta(42), a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*epsilon 4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results. C1 [Aarsland, Dag; Creese, Byron; Politis, Marios; Chaudhuri, K. Ray; Ffytche, Dominic H.; Weintraub, Daniel; Ballard, Clive] Kings Coll London, Inst Psychiat Psychol & Neurosci, KCL PARCOG Grp, De Crespigny Pk, London SE5 8AF, England. [Aarsland, Dag; Ffytche, Dominic H.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Old Age Psychiat, De Crespigny Pk, London SE5 8AF, England. [Creese, Byron; Ballard, Clive] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Politis, Marios] Kings Coll London, Neurodegenerat Imaging Grp, Maurice Wohl Clin Neurosci Inst, Inst Psychiat Psychol & Neurosci, 125 Coldharbour Lane, London SE5 9NU, England. [Chaudhuri, K. Ray] Kings Coll London, Dept Basic & Clin Neurosci, Maurice Wohl Clin Neurosci Inst, Natl Parkinson Fdn Ctr Excellence,Kings Coll Hosp, 5 Cutcombe Rd, London SE5 9RT, England. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Psychiat, 3615 Chestnut St,330, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Neurol, 3615 Chestnut St,330, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Ctr, PADRECC & MIRECC, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, PADRECC & MIRECC, 3900 Woodland Ave, Philadelphia, PA 19104 USA. RP Aarsland, D (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, KCL PARCOG Grp, De Crespigny Pk, London SE5 8AF, England. EM daarsland@gmail.com OI Aarsland, Dag/0000-0001-6314-216X FU National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust; Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Wolfson Foundation; Royal Society FX The authors thank Dr Michael Haworth for help in preparing the final manuscript. The authors would like to thank the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. D.A. is a Royal Society Wolfson Research Merit Award Holder and would like to thank the Wolfson Foundation and the Royal Society for their support. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. NR 215 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 13 IS 4 BP 217 EP 231 DI 10.1038/nrneurol.2017.27 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA EP7KU UT WOS:000397557500005 PM 28257128 ER PT J AU Toombs, JA Sytnikova, YA Chirn, GW Ang, I Lau, NC Blower, MD AF Toombs, James A. Sytnikova, Yuliya A. Chirn, Gung-Wei Ang, Ignatius Lau, Nelson C. Blower, Michael D. TI Xenopus Piwi proteins interact with a broad proportion of the oocyte transcriptome SO RNA LA English DT Article DE Piwi; Xenopus; oocyte; XIWI; XILI ID RNA-BINDING PROTEIN; PRIMARY PIRNA BIOGENESIS; GERMLINE STEM-CELLS; LARGE GENE LISTS; MESSENGER-RNA; ALTERNATIVE POLYADENYLATION; ARGININE METHYLATION; TRANSLATIONAL CONTROL; WIDE IDENTIFICATION; NUAGE FORMATION AB Piwi proteins utilize small RNAs (piRNAs) to recognize target transcripts such as transposable elements (TE). However, extensive piRNA sequence diversity also suggests that Piwi/piRNA complexes interact with many transcripts beyond TEs. To determine Piwi target RNAs, we used ribonucleoprotein-immunoprecipitation (RIP) and cross-linking and immunoprecipitation (CLIP) to identify thousands of transcripts associated with the Piwi proteins XIWI and XILI (Piwi-protein-associated transcripts, PATs) from early stage oocytes of X. laevis and X. tropicalis. Most PATs associate with both XIWI and XILI and include transcripts of developmentally important proteins in oogenesis and embryogenesis. Only a minor fraction of PATs in both frog species displayed near perfect matches to piRNAs. Since predicting imperfect pairing between all piRNAs and target RNAs remains intractable, we instead determined that PAT read counts correlate well with the lengths and expression levels of transcripts, features that have also been observed for oocyte mRNAs associated with Drosophila Piwi proteins. We used an in vitro assay with exogenous RNA to confirm that XIWI associates with RNAs in a length-and concentration-dependent manner. In this assay, noncoding transcripts with many perfectly matched antisense piRNAs were unstable, whereas coding transcripts with matching piRNAs were stable, consistent with emerging evidence that Piwi proteins both promote the turnover of TEs and other RNAs, and may also regulate mRNA localization and translation. Our study suggests that Piwi proteins play multiple roles in germ cells and establishes a tractable vertebrate system to study the role of Piwi proteins in transcript regulation. C1 [Toombs, James A.; Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Toombs, James A.; Blower, Michael D.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Sytnikova, Yuliya A.; Chirn, Gung-Wei; Ang, Ignatius; Lau, Nelson C.] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Sytnikova, Yuliya A.; Chirn, Gung-Wei; Ang, Ignatius; Lau, Nelson C.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Toombs, James A.] Brigham & Womens Hosp, Brigham Res Inst, 75 Francis St, Boston, MA 02115 USA. [Sytnikova, Yuliya A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Chirn, Gung-Wei] iBioinfo Grp LLC, Lexington, MA 02421 USA. [Ang, Ignatius] Univ New England, Sch Osteopath Med, Biddeford, ME 04005 USA. RP Blower, MD (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Blower, MD (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Lau, NC (reprint author), Brandeis Univ, Dept Biol, Waltham, MA 02454 USA.; Lau, NC (reprint author), Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. EM nlau@brandeis.edu; blower@molbio.mgh.harvard.edu FU National Institutes of Health via Core Facilities [P30 NS045713]; Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund; [R00HD057298]; [R01AG052465]; [R01GM086434]; [R01GM108548] FX We are grateful to Ulandt Kim and the MGH sequencing core for all Illumina sequencing of X. laevis sequences, members of the Blower laboratory for critical comments on this work, Michael Rosbash's laboratory for assistance in deep-sequencing X. tropicalis libraries, and Dianne Schwarz for critical comments on the manuscript. This work was supported by the National Institutes of Health via Core Facilities grant P30 NS045713 to the Brandeis Biology Department; R00HD057298 and R01AG052465 to N.C.L.; and R01GM086434 and R01GM108548 to M.D.B. N.C.L. was a Searle Scholar, and M.D.B. was also supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund. NR 127 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD APR PY 2017 VL 23 IS 4 BP 504 EP 520 DI 10.1261/rna.058859.116 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO6EZ UT WOS:000396786100008 PM 28031481 ER PT J AU Egervari, G Landry, J Callens, J Fullard, JF Roussos, P Keller, E Hurd, YL AF Egervari, Gabor Landry, Joseph Callens, James Fullard, John F. Roussos, Panos Keller, Eva Hurd, Yasmin L. TI Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; Epigenetics; Glutamate; Heroin; Histone acetylation; JQ1 ID BROMODOMAIN INHIBITOR OTX015; GLOBAL HISTONE ACETYLATION; COCAINE-INDUCED PLASTICITY; ACTIVATES TRANSCRIPTION; EPIGENETIC MECHANISMS; DOSE-ESCALATION; DRUG-ADDICTION; EXPRESSION; CHROMATIN; METHYLATION AB BACKGROUND: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain. METHODS: We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights. RESULTS: Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior. CONCLUSIONS: Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder. C1 [Egervari, Gabor; Landry, Joseph; Callens, James; Fullard, John F.; Roussos, Panos; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Psychiat, 1470 Madison Ave, New York, NY 10029 USA. [Egervari, Gabor; Landry, Joseph; Callens, James; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Neurosci, New York, NY USA. [Fullard, John F.; Roussos, Panos] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA. [Fullard, John F.; Roussos, Panos] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY USA. [Roussos, Panos] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 3, Bronx, NY USA. [Keller, Eva] Semmelweis Univ, Dept Forens Med, Budapest, Hungary. RP Hurd, YL (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Psychiat, 1470 Madison Ave, New York, NY 10029 USA. EM Yasmin.Hurd@mssm.edu FU National Institutes of Health [DA15446, DA008227, AG050986]; Veterans Affairs [BX002395] FX This work was supported by grants from the National Institutes of Health (Grant Nos. DA15446 to YLH and EK, DA008227 to YLH, AG050986 to PR) and the Veterans Affairs (Merit Grant No. BX002395 to PR). NR 62 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 APR 1 PY 2017 VL 81 IS 7 BP 585 EP 594 DI 10.1016/j.biopsych.2016.09.015 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RX UT WOS:000397300500013 PM 27863698 ER PT J AU Moshiri, AS Doumani, R Yelistratova, L Blom, A Lachance, K Shinohara, MM Delaney, M Chang, O McArdle, S Thomas, H Asgari, MM Huang, ML Schwartz, SM Nghiem, P AF Moshiri, Ata S. Doumani, Ryan Yelistratova, Lola Blom, Astrid Lachance, Kristina Shinohara, Michi M. Delaney, Martha Chang, Oliver McArdle, Susan Thomas, Hannah Asgari, Maryam M. Huang, Meei-Li Schwartz, Stephen M. Nghiem, Paul TI Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID EXPRESSION; INFECTION; CANCER; GENE; LOAD AB Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20-2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19-2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up. C1 [Moshiri, Ata S.; Doumani, Ryan; Yelistratova, Lola; Blom, Astrid; Lachance, Kristina; Shinohara, Michi M.; Thomas, Hannah; Nghiem, Paul] Univ Washington, Dept Med, Div Dermatol, Seattle, WA USA. [Shinohara, Michi M.; Delaney, Martha; Chang, Oliver] Univ Washington, Dept Pathol, Div Dermatopathol, Seattle, WA 98195 USA. [McArdle, Susan; Huang, Meei-Li] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Asgari, Maryam M.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Schwartz, Stephen M.; Nghiem, Paul] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Delaney, Martha] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Moshiri, Ata S.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. RP Nghiem, P (reprint author), 850 Republican St, Seattle, WA 98109 USA. EM pnghiem@uw.edu FU National Institutes of Health [RO1CA176841, R01CA162522, K24CA139052, TL1TR000422]; Colin Johnston Fund; Janet Canning Fund FX We thank James DeCaprio at the Dana Farber Cancer Institute for the generous gift of the Ab3 monoclonal antibody. We thank Julie Randolph-Habecker and Kim Melton of the FHCRC experimental histopathology core facility for performing immunohistochemistry. We acknowledge support from the following National Institutes of Health grants, RO1CA176841, R01CA162522, K24CA139052, and TL1TR000422, as well as the Colin Johnston Fund and the Janet Canning Fund. NR 29 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 APR PY 2017 VL 137 IS 4 BP 819 EP 827 DI 10.1016/j.jid.2016.10.028 PG 9 WC Dermatology SC Dermatology GA EO7QE UT WOS:000396884400010 PM 27815175 ER PT J AU Alves, CP Yokoyama, S Goedert, L Pontes, CLS Sousa, JF Fisher, DE Espreafico, EM AF Alves, Cleidson P. Yokoyama, Satoru Goedert, Lucas Pontes, Carmen L. S. Sousa, Josane F. Fisher, David E. Espreafico, Enilza M. TI MYO5A Gene Is a Target of MITF in Melanocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID MYOSIN-VA; TRANSCRIPTION FACTOR; MELANOMA-CELLS; ORGANELLE; TRANSPORT C1 [Alves, Cleidson P.; Goedert, Lucas; Pontes, Carmen L. S.; Sousa, Josane F.; Espreafico, Enilza M.] Univ Sao Paulo, Dept Cell & Mol Biol, Fac Med Ribeirao Preto, Sao Paulo, Brazil. [Alves, Cleidson P.; Sousa, Josane F.] Fac Med Ribeirao Preto, Ctr Integrat Syst Biol CISBi NAP USP, Sao Paulo, Brazil. [Alves, Cleidson P.; Sousa, Josane F.] Fac Med Ribeirao Preto, Dept Genet, Sao Paulo, Brazil. [Yokoyama, Satoru] Toyama Univ, Inst Nat Med, Div Pathogen Biochem, Toyama, Japan. [Alves, Cleidson P.; Yokoyama, Satoru; Fisher, David E.] Harvard Med Sch, Dept Dermatol, Cutaneous Biol Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Espreafico, EM (reprint author), Univ Sao Paulo, Dept Cell & Mol Biol, Fac Med Ribeirao Preto, Sao Paulo, Brazil.; Fisher, DE (reprint author), Harvard Med Sch, Dept Dermatol, Cutaneous Biol Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM DFISHER3@partners.org; emesprea@fmrp.usp.br FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP-2009/50167-3, 2014/18189-5]; CNPq [311347/2011-8, 309187/2015-0, 201905/2009-4]; FAPESP [2014/07726-0, 2012/13900-7]; National Institutes of Health [5P01 CA163222, 5R01 AR043369-19, 5R01CA150226-04]; Dr Miriam and Sheldon G. Adelson Medical Research Foundation; Melanoma Research Alliance; Doris Duke Medical Foundation; US-Israel Binational Science Foundation FX We are thankful to Silmara Banzi, Benedita de Souza, and Vivien Igras for their technical assistance and Claudia Alves for critical review. This work was supported by grants to EME from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-2009/50167-3 and 2014/18189-5) and CNPq (311347/2011-8 and 309187/2015-0). CPA received fellowship from CNPq (201905/2009-4). LG received fellowship from FAPESP (2014/07726-0). CPA, LG, and EME are members of Center for Cell-Therapy, CEPID/FAPESP (2013/08135-2). CLSP received fellowship from FAPESP (2012/13900-7). DEF was supported by grants from National Institutes of Health (5P01 CA163222, 5R01 AR043369-19, and 5R01CA150226-04), the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Doris Duke Medical Foundation, and the US-Israel Binational Science Foundation. Some results shown here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. 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 APR PY 2017 VL 137 IS 4 BP 985 EP 989 DI 10.1016/j.jid.2016.11.026 PG 5 WC Dermatology SC Dermatology GA EO7QE UT WOS:000396884400036 PM 27939378 ER PT J AU Matos, TR Liu, HY Ritz, J AF Matos, Tiago R. Liu, Hongye Ritz, Jerome TI Research Techniques Made Simple: Experimental Methodology for Single-Cell Mass Cytometry SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID T-CELLS C1 [Matos, Tiago R.; Liu, Hongye; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Matos, Tiago R.; Liu, Hongye; Ritz, Jerome] Harvard Med Sch, Boston, MA USA. [Matos, Tiago R.] Univ Amsterdam, Acad Med Ctr, Dept Dermatol, Room L3-119,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Matos, TR (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Dermatol, Room L3-119,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM tiagoreismatos@gmail.com FU Harvard Medical School-Portugal Program in Translational Research [HMSP-ICT/0001/201] FX We would like to thank Jodi L. Johnson for helpful comments, critical reading of the manuscript, and editorial assistance. Funded by the Harvard Medical School-Portugal Program in Translational Research HMSP-ICT/0001/201. NR 15 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2017 VL 137 IS 4 BP E31 EP E38 DI 10.1016/j.jid.2017.02.006 PG 8 WC Dermatology SC Dermatology GA EO7QE UT WOS:000396884400001 PM 28340685 ER PT J AU Sonpavde, G Pond, GR Mullane, S Ramirez, AA Vogelzang, NJ Necchi, A Powles, T Bellmunt, J AF Sonpavde, Guru Pond, Gregory R. Mullane, Stephanie Ramirez, Ana A. Vogelzang, Nicholas J. Necchi, Andrea Powles, Thomas Bellmunt, Joaquim TI Outcomes in patients with advanced urothelial carcinoma after discontinuation of programmed death (PD)-1 or PD ligand 1 inhibitor therapy SO BJU INTERNATIONAL LA English DT Article DE urothelial carcinoma; PD-1 inhibitors; PD-L1 inhibitors; post-progression therapy; outcomes ID TRANSITIONAL-CELL CARCINOMA; PHASE-II TRIAL; PRIOR CHEMOTHERAPY; LUNG-CANCER; DOCETAXEL; NIVOLUMAB AB Objective To study the subsequent therapy and disease outcomes of patients with advanced urothelial carcinoma (UC) after discontinuation of programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors. Patients and Methods We performed a retrospective analysis to examine outcomes and systemic therapy administration after PD-1/PD-L1 inhibitor therapy in patients with advanced UC. Data on demographics and therapy administered were collected from the institutions involved in the study. Univariable Cox regression analyses were performed to examine the clinical factors potentially associated with overall survival (OS) after PD-1/PD-L1 inhibitor therapy. Results Data from 62 patients were available from four institutions, with capture of subsequent therapy and outcomes after checkpoint inhibitor immunotherapy. The median patient age was 65.5 years and 51 patients (82.3%) were male. The median (range) duration of PD-1/PD-L1 inhibitor therapy in 55 patients for whom these data were available was 64 (7669) days. Of these, 22 patients (35.5%) received post-PD-1/PD-L1 inhibitor therapy through a variety of different chemotherapy regimens (n = 16), chemobiological combination (n = 1), biological agents (n = 4) and immunotherapy (n = 1). The median (range) time from last PD-1/PD-L1 inhibitor therapy to subsequent therapy was 58 (14-242) days. The median OS of all patients after completion of PD-1/PD-L1 inhibitor therapy was 149 days (95% confidence interval [CI]: 75-359). Among those who received some post-PD-1/PD-L1 inhibitor therapy, the median OS was 182 days (95% CI: 121-372), and the median time to progression was 124 days (95% CI: 61-273) from the start of post-PD-1/PD-L1 therapy. Among these 22 patients, the only significant baseline prognostic factor associated with OS was performance status. Conclusions In this dataset, 35.5% of patients with advanced UC received systemic therapy after salvage therapy with PD-1/PD-L1 inhibitors. Outcomes after subsequent therapy appear similar to those historically observed in patients who had not received prior PD-1/PD-L1 inhibitor therapy. Further study of patients receiving post-PD-1/PD-L1 inhibitor therapy is warranted to identify factors associated with outcomes and potentially synergistic sequences. C1 [Sonpavde, Guru] UAB Comprehens Canc Ctr, 1720 2nd Ave S,NP2540B, Birmingham, AL 35294 USA. [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. [Mullane, Stephanie; Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mullane, Stephanie; Bellmunt, Joaquim] Harvard Med Sch, Boston, MA USA. [Ramirez, Ana A.; Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Powles, Thomas] Barts Canc Inst, London, England. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, 1720 2nd Ave S,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu FU Merck; Pfizer; MerckSharpDohme; Astra Zeneca; Millennium Takeda; Amgen; GlaxoSmithKline; Roche; Sanofi; Novartis FX G. Sonpavde has served on the Advisory Boards of Merck, Pfizer, Astrazeneca and Genentech, and has received research support from Merck and Pfizer. N. J. Vogelzang has been a consultant to Genentech, Merck, Pfizer and Astra-Zeneca. A. Necchi has been an advisor for Astra Zeneca, Roche and MerckSharp&Dohme, and has received research support from MerckSharp&Dohme, Astra Zeneca, Millennium Takeda, Amgen and GlaxoSmithKline. T. Powles has received honoraria from BMS, Merck, Roche and Pfizer and research funding from Astra Zeneca and Roche. J. Bellmunt has served on the Advisory Board for Merck, Genentech, Astra-Zeneca and Pfizer and has received research support from Sanofi and Novartis. G.R. Pond, S. Mullane and A. A. Ramirez have no conflicts of interest to declare. NR 17 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD APR PY 2017 VL 119 IS 4 BP 579 EP 584 DI 10.1111/bju.13674 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EO5CC UT WOS:000396709600020 PM 27700015 ER PT J AU Morton, GJ Muta, K Kaiyala, KJ Rojas, JM Scarlett, JM Matsen, ME Nelson, JT Acharya, NK Piccinini, F Stefanovski, D Bergman, RN Taborsky, GJ Kahn, SE Schwartz, MW AF Morton, Gregory J. Muta, Kenjiro Kaiyala, Karl J. Rojas, Jennifer M. Scarlett, Jarrad M. Matsen, Miles E. Nelson, Jarrell T. Acharya, Nikhil K. Piccinini, Francesca Stefanovski, Darko Bergman, Richard N. Taborsky, Gerald J., Jr. Kahn, Steven E. Schwartz, Michael W. TI Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure SO DIABETES LA English DT Article ID GLUCOSE-TOLERANCE; INTRAVENOUS GLUCOSE; PERIPHERAL-TISSUES; DISPOSITION INDEX; B-CELL; RESISTANCE; RATS; DIET; DOGS; QUANTIFICATION AB Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5 degrees C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22 degrees C) for 4 h or by intravenous infusion of the alpha-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure. C1 [Morton, Gregory J.; Muta, Kenjiro; Rojas, Jennifer M.; Scarlett, Jarrad M.; Matsen, Miles E.; Nelson, Jarrell T.; Acharya, Nikhil K.; Schwartz, Michael W.] Univ Washington, Dept Med, Inst Diabet, Seattle, WA 98105 USA. [Kaiyala, Karl J.] Univ Washington, Sch Dent, Dept Oral Hlth Sci, Seattle, WA 98195 USA. [Scarlett, Jarrad M.] Seattle Childrens Hosp, Dept Pediat Gastroenterol & Hepatol, Seattle, WA USA. [Piccinini, Francesca; Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Stefanovski, Darko] Univ Penn, Sch Vet Med, New Bolton Ctr, Philadelphia, PA 19104 USA. [Taborsky, Gerald J., Jr.; Kahn, Steven E.] Vet Affairs Puget Sound Hlth Care Syst, Dept Vet Affairs Med Ctr, Seattle, WA USA. RP Schwartz, MW (reprint author), Univ Washington, Dept Med, Inst Diabet, Seattle, WA 98105 USA. EM mschwart@u.washington.edu FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [DK-089056, DK-27619, DK-29867, DK-50154, DK-083042, DK-090320, DK-101997]; National Institute of Diabetes and Digestive Kidney Diseases-funded Nutrition Obesity Research Center [DK-035816]; Diabetes Research Center [DK-017047]; Nutrition, Obesity and Atherosclerosis Training Grant from the National Heart, Lung, and Blood Institute [T32-HL007028]; Diabetes and Metabolism Training Grant at the University of Washington [T32-DK-0007247]; Department of Veterans Affairs [BX001060] FX This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grants DK-089056 (G.J.M.), DK-27619 and DK-29867 (R.N.B.), DK-50154 (G.J.T.), DK-083042, DK-090320, and DK-101997 (M.W.S.); the National Institute of Diabetes and Digestive Kidney Diseases-funded Nutrition Obesity Research Center (DK-035816) and Diabetes Research Center (DK-017047); the Nutrition, Obesity and Atherosclerosis Training Grant from the National Heart, Lung, and Blood Institute (T32-HL007028) and the Diabetes and Metabolism Training Grant (T32-DK-0007247) at the University of Washington; and the Department of Veterans Affairs grant BX001060 (S.E.K.). NR 39 TC 0 Z9 0 U1 2 U2 2 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 APR PY 2017 VL 66 IS 4 BP 823 EP 834 DI 10.2337/db16-1351 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0ZJ UT WOS:000397114900007 PM 28115396 ER PT J AU Ussar, S Haering, MF Fujisaka, S Lutter, D Lee, KY Li, N Gerber, GK Bry, L Kahn, CR AF Ussar, Siegfried Haering, Max-Felix Fujisaka, Shiho Lutter, Dominik Lee, Kevin Y. Li, Ning Gerber, Georg K. Bry, Lynn Kahn, C. Ronald TI Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor SO DIABETES LA English DT Article ID GROWTH-FACTOR-I; GASTRIC-INHIBITORY POLYPEPTIDE; DIABETES-MELLITUS; ORGAN-CULTURE; GUT; ABSORPTION; CELL; PROLIFERATION; TRANSPORT; LOCALIZATION AB Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states. C1 [Ussar, Siegfried; Haering, Max-Felix; Fujisaka, Shiho; Lee, Kevin Y.; Kahn, C. Ronald] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Ussar, Siegfried] Helmholtz Ctr Munich, Helmholtz Diabet Ctr, Inst Diabet & Obes, JRG Adipocytes & Metab, Neuherberg, Germany. [Ussar, Siegfried; Lutter, Dominik] German Ctr Diabet Res DZD, Neuherberg, Germany. [Haering, Max-Felix] Univ Hosp Tubingen, Div Clin Chem & Pathobiochem, Dept Internal Med 4, Tubingen, Germany. [Fujisaka, Shiho] Toyama Univ, Dept Internal Med 1, Toyama, Japan. [Lutter, Dominik] Helmholtz Ctr Munich, Helmholtz Diabet Ctr, Inst Diabet & Obes, Neuherberg, Germany. [Lee, Kevin Y.] Ohio Univ, Heritage Coll Osteopath Med, Dept Biomed Sci, Athens, OH 45701 USA. [Lee, Kevin Y.] Ohio Univ, Inst Diabet, Athens, OH 45701 USA. [Li, Ning; Gerber, Georg K.; Bry, Lynn] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Ctr Clin & Translat Metagen, Boston, MA USA. RP Kahn, CR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health (NIH) [P30-DK-036836]; Brigham and Women's Hospital/Harvard Digestive Diseases Center for Clinical and Translational Metagenomics; NIH [P30-DK-034854, DK-31036, DK-36836]; iMed, the Helmholtz Initiative on Personalized Medicine; Sunstar Foundation postdoctoral fellowship; Mary K. Iacocca Professorship FX The Joslin Diabetes Research Center (DRC) Bioinformatics Core, which helped with data analysis, was supported by National Institutes of Health (NIH) grant P30-DK-036836, and the Brigham and Women's Hospital/Harvard Digestive Diseases Center for Clinical and Translational Metagenomics, which helped with microbiome analyses, was supported by NIH grant P30-DK-034854. This work was also supported by NIH grants DK-31036 to C.R.K. and DK-36836 to the Joslin DRC. S.U. is supported by iMed, the Helmholtz Initiative on Personalized Medicine. S.F. was supported by the Sunstar Foundation postdoctoral fellowship. The authors also thank the Mary K. Iacocca Professorship (C.R.K.) for their support. NR 49 TC 0 Z9 0 U1 5 U2 5 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 APR PY 2017 VL 66 IS 4 BP 886 EP 896 DI 10.2337/db15-1349 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0ZJ UT WOS:000397114900013 PM 28096258 ER PT J AU Prckovska, V Huijbers, W Schultz, A Ortiz-Teran, L Pena-Gomez, C Villoslada, P Johnson, K Sperling, R Sepulcre, J AF Prckovska, Vesna Huijbers, Willem Schultz, Aaron Ortiz-Teran, Laura Pena-Gomez, Cleofe Villoslada, Pablo Johnson, Keith Sperling, Reisa Sepulcre, Jorge TI Epicenters of Dynamic Connectivity in the Adaptation of the Ventral Visual System SO HUMAN BRAIN MAPPING LA English DT Article DE dynamic connectivity; repetition suppression; adaptation; visual system; face processing; multimodal integration; graph theory ID INTRINSIC FUNCTIONAL CONNECTIVITY; MONKEY INFEROTEMPORAL CORTEX; MILD COGNITIVE IMPAIRMENT; HUMAN CEREBRAL-CORTEX; REPETITION SUPPRESSION; HUMAN BRAIN; NEURAL ACTIVITY; MRI; REPRESENTATION; EXPERIENCE AB Objectives and design: Neuronal responses adapt to familiar and repeated sensory stimuli. Enhanced synchrony across wide brain systems has been postulated as a potential mechanism for this adaptation phenomenon. Here, we used recently developed graph theory methods to investigate hidden connectivity features of dynamic synchrony changes during a visual repetition paradigm. Particularly, we focused on strength connectivity changes occurring at local and distant brain neighborhoods. Principal observations: We found that connectivity reorganization in visual modal cortex-such as local suppressed connectivity in primary visual areas and distant suppressed connectivity in fusiform areas-is accompanied by enhanced local and distant connectivity in higher cognitive processing areas in multimodal and association cortex. Moreover, we found a shift of the dynamic functional connections from primary-visual-fusiform to primary-multimodal/association cortex. Conclusions: These findings suggest that repetition-suppression is made possible by reorganization of functional connectivity that enables communication between low-and high-order areas. (C) 2016 Wiley Periodicals, Inc. C1 [Prckovska, Vesna; Villoslada, Pablo] Inst Invest Biomed August Pi Sunyer, Ctr Neuroimmunol, Barcelona, Spain. [Prckovska, Vesna; Ortiz-Teran, Laura; Pena-Gomez, Cleofe; Johnson, Keith; Sepulcre, Jorge] Harvard Med Sch, Div Nucl Med & Mol Imaging, Dept Radiol, Gordon Ctr Med Imaging, Boston, MA USA. [Huijbers, Willem; Schultz, Aaron; Sperling, Reisa; Sepulcre, Jorge] Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Huijbers, Willem] German Ctr Neurodegenerat Dis, Dept Populat Hlth Sci, Bonn, Germany. [Villoslada, Pablo] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Johnson, Keith; Sperling, Reisa] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA. [Johnson, Keith; Sperling, Reisa] Harvard Med Sch, Boston, MA USA. [Johnson, Keith; Sperling, Reisa] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. RP Sepulcre, J (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. EM sepulcre@nmr.mgh.harvard.edu FU National Institutes of Health (NIH) [1K23EB019023-01RM, R01-AG027435-S1, P50-AG00513421, P01-AG036694, 2T32EB013180-06]; Massachusetts ADRC; FP7 Marie Curie Intra-European Fellowship (ConnectMS) [328060]; La Marato de TV3 [0891430] FX Contract grant sponsor: National Institutes of Health (NIH); Contract grant numbers: 1K23EB019023-01RM (to J.S.), R01-AG027435-S1 (to R.A.S. and K.A.J.), P50-AG00513421 (to K.A.J. and R.A.S.), P01-AG036694 (to R.A.S. and K.A.J.), and 2T32EB013180-06 (to L.O-T.); Contract grant sponsors: Massachusetts ADRC and FP7 Marie Curie Intra-European Fellowship (ConnectMS); Contract grant number: 328060; Contract grant sponsor: La Marato de TV3; Contract grant number: 0891430 NR 50 TC 0 Z9 0 U1 6 U2 6 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 APR PY 2017 VL 38 IS 4 BP 1965 EP 1976 DI 10.1002/hbm.23497 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5GF UT WOS:000396032900018 PM 28029725 ER PT J AU Mottet, N Bellmunt, J Bolla, M Briers, E Cumberbatch, MG De Santis, M Fossati, N Gross, T Henry, AM Joniau, S Lam, TB Mason, MD Matveev, VB Moldovan, PC van den Bergh, RCN Van den Broeck, T van der Poel, HG van der Kwast, TH Rouviere, O Schoots, IG Wiegel, T Cornford, P AF Mottet, Nicolas Bellmunt, Joaquim Bolla, Michel Briers, Erik Cumberbatch, Marcus G. De Santis, Maria Fossati, Nicola Gross, Tobias Henry, Ann M. Joniau, Steven Lam, Thomas B. Mason, Malcolm D. Matveev, Vsevolod B. Moldovan, Paul C. van den Bergh, Roderick C. N. Van den Broeck, Thomas van der Poel, Henk G. van der Kwast, Theo H. Rouviere, Olivier Schoots, Ivo G. Wiegel, Thomas Cornford, Philip TI EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Localised; EAU-ESTRO-SIOG Guidelines; Screening; Diagnosis; Staging; Treatment; Radical prostatectomy; Radiation therapy; Androgen deprivation ID RANDOMIZED CONTROLLED-TRIAL; ANDROGEN-DEPRIVATION THERAPY; RADICAL PROSTATECTOMY; MAGNETIC-RESONANCE; ACTIVE SURVEILLANCE; RADIATION-THERAPY; FOLLOW-UP; PELVIC LYMPHADENECTOMY; MODULATED RADIOTHERAPY; ADJUVANT RADIOTHERAPY AB Objective: To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on screening, diagnosis, and local treatment with curative intent of clinically localised prostate cancer (PCa). Evidence acquisition: The working panel performed a literature review of the new data (2013-2015). The guidelines were updated and the levels of evidence and/or grades of recommendation were added based on a systematic review of the evidence. Evidence synthesis: BRCA2 mutations have been added as risk factors for early and aggressive disease. In addition to the Gleason score, the five-tier 2014 International Society of Urological Pathology grading system should now be provided. Systematic screening is still not recommended. Instead, an individual risk-adapted strategy following a detailed discussion and taking into account the patient's wishes and life expectancy must be considered. An early prostate-specific antigen test, the use of a risk calculator, or one of the promising biomarker tools are being investigated and might be able to limit the overdetection of insignificant PCa. Breaking the link between diagnosis and treatment may lower the overtreatment risk. Multiparametric magnetic resonance imaging using standardised reporting cannot replace systematic biopsy, but robustly nested within the diagnostic work-up, it has a key role in local staging. Active surveillance always needs to be discussed with very low-risk patients. The place of surgery in high-risk disease and the role of lymph node dissection have been clarified, as well as the management of node-positive patients. Radiation therapy using dose-escalated intensity-modulated technology is a key treatment modality with recent improvement in the outcome based on increased doses as well as combination with hormonal treatment. Moderate hypofractionation is safe and effective, but longer-term data are still lacking. Brachytherapy represents an effective way to increase the delivered dose. Focal therapy remains experimental while cryosurgery and HIFU are still lacking long-term convincing results. Conclusions: The knowledge in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for the use in clinical practice. These are the first PCa guidelines endorsed by the European Society for Radiotherapy and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office and online (http://uroweb.org/guideline/prostate-cancer/). Patient summary: The 2016 EAU-STRO-IOG Prostate Cancer (PCa) Guidelines present updated information on the diagnosis, and treatment of clinically localised prostate cancer. In Northern and Western Europe, the number of men diagnosed with PCa has been on the rise. This may be due to an increase in opportunistic screening, but other factors may also be involved (eg, diet, sexual behaviour, low exposure to ultraviolet radiation). We propose that men who are potential candidates for screening should be engaged in a discussion with their clinician (also involving their families and caregivers) so that an informed decision may be made as part of an individualised risk-adapted approach. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Mottet, Nicolas] Univ Hosp, Dept Urol, St Etienne, France. [Bellmunt, Joaquim] Dana Farber Canc Inst, Bladder Canc Ctr, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Med Sch, Boston, MA USA. [Bolla, Michel] CHU Grenoble, Dept Radiat Therapy, Grenoble, France. [Cumberbatch, Marcus G.] Univ Sheffield, Acad Urol Unit, Sheffield, S Yorkshire, England. [De Santis, Maria] Univ Warwick, Canc Res Ctr, Coventry, W Midlands, England. [Fossati, Nicola] Osped San Raffaele, IRCCS, URI, Unit Urol,Div Oncol, Milan, Italy. [Fossati, Nicola] Univ Vita Salute San Raffaele, Milan, Italy. [Gross, Tobias] Univ Bern, Dept Urol, Inselspital, Bern, Switzerland. [Henry, Ann M.] St James Univ Hosp, Leeds Canc Ctr, Leeds, W Yorkshire, England. [Henry, Ann M.] Univ Leeds, Leeds, W Yorkshire, England. [Joniau, Steven; Van den Broeck, Thomas] Univ Hosp Leuven, Dept Urol, Leuven, Belgium. [Lam, Thomas B.] Univ Aberdeen, Acad Urol Unit, Aberdeen, Scotland. [Lam, Thomas B.] Aberdeen Royal Infirm, Dept Urol, Aberdeen, Scotland. [Mason, Malcolm D.] Cardiff Univ, Velindre Hosp, Cardiff, S Glam, Wales. [Matveev, Vsevolod B.] NN Blokhin Canc Res Ctr, Moscow, Russia. [Moldovan, Paul C.; Rouviere, Olivier] Hop Edouard Herriot, Dept Radiol, Hosp Civils Lyon, Lyon, France. [van den Bergh, Roderick C. N.] Canisius Wilhelmina Hosp, Dept Urol, Nijmegen, Netherlands. [van der Poel, Henk G.] Netherlands Canc Inst, Dept Urol, Amsterdam, Netherlands. [van der Kwast, Theo H.] Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [Schoots, Ivo G.] Erasmus MC Univ, Med Ctr, Dept Radiol & Nucl Med, Rotterdam, Netherlands. [Wiegel, Thomas] Univ Hosp Ulm, Dept Radiat Oncol, Ulm, Germany. [Cornford, Philip] Royal Liverpool & Broadgreen Hosp NHS Trust, Liverpool, Merseyside, England. RP Mottet, N (reprint author), Univ Hosp, Dept Urol, St Etienne, France. EM nicolas.mottet@chu-st-etienne.fr OI Gross, Tobias/0000-0002-3843-2672 FU Takeda Pharmaceutical; Millennium; Astellas; Pierre Fabre; Sanofi; Pasteur; Janssen; BMS; Bayer; Ipsen; Ferring; Novartis; Nucletron; Zeneca; Takeda FX Nicolas Mottet certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Nicolas Mottet receives grants/research support from Takeda Pharmaceutical, Millennium, Astellas, Pierre Fabre, Sanofi, and Pasteur. He receives honoraria or consultation fees from Takeda Pharmaceutical, Millennium, Janssen, Astellas, BMS, Bayer, Ipsen, Ferring, Novartis, Nucletron, Pierre Fabre, Sanofi, and Zeneca. Joaquim Bellmunt is a company consultant for Janssen, Astellas, Pierre Fabre, Genentech, Merck, Ipsen, Pfizer, Novartis and Sanofi Aventis. He has received research support from Takeda, Novartis and Sanofi and received travel grants from Pfizer and Pierre Fabre. Michel Bolla receives company honoraria from Ipsen and Astra Zeneca, is a company consultant for Janssen, and receives travel grants from Janssen, AstraZeneca, and Astellas. Erik Briers is a liaison officer for the European Prostate Cancer Coalition, a member of the ethics committee/patient advisory group for REQUITE (Validating predictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve quality of life in cancer survivors), member of ESR-PAG (patient advisory group on medical imaging), member of the Skeletal Care Academy, and member of the European Medicines Agency's Patients' and Consumers' Working Party. Maria De Santis is a company consultant for Glaxo Smith Kline, Janssen, Bayer, Novartis, Pierre Fabre, Astellas, Amgen, Eisai Inc., ESSA, Merck, and Synthon. She receives company speaker honoraria from Pfizer, Takeda, Sanofi Aventis, Shionogi, Celgene, and Teva OncoGenex, participates in trials for Pierre Fabre, Astellas, and Roche, and receives fellowships and travel grants from Bayer, Novartis, Ferring, Astellas, Sanofi Aventis, and Janssen. She receives grants/research support from Pierre Fabre and honoraria from AstraZeneca, participates in trials for Exelixis, Bayer, and Roche, and is a company consultant for Synthon. Steven Joniau is a company consultant for Astellas, Ipsen, Bayer, Sanofi, and Janssen. He receives company honoraria from Astellas, Amgen, Bayer, Sanofi, Janssen, and Ipsen, participates in trials for Astellas, Bayer, and Janssen, receives fellowships and travel grants from Astellas, Amgen, Bayer, Sanofi, Janssen, Ipsen, and Pfizer. Thomas B. Lam is a company consultant for Pfizer, GSK, Astellas, and Ipsen, receives company speaker honoraria from Pfizer, GSK, Astellas, and Ipsen. Malcolm D. Mason is a company consultant for Bristol-Myers Squibb, Janssen, Bayer, Sanofi, and Dendreon, and he receives company speaker honoraria from Takeda and Bayer. Seva Matveev participates in trials for Astellas, Pfizer, and Novartis, and receives company speaker honoraria from Sanofi and Astellas. Henk G. van der Poel is a company consultant for Intuitive Surgical and participates in trials for Astellas and Steba Biotech. He receives grants/research support from Astellas. Olivier Rouvie` re is a company consultant for EDAP-TMS, Bracco, and Philips. He receives company speaker honoraria from EDAP-TMS and Bracco and participates in trials for EDAP-TMS and Bracco. Thomas Wiegel receives company speaker honoraria from Astellas, Takeda, Hexal, Ipsen, JanssenCilac, and Ferring.; Philip Cornford is a company consultant for Astellas, Ipsen and Ferring. He receives company speaker honoraria from Astellas, Janssen, Ipsen and Pfizer and participates in trials from Ferring, and receives fellowships and travel grants from Astellas and Janssen. Marcus G. Cumberbatch, Nicola Fossati, Tobias Gross, Ann M. Henry, Paul L. Moldovan, Ivo G. Schoots, Roderick C. N. van den Bergh, Thomas Van den Broeck, and Theo van der Kwast have nothing to disclose. NR 89 TC 6 Z9 6 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2017 VL 71 IS 4 BP 618 EP 629 DI 10.1016/j.eururo.2016.08.003 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA EN9RB UT WOS:000396336200030 PM 27568654 ER PT J AU Cornford, P Bellmunt, J Bolla, M Briers, E De Santis, M Gross, T Henry, AM Joniau, S Lam, TB Mason, MD van der Poel, HG van der Kwast, TH Rouviere, O Wiegel, T Mottet, N AF Cornford, Philip Bellmunt, Joaquim Bolla, Michel Briers, Erik De Santis, Maria Gross, Tobias Henry, Ann M. Joniau, Steven Lam, Thomas B. Mason, Malcolm D. van der Poel, Henk G. van der Kwast, Theo H. Rouviere, Olivier Wiegel, Thomas Mottet, Nicolas TI EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Staging; Relapse; Metastatic; Castration-resistant; EAU-ESTRO-SIOG Guidelines; Hormonal therapy; Chemotherapy; Follow-up; Palliative ID ANDROGEN-DEPRIVATION THERAPY; EMISSION TOMOGRAPHY/COMPUTERIZED TOMOGRAPHY; EXTERNAL-BEAM RADIOTHERAPY; PLACEBO-CONTROLLED PHASE-3; CLINICAL DECISION-MAKING; LOCAL CURATIVE TREATMENT; DOSE-RATE BRACHYTHERAPY; LYMPH-NODE DISSECTION; OF-THE-LITERATURE; RADICAL PROSTATECTOMY AB Objective: To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (CRPC). Evidence acquisition: The working panel performed a literature review of the new data (2013-2015). The guidelines were updated, and the levels of evidence and/or grades of recommendation were added based on a systematic review of the literature. Evidence synthesis: Relapse after local therapy is defined by a rising prostate-specific antigen (PSA) level >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir after radiation therapy (RT). C-11-choline positron emission tomography/ computed tomography is of limited importance if PSA is < 1.0 ng/ml; bone scans and computed tomography can be omitted unless PSA is > 10 ng/ml. Multiparametric magnetic resonance imaging and biopsy are important to assess biochemical failure following RT. Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5 ng/ml and salvage RP, high-intensity focused ultrasound, cryosurgical ablation or salvage brachytherapy of the prostate in radiation failures. Androgen deprivation therapy (ADT) remains the basis for treatment of men with metastatic prostate cancer (PCa). However, docetaxel combined with ADT should be considered the standard of care for men with metastases at first presentation, provided they are fit enough to receive the drug. Followup of ADT should include analysis of PSA, testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Level 1 evidence for the treatment of metastatic CRPC (mCRPC) includes, abiraterone acetate plus prednisone (AA/P), enzalutamide, radium 223 (Ra 223), docetaxel at 75 mg/m(2) every 3 wk and sipuleucel-T. Cabazitaxel, AA/P, enzalutamide, and radium are approved for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with mCRPC and osseous metastases to prevent skeletal-related complications. Conclusions: The knowledge in the field of advanced and metastatic PCa and CRPC is changing rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for use in clinical practice. These PCa guidelines are the first endorsed by the European Society for Therapeutic Radiology and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office or online (http://uroweb.org/guideline/prostate-cancer/). Patient summary: In men with a rise in their PSA levels after prior local treatment for prostate cancer only, it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients. For patients diagnosed with metastatic castrate-resistant prostate cancer, several new drugs have become available which may provide a clear survival benefit but the optimal choice will have to be made on an individual basis. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Cornford, Philip] Royal Liverpool & Broadgreen Hosp NHS Trust, Liverpool, Merseyside, England. [Bellmunt, Joaquim] Dana Farber Canc Inst, Bladder Canc Ctr, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Med Sch, Boston, MA USA. [Bolla, Michel] CHU Grenoble, Dept Radiat Therapy, Grenoble, France. [De Santis, Maria] Univ Warwick, Canc Res Ctr, Coventry, W Midlands, England. [Gross, Tobias] Univ Bern, Inselspital, Dept Urol, Bern, Switzerland. [Henry, Ann M.] St James Univ Hosp, Leeds Canc Ctr, Leeds, W Yorkshire, England. [Joniau, Steven] Univ Hosp Leuven, Dept Urol, Leuven, Belgium. [Lam, Thomas B.] Univ Aberdeen, Acad Urol Unit, Aberdeen, Scotland. [Lam, Thomas B.] Aberdeen Royal Infirm, Dept Urol, Aberdeen, Scotland. [Mason, Malcolm D.] Velindre Hosp, Cardiff, S Glam, Wales. [van der Poel, Henk G.] Netherlands Canc Inst, Dept Urol, Amsterdam, Netherlands. [van der Kwast, Theo H.] Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [Rouviere, Olivier] Hop Edouard Herriot, Hosp Civils Lyon, Dept Radiol, Lyon, France. [Wiegel, Thomas] Univ Hosp Ulm, Dept Radiat Oncol, Ulm, Germany. [Mottet, Nicolas] Univ Hosp, Dept Urol, St Etienne, France. RP Cornford, P (reprint author), Royal Liverpool & Broadgreen Hosp NHS Trust, Dept Urol, Prescott St, Liverpool L7 8XP, Merseyside, England. EM Philip.Cornford@rlbuht.nhs.uk OI Gross, Tobias/0000-0002-3843-2672 FU Astellas; Janssen; Takeda; Novartis; Sanofi; Pfizer; Pierre Fabre; AstraZeneca; Ipsen; European Association of Urology; Bayer FX Philip Cornford certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: P. Cornford is a company consultant for Astellas, Ipsen and Ferring. He receives company speaker honoraria from Astellas, Janssen, Ipsen and Pfizer and participates in trials from Ferring, and receives fellowships and travel grants from Astellas and Janssen. Joaquim Bellmunt is a company consultant for Janssen, Astellas, Pierre Fabre, Genentech, Merck, Ipsen, Pfizer, Novartis and Sanofi Aventis. He has received research support from Takeda, Novartis and Sanofi and received travel grants from Pfizer and Pierre Fabre. Bolla has received company speaker honoraria from Ipsen and Astellas, has received honoraria or consultation fees from Janssen, and has received fellowship and travel grants from Janssen, AstraZeneca and Astellas. E. Briers has received grant and research support from Ipsen, European Association of Urology, and Bayer; is an ex officio board member for Europa UOMO; is an ethics committee and advisory group member for REQUITE; is a member patient advisory board member for PAGMI; and is a member of SCA and EMA PCWP. M. De Santis is a company consultant for GlaxoSmithKline, Janssen, Bayer, Novartis, Pierre Fabre, Astellas, Amgen, Eisai Inc., ESSA, Merck, and Synthon; has received company speaker honoraria from Pfizer, Takeda, Sanofi Aventis, Shionogi, Celgene, and Teva OncoGenex; has participated in trials for Pierre Fabre, Astellas, Exelixis, Bayer, and Roche; has received fellowship and travel grants from Bayer, Novartis, Ferring, Astellas, Sanofi Aventis, and Janssen; has received grant and research support fromPierre Fabre; has received honoraria from AstraZeneca; and is associated with Amgen. S. Joniau is a company consultant for Astellas, Ipsen, Bayer, Sanofi, and Janssen; has received company speaker honoraria from Astellas, Amgen, Bayer, Sanofi, Janssen, and Ipsen; has participated in trials for Astellas, Janssen, and Bayer; has received fellowship and travel grants from Astellas, Amgen, Bayer, Sanofi, Janssen, Ipsen, and Pfizer; and has received grant and research support from Astellas, Bayer, and Janssen. T. B. Lam is a company consultant for and has received company speaker honoraria from Pfizer, GSK, Astellas, and Ipsen. M. D. Mason is a company consultant for Bristol-Myers Squibb, Janssen, Bayer, Sanofi, and Dendreon and has received company speaker honoraria from Takeda and Bayer. H. van der Poel is a company consultant for Intuitive Surgical, has participated in trials for Astellas and Steba Biotech, has received grant and research support from Astellas. O. Rouviere is a company consultant for EDAP-TMS, Bracco, and Philips and has received company speaker honoraria from EDAP-TMS, Bracco and Philips and has participated in trials for EDAP-TMS and Bracco. T. Wiegel has received company speaker honoraria from Astellas, Takeda, Hexal, Ipsen, Janssen-Cilac, and Ferring. N. Mottet has received grant and research support from Takeda Pharmaceutical, Millenium, Astellas, Pierre Fabre, Sanofi, and Pasteur and has received honoraria or consultation fees from Takeda Pharaceutical, Millenium, Jansen, Astellas, BMS, Bayer, Ipsen, Ferring, Novartis, Nucletron, Pierre Fabre, Sanofi, and Zeneca. T. Gross, Ann M. Henry and T. H.; van der Kwast have nothing to disclose. NR 103 TC 1 Z9 1 U1 9 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2017 VL 71 IS 4 BP 630 EP 642 DI 10.1016/j.eururo.2016.08.002 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA EN9RB UT WOS:000396336200031 PM 27591931 ER PT J AU de Bono, JS Smith, MR Saad, F Rathkopf, DE Mulders, PFA Small, EJ Shore, ND Fizazi, K De Porre, P Kheoh, T Li, JH Todd, MB Ryan, CJ Flaig, TW AF de Bono, Johann S. Smith, Matthew R. Saad, Fred Rathkopf, Dana E. Mulders, Peter F. A. Small, Eric J. Shore, Neal D. Fizazi, Karim De Porre, Peter Kheoh, Thian Li, Jinhui Todd, Mary B. Ryan, Charles J. Flaig, Thomas W. TI Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302 SO EUROPEAN UROLOGY LA English DT Article DE Abiraterone acetate; Docetaxel; Elderly; Metastatic castration-resistant prostate cancer; Subsequent therapy; Treatment patterns ID PLACEBO-CONTROLLED PHASE-3; DOCETAXEL-BASED CHEMOTHERAPY; DOUBLE-BLIND; ELDERLY-PATIENTS; ANTITUMOR-ACTIVITY; SURVIVAL ANALYSIS; CLINICAL ACTIVITY; PLUS PREDNISONE; NAIVE PATIENTS; ENZALUTAMIDE AB Background: Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naive men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P). Objective: This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (>= 75 yr) and younger (<75 yr) patient subgroups. Design, setting, and participants: Data were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug. Intervention: At the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC. Outcome measurements and statistical analysis: Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available. Results and limitations: Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed >= 50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed >= 50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients. Conclusions: Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. Trial registration: ClinicalTrials. gov NCT00887198. Patient summary: Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy. (C) 2016 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [de Bono, Johann S.] Inst Canc Res, Sutton, Surrey, England. [de Bono, Johann S.] Royal Marsden Hosp, Sutton, Surrey, England. [Smith, Matthew R.] Harvard Med Sch, Boston, MA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Saad, Fred] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Rathkopf, Dana E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Rathkopf, Dana E.] Weill Cornell Med Coll, New York, NY USA. [Mulders, Peter F. A.] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Small, Eric J.; Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Shore, Neal D.] Atlantic Urol Clin, Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Fizazi, Karim] Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. [De Porre, Peter] Janssen Res & Dev, Beerse, Belgium. [Kheoh, Thian] Janssen Res & Dev, San Diego, CA USA. [Li, Jinhui] Johnson & Johnson Med China, Shanghai, Peoples R China. [Todd, Mary B.] Janssen Global Serv, Raritan, NJ USA. [Flaig, Thomas W.] Univ Colorado, Ctr Canc, Aurora, CO USA. RP de Bono, JS (reprint author), Inst Canc Res, Sutton, Surrey, England.; de Bono, JS (reprint author), Royal Marsden Hosp, Sutton, Surrey, England. EM johann.de-bono@icr.ac.uk FU Janssen Research Development FX This work was supported by Janssen Research & Development (formerly Ortho Biotech Oncology Research & Development, Cougar Biotechnology Unit). The sponsor played a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. NR 39 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2017 VL 71 IS 4 BP 656 EP 664 DI 10.1016/j.eururo.2016.06.033 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EN9RB UT WOS:000396336200034 PM 27402060 ER PT J AU Steinestel, J Bernemann, C Schrader, AJ Lennerz, JK AF Steinestel, Julie Bernemann, Christof Schrader, Andres J. Lennerz, Jochen K. TI Reply to Marcus V. Cronauer, Axel S. Merseburger, and M. Raschid Hoda's Letter to the Editor re: Christof Bernemann, Thomas J. Schnoeller, Manuel Luedeke, et al. Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer. Eur Urol 2017; 71: 1-3 SO EUROPEAN UROLOGY LA English DT Letter C1 [Steinestel, Julie; Bernemann, Christof; Schrader, Andres J.] Univ Hosp Muenster, Urol Clin, Albert Schweitzer Campus 1, D-48149 Munster, Germany. [Lennerz, Jochen K.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Steinestel, J (reprint author), Univ Hosp Muenster, Urol Clin, Albert Schweitzer Campus 1, D-48149 Munster, Germany. EM julie.steinestel@ukmuenster.de NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2017 VL 71 IS 4 BP E107 EP E108 DI 10.1016/j.eururo.2016.09.022 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EN9RB UT WOS:000396336200002 PM 27647434 ER PT J AU Siedner, MJ Kraemer, JD AF Siedner, Mark J. Kraemer, John D. TI The end of the Ebola virus disease epidemic: has the work just begun? SO LANCET GLOBAL HEALTH LA English DT Editorial Material C1 [Siedner, Mark J.] Harvard Med Sch, Dept Med, Boston, MA 02130 USA. [Siedner, Mark J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Siedner, Mark J.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Kraemer, John D.] Georgetown Univ, Washington, DC USA. RP Siedner, MJ (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02130 USA.; Siedner, MJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Siedner, MJ (reprint author), Mbarara Univ Sci & Technol, Mbarara, Uganda. EM msiedner@mgh.harvard.edu FU National Institutes of Health [K23 MH099916]; Harvard Center for AIDS Research [P30 AI060354] FX MJS receives funding from the National Institutes of Health (K23 MH099916) and the Harvard Center for AIDS Research (P30 AI060354). JDK declares no competing interests. NR 11 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 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD APR PY 2017 VL 5 IS 4 BP E381 EP E382 DI 10.1016/S2214-109X(17)30079-7 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN9SG UT WOS:000396339300007 PM 28237251 ER PT J AU Schrag, A Weintraub, D Schott, JM AF Schrag, Anette Weintraub, Daniel Schott, Jonathan M. TI Cognitive decline before diagnosis of Parkinson's disease Reply SO LANCET NEUROLOGY LA English DT Letter C1 [Schrag, Anette; Schott, Jonathan M.] UCL, UCL Inst Neurol, London, England. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Schrag, A (reprint author), UCL, UCL Inst Neurol, London, England. EM a.schrag@ucl.ac.uk FU Economic and Social Research Council; GE Healthcare; Parkinson's UK; EU FP7; Movement Disorders Society; Medtronic; AstraZeneca; Roche; Eli Lilly; AVID Radiopharmaceuticals FX AS reports grants from Economic and Social Research Council, GE Healthcare, Parkinson's UK, EU FP7, and the Movement Disorders Society; and personal fees from Medtronic and AstraZeneca. JMS reports personal fees from Roche and Eli Lilly, grants and non-financial support from AVID Radiopharmaceuticals, and serves on a data safety management board for Axon Neuroscience. DW declares no competing interests. NR 5 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 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD APR PY 2017 VL 16 IS 4 BP 262 EP 262 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA EN9RF UT WOS:000396336600012 PM 28327332 ER PT J AU Celano, CM Beale, EE Mastromauro, CA Stewart, JG Millstein, RA Auerbach, RP Bedoya, CA Huffman, JC AF Celano, C. M. Beale, E. E. Mastromauro, C. A. Stewart, J. G. Millstein, R. A. Auerbach, R. P. Bedoya, C. A. Huffman, J. C. TI Psychological interventions to reduce suicidality in high-risk patients with major depression: a randomized controlled trial SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Cognition; depression; optimism; positive psychology; suicide. ID TRACKING SELF-REPORT; PSYCHIATRIC OUTPATIENTS; BIPOLAR DISORDER; POSITIVE AFFECT; FOLLOW-UP; IDEATION; HOPELESSNESS; OPTIMISM; METAANALYSIS; BEHAVIOR AB Background. Positive psychological constructs have been associated with reduced suicidal ideation, and interventions to cultivate positive feelings have the potential to reduce suicide risk. This study compares the efficacy of a 6-week, telephone-based positive psychology (PP) intervention against a cognition-focused (CF) control intervention among patients recently hospitalized for depression and suicidal ideation or behavior. Method. A total of 65 adults with a current major depressive episode reporting suicidal ideation or a recent suicide attempt were enrolled from participating in-patient psychiatric units. Prior to discharge, participants were randomized to the PP (n = 32) or CF (n = 33) intervention. In both interventions, participants received a treatment manual, performed weekly PP (e.g. gratitude letter) or CF (e.g. recalling daily events) exercises, and completed weekly one-on-one telephone sessions over 6 weeks. Between-group differences in hopelessness (primary outcome), depression, suicidality and positive psychological constructs at 6 and 12 weeks were tested using mixed-effects models accounting for intensity of posthospitalization psychiatric treatment. Results. Compared with PP, the CF intervention was associated with significantly greater improvements in hopelessness at 6 weeks (beta=-3.15, 95% confidence interval -6.18 to -0.12, effect size = -0.84, p = 0.04), but not 12 weeks. Similarly, the CF intervention led to greater improvements in depression, suicidal ideation, optimism and gratitude at 6 and 12 weeks. Conclusions. Contrary to our hypothesis, the CF intervention was superior to PP in improving hopelessness, other suicide risk factors and positive psychological constructs during a key post-discharge period among suicidal patients with depression. Further study of this CF intervention is warranted in populations at high suicide risk. C1 [Celano, C. M.; Stewart, J. G.; Millstein, R. A.; Auerbach, R. P.; Bedoya, C. A.; Huffman, J. C.] Harvard Med Sch, Boston, MA USA. [Celano, C. M.; Beale, E. E.; Mastromauro, C. A.; Millstein, R. A.; Bedoya, C. A.; Huffman, J. C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Stewart, J. G.; Auerbach, R. P.] McLean Hosp, Dept Psychiat, 115 Mill St, Belmont, MA 02178 USA. RP Celano, CM (reprint author), Massachusetts Gen Hosp, Blake 11,55 Fruit St, Boston, MA 02114 USA. EM ccelano@partners.org FU American Foundation for Suicide Prevention [SRG-1-035-11]; National Heart, Lung and Blood Institute [K23HL123607, R01HL113272]; National Institute of Mental Health [K23MH097786] FX This research project was supported by the American Foundation for Suicide Prevention (grant no. SRG-1-035-11 to J.C.H.). Time for analysis and article preparation was also funded by the National Heart, Lung and Blood Institute through grants K23HL123607 (to C.M.C.) and R01HL113272 (to J.C.H.). The National Institute of Mental Health funded time and effort through grant K23MH097786 (to R.P.A.). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or other funders. NR 60 TC 0 Z9 0 U1 11 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD APR PY 2017 VL 47 IS 5 BP 810 EP 821 DI 10.1017/S0033291716002798 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EN9FC UT WOS:000396305100003 PM 27876105 ER PT J AU Gewirtz, H Dilsizian, V AF Gewirtz, Henry Dilsizian, Vasken TI Myocardial Viability Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia SO CIRCULATION RESEARCH LA English DT Review DE fluorodeoxyglucose; gene programs; mitochondria; molecular imaging; myocardial blood flow; myocardium; oxidant stress; renin-angiotensin-aldosterone system ID POSITRON-EMISSION-TOMOGRAPHY; CORONARY-ARTERY-DISEASE; CHRONIC HIBERNATING MYOCARDIUM; LEFT-VENTRICULAR DYSFUNCTION; FATTY-ACID-METABOLISM; RENIN-ANGIOTENSIN SYSTEM; ELECTRICAL POTENTIAL GRADIENT; RANDOMIZED CONTROLLED-TRIAL; PERFUSED RAT HEARTS; BLOOD-FLOW AB Myocardial responses to acute ischemia/reperfusion and to chronic ischemic conditions have been studied extensively at all levels of organization. These include subcellular (eg, mitochondria in vitro); intact, large animal models (eg, swine with chronic coronary stenosis); as well as human subjects. Investigations in humans have used positron emission tomographic metabolic and myocardial blood flow measurements, assessment of gene expression and anatomic description of myocardium obtained at the time of coronary artery revascularization, ventricular assist device placement, or heart transplantation. A multitude of genetic, molecular, and metabolic pathways have been identified, which may promote either myocyte survival or death or, most interestingly, both. Many of these potential mediators in both acute ischemia/reperfusion and adaptations to chronic ischemic conditions involve the mitochondria, which play a central role in cellular energy production and homeostasis. The present review is focused on operative survival mechanisms and potential myocardial viability molecular imaging targets in acute and chronic ischemia, especially those which impact mitochondrial function. C1 [Gewirtz, Henry] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Dilsizian, Vasken] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. RP Dilsizian, V (reprint author), Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. EM vdilsizian@umm.edu NR 146 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 31 PY 2017 VL 120 IS 7 BP 1197 EP 1212 DI 10.1161/CIRCRESAHA.116.307898 PG 16 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EQ0WP UT WOS:000397791600024 PM 28360350 ER PT J AU Venteicher, AS Tirosh, I Hebert, C Yizhak, K Neftel, C Filbin, MG Hovestadt, V Escalante, LE Shaw, ML Rodman, C Gillespie, SM Dionne, D Luo, CC Ravichandran, H Mylvaganam, R Mount, C Onozato, ML Nahed, BV Wakimoto, H Curry, WT Iafrate, AJ Rivera, MN Frosch, MP Golub, TR Brastianos, PK Getz, G Patel, AP Monje, M Cahill, DP Rozenblatt-Rosen, O Louis, DN Bernstein, BE Regev, A Suva, ML AF Venteicher, Andrew S. Tirosh, Itay Hebert, Christine Yizhak, Keren Neftel, Cyril Filbin, Mariella G. Hovestadt, Volker Escalante, Leah E. Shaw, McKenzie L. Rodman, Christopher Gillespie, Shawn M. Dionne, Danielle Luo, Christina C. Ravichandran, Hiranmayi Mylvaganam, Ravindra Mount, Christopher Onozato, Maristela L. Nahed, Brian V. Wakimoto, Hiroaki Curry, William T. Iafrate, A. John Rivera, Miguel N. Frosch, Matthew P. Golub, Todd R. Brastianos, Priscilla K. Getz, Gad Patel, Anoop P. Monje, Michelle Cahill, Daniel P. Rozenblatt-Rosen, Orit Louis, David N. Bernstein, Bradley E. Regev, Aviv Suva, Mario L. TI Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq SO SCIENCE LA English DT Article ID T-SEQ; REVEALS; TRANSCRIPTOMES; HETEROGENEITY; GENOMES; TISSUE; GENES; P53 AB Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses. C1 [Venteicher, Andrew S.; Hebert, Christine; Yizhak, Keren; Neftel, Cyril; Filbin, Mariella G.; Hovestadt, Volker; Escalante, Leah E.; Shaw, McKenzie L.; Gillespie, Shawn M.; Luo, Christina C.; Ravichandran, Hiranmayi; Mylvaganam, Ravindra; Onozato, Maristela L.; Iafrate, A. John; Rivera, Miguel N.; Frosch, Matthew P.; Getz, Gad; Louis, David N.; Bernstein, Bradley E.; Suva, Mario L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Venteicher, Andrew S.; Hebert, Christine; Yizhak, Keren; Neftel, Cyril; Filbin, Mariella G.; Hovestadt, Volker; Escalante, Leah E.; Shaw, McKenzie L.; Gillespie, Shawn M.; Luo, Christina C.; Ravichandran, Hiranmayi; Mylvaganam, Ravindra; Onozato, Maristela L.; Iafrate, A. John; Rivera, Miguel N.; Frosch, Matthew P.; Getz, Gad; Louis, David N.; Bernstein, Bradley E.; Suva, Mario L.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Venteicher, Andrew S.; Hebert, Christine; Yizhak, Keren; Neftel, Cyril; Filbin, Mariella G.; Hovestadt, Volker; Escalante, Leah E.; Shaw, McKenzie L.; Gillespie, Shawn M.; Luo, Christina C.; Ravichandran, Hiranmayi; Mylvaganam, Ravindra; Onozato, Maristela L.; Nahed, Brian V.; Wakimoto, Hiroaki; Curry, William T.; Iafrate, A. John; Rivera, Miguel N.; Frosch, Matthew P.; Brastianos, Priscilla K.; Getz, Gad; Patel, Anoop P.; Cahill, Daniel P.; Louis, David N.; Bernstein, Bradley E.; Suva, Mario L.] Harvard Med Sch, Boston, MA 02114 USA. [Venteicher, Andrew S.; Tirosh, Itay; Hebert, Christine; Yizhak, Keren; Neftel, Cyril; Filbin, Mariella G.; Hovestadt, Volker; Escalante, Leah E.; Shaw, McKenzie L.; Rodman, Christopher; Dionne, Danielle; Rivera, Miguel N.; Golub, Todd R.; Getz, Gad; Rozenblatt-Rosen, Orit; Bernstein, Bradley E.; Regev, Aviv; Suva, Mario L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Venteicher, Andrew S.; Nahed, Brian V.; Wakimoto, Hiroaki; Curry, William T.; Patel, Anoop P.; Cahill, Daniel P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Neftel, Cyril] CHU Vaudois, Fac Biol & Med, Inst Pathol, CH-1011 Lausanne, Switzerland. [Filbin, Mariella G.; Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Filbin, Mariella G.; Golub, Todd R.] Childrens Hosp, Ctr Canc, Boston, MA 02215 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Dept Neurol, Sch Med, Stanford, CA 94305 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Mount, Christopher; Monje, Michelle] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Golub, Todd R.; Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Regev, Aviv] MIT, Koch Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Regev, Aviv] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Suva, ML (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Suva, ML (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.; Suva, ML (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Tirosh, I; Regev, A; Suva, ML (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Regev, A (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA.; Regev, A (reprint author), MIT, Koch Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Regev, A (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM tirosh@broadinstitute.org; aregev@broadinstitute.org; suva.mario@mgh.harvard.edu FU Smith Family Foundation; V Foundation for Cancer Research; Merkin Institute Fellows at the Bead Institute; American Cancer Society; NIH-NCI brain cancer SPORE [P50CA165962]; Broad Institute Broadnext10 program; National Brain Turner Society; Rachel Molly Markoff Foundation; NIH [NS065743]; American Brain. Tumor Association and Neurosurgery Research and Education Foundation; Human Frontier Science Program fellowship; Rothschild fellowship; Placide Nicod Foundation; EMBO long-term fellowship; Burroughs-Wellcome Fund CAMS; K12 Paul Calabresi Career Award for Clinical Oncology Training Program in Nervous System Tumors [K12CA090354]; Hughes Medical Institute; Klarman Family Foundation; STARR cancer consortium; NCI [1U24CA180922, R33CA202820]; Koch Institute Support from NCI [P30-CA14051]; Ludwig Center; Me Broad Institute; Burroughs-Wellcome Fund CAMS [BPIF 1007616.02]; California Institute of Regenerative Medicine [RB4-06093, RN3-06510]; Virginia and D. K. Ludwig Fund for Cancer Research; MGH Department of Pathology; [1S10RR023440-01A1] FX We thank L. Gaffney, L. Friedman, and A. We thank L. Gaffney, L. Friedman, and A. Hupalowska for assistance with design of figures. Supported by the Smith Family Foundation, the V Foundation for Cancer Research, the Merkin Institute Fellows at the Bead Institute, the American Cancer Society, and NIH-NCI brain cancer SPORE P50CA165962 (Developmental Research Project) (M.L.S.); the Broad Institute Broadnext10 program (M.L.S. and O.R.-R.): the National Brain Turner Society (M.L.S. and D.N.L.); the Rachel Molly Markoff Foundation (M.L.S. and B.E.B.); NIH R25 fellowship NS065743 and research grants from the American Brain. Tumor Association and Neurosurgery Research and Education Foundation (A.S.V.); a Human Frontier Science Program fellowship and a Rothschild fellowship (I.T.); the Placide Nicod Foundation (C.N.); an EMBO long-term fellowship (V.H.); the Burroughs-Wellcome Fund CAMS and K12 Paul Calabresi Career Award for Clinical Oncology Training Program in Nervous System Tumors grant K12CA090354 (M.G.F.); the Howard Hughes Medical Institute, the Klarman Family Foundation, STARR cancer consortium, NCI grants 1U24CA180922 and R33CA202820, and Koch Institute Support (core) grant P30-CA14051 from NCI, the Ludwig Center and Me Broad Institute (A.R.); Burroughs-Wellcome Fund CAMS grant BPIF 1007616.02 (D.P.C.); California Institute of Regenerative Medicine grants RB4-06093 and RN3-06510 and the Virginia and D. K. Ludwig Fund for Cancer Research (M.M.); and start-up funds from the MGH Department of Pathology. Flow cytometry and sorting services were supported by shared instrumentation grant 1S10RR023440-01A1. A.R. is a scientific advisory board member for ThermoFisher Scientific and Syros Pharmaceuticals and a consultant for Driver Group. A.S.V., A.R., B.E.B., I.T., M.L.S., and O.R.-R.. are inventors on patent application PCT/0517/14995 submitted by the Broad Institute, MIT, and MGH that covers certain subject matter of this manuscript, including gene signatures and application to development of therapeutics. A.J.I. holds equity in ArcherDx. Data generated for this study are available through the Gene Expression Omnibus (GEO) under accession number GSE89567. NR 31 TC 0 Z9 0 U1 0 U2 0 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 MAR 31 PY 2017 VL 355 IS 6332 BP 1391 EP + AR eaai8478 DI 10.1126/science.aai8478 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EQ1DL UT WOS:000397809500034 ER PT J AU Kamphorst, AO Wieland, A Nasti, T Yang, S Zhang, R Barber, DL Konieczny, BT Daugherty, CZ Koenig, L Yu, K Sica, GL Sharpe, AH Freeman, GJ Blazar, BR Turka, LA Owonikoko, TK Pillai, RN Ramalingam, SS Araki, K Ahmed, R AF Kamphorst, Alice O. Wieland, Andreas Nasti, Tahseen Yang, Shu Zhang, Ruan Barber, Daniel L. Konieczny, Bogumila T. Daugherty, Candace Z. Koenig, Lydia Yu, Ke Sica, Gabriel L. Sharpe, Arlene H. Freeman, Gordon J. Blazar, Bruce R. Turka, Laurence A. Owonikoko, Taofeek K. Pillai, Rathi N. Ramalingam, Suresh S. Araki, Koichi Ahmed, Rafi TI Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent SO SCIENCE LA English DT Article ID CHRONIC VIRAL-INFECTION; RESPONSES; IMMUNITY; CANCER; PD-1; COSTIMULATION; BLOCKADE; EFFECTOR; MEMORY AB Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients. C1 [Kamphorst, Alice O.; Wieland, Andreas; Nasti, Tahseen; Yang, Shu; Barber, Daniel L.; Konieczny, Bogumila T.; Daugherty, Candace Z.; Araki, Koichi; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Yang, Shu] Cent S Univ, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China. [Zhang, Ruan; Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02144 USA. [Zhang, Ruan; Turka, Laurence A.] Harvard Med Sch, Boston, MA 02144 USA. [Barber, Daniel L.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Koenig, Lydia; Yu, Ke; Owonikoko, Taofeek K.; Pillai, Rathi N.; Ramalingam, Suresh S.] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Sica, Gabriel L.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Yang, Shu] Tianjin Med Univ, Gen Hosp, Dept Neurol, Tianjin 300052, Peoples R China. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. EM rahmed@emory.edu OI Nasti, Tahseen/0000-0002-5650-1563 FU Merck [52507]; National Institutes of Health [R01 AI30048, P01 AI080192, P01 AI056299, P01 AI054456, R01 AI089955, R01 CA72669, R01 AI037691] FX This work was supported by Merck preclinical grant 52507 (R.A. and A.O.K.) and the National Institutes of Health grants R01 AI30048 (R.A.), P01 AI080192 (R.A. and G.J.F.), P01 AI056299 (A.H.S., R.A., G.J.F., and B.R.B.), P01 AI054456 (A.H.S.), R01 AI089955 (G.J.F.), R01 CA72669 (B.R.B.), and R01 AI037691 (L.A.T. and R.Z.). The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. We thank M. Ford (Emory University) for reagents and E. Eruslanov (University of Pennsylvania School of Medicine) for experimental advice. R.A., D.L.B., G.J.F., and A.H.S. are inventors on patent numbers US 8552154 B2, US 8652465 B2, and US 9102727 B2, held by Emory University (Atlanta), Dana-Farber Cancer Institute (Boston), Brigham and Women's Hospital (Boston), and Harvard University (Cambridge), which cover the topic of PD-1-directed immunotherapy. G.F. is the inventor on patent numbers US 6,808,710, US 7,101,550, US 7,638,492, US 7,700,301, US 7,432,059, US 7,709,214, US 7,722,868, US 7,635,757, US 7,038,013, US 6,936,704, and US 7,105,328 held by Dana-Farber Cancer Institute, which cover the topic of PD-1-directed immunotherapy. NR 25 TC 2 Z9 2 U1 0 U2 0 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 MAR 31 PY 2017 VL 355 IS 6332 BP 1423 EP 1427 DI 10.1126/science.aaf0683 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EQ1DL UT WOS:000397809500043 PM 28280249 ER PT J AU Jimenez, AM Lee, J Green, MF Wynn, JK AF Jimenez, Amy M. Lee, Junghee Green, Michael F. Wynn, Jonathan K. TI Functional connectivity when detecting rare visual targets in schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE fMRI; Psychophysiological interaction; Attention; Salience; Oddball; Target detection ID EVENT-RELATED FMRI; VENTRAL ATTENTION SYSTEMS; NEGATIVE SYMPTOMS; BRAIN NETWORKS; HEMODYNAMIC-RESPONSES; ODDBALL FMRI; SEARCH; DORSAL; P300; TASK AB Individuals with schizophrenia demonstrate difficulties in attending to important stimuli (e.g., targets) and ignoring distractors (e.g., non-targets). We used a visual oddball task during fMRI to examine functional connectivity within and between the ventral and dorsal attention networks to determine the relative contribution of each network to detection of rare visual targets in schizophrenia. The sample comprised 25 schizophrenia patients and 27 healthy controls. Psychophysiological interaction analysis was used to examine whole-brain functional connectivity in response to targets. We used the right temporo parietal junction (TPJ) as the seed region for the ventral network and the right medial intraparietal sulcus (IPS) as the seed region for the dorsal network. We found that connectivity between right IPS and right anterior insula (AI; a component of the ventral network) was significantly greater in controls than patients. Expected patterns of within-and between network connectivity for right TPJ were observed in controls, and not significantly different in patients. These findings indicate functional connectivity deficits between the dorsal and ventral attention networks in schizophrenia that may create problems in processing relevant versus irrelevant stimuli. Understanding the nature of network disruptions underlying cognitive deficits of schizophrenia may help shed light on the pathophysiology of this disorder. C1 [Jimenez, Amy M.; Lee, Junghee; Green, Michael F.; Wynn, Jonathan K.] VA Greater Los Angeles Healthcare Syst, Desert Pacific MIRECC, Los Angeles, CA USA. [Jimenez, Amy M.; Lee, Junghee; Green, Michael F.; Wynn, Jonathan K.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Jimenez, AM (reprint author), VA Greater Los Angeles Healthcare Syst, MIRECC, Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM amjimenez@ucla.edu FU VA Career Development Award; NIMH [MH43292, MH065707] FX This research was supported by a VA Career Development Award to Jonathan K. Wynn, Ph.D. and NIMH Grants MH43292 and MH065707 (PI: Michael F. Green, Ph.D.). Writing of this manuscript was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs. For generous support, we also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson -Lovelace Foundation, The Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, and Northstar Fund. The authors thank Poorang Nori and Crystal Gibson for assistance in data collection. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. These data were presented, in part, as a poster at the 2015 Annual Meeting of the Society for Research in Psychopathology. NR 77 TC 0 Z9 0 U1 1 U2 1 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 MAR 30 PY 2017 VL 261 BP 35 EP 43 DI 10.1016/j.pscychresns.2017.01.007 PG 9 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EN4DT UT WOS:000395958900005 PM 28126618 ER PT J AU Allister, LM Lim, R Goldstein, AM Lennerz, JK AF Allister, Lauren M. Lim, Ruth Goldstein, Allan M. Lennerz, Jochen K. TI Case 10-2017: A 6-Month-Old Boy with Gastrointestinal Bleeding and Abdominal Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MECKELS-DIVERTICULUM C1 [Allister, Lauren M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Lim, Ruth] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Goldstein, Allan M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lennerz, Jochen K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Allister, Lauren M.] Harvard Med Sch, Dept Emergency Med, Boston, MA 02115 USA. [Lim, Ruth] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Goldstein, Allan M.] Harvard Med Sch, Dept Surg, Boston, MA USA. [Lennerz, Jochen K.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Allister, LM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA.; Allister, LM (reprint author), Harvard Med Sch, Dept Emergency Med, Boston, MA 02115 USA. NR 14 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 MAR 30 PY 2017 VL 376 IS 13 BP 1269 EP 1277 DI 10.1056/NEJMcpc1616020 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EP8KS UT WOS:000397624900012 PM 28355500 ER PT J AU Losman, JA AF Losman, Julie-Aurore TI CANCER THERAPY The leukaemia epigenome targeted SO NATURE LA English DT Editorial Material ID MUTATIONS C1 [Losman, Julie-Aurore] Harvard Univ, Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Losman, JA (reprint author), Harvard Univ, Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM julieaurore_losman@dfci.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 30 PY 2017 VL 543 IS 7647 BP 634 EP 635 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP8IS UT WOS:000397619700040 PM 28358070 ER PT J AU Srinivasainagendra, V Sandel, MW Singh, B Sundaresan, A Mooga, VP Bajpai, P Tiwari, HK Singh, KK AF Srinivasainagendra, Vinodh Sandel, Michael W. Singh, Bhupendra Sundaresan, Aishwarya Mooga, Ved P. Bajpai, Prachi Tiwari, Hemant K. Singh, Keshav K. TI Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma SO GENOME MEDICINE LA English DT Article DE Cancer; Tumor; Colorectal cancer; Mitochondria; Mitochondrial DNA; YME1L1; NUMT; Numtogenesis; mtDNA transfer; Genetic instability ID HUMAN MYOCARDIAL-CELLS; HUMAN GENETIC-DISEASE; SACCHAROMYCES-CEREVISIAE; INTRANUCLEAR MITOCHONDRIA; CANCER-CELLS; COPY NUMBER; DYSFUNCTION; MUTATIONS; TRANSFORMATION; PSEUDOGENES AB Background: Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description of NUMT abundance and distribution in tumor versus matched blood-derived normal genomes. Methods: Whole-genome sequence data were obtained for colon adenocarcinoma and rectum adenocarcinoma patients participating in The Cancer Genome Atlas, via the Cancer Genomics Hub, using the GeneTorrent file acquisition tool. Data were analyzed to determine NUMT proportion and distribution on a genome-wide scale. A NUMT suppressor gene was identified by comparing numtogenesis in other organisms. Results: Our study reveals that colorectal adenocarcinoma genomes, on average, contains up to 4.2-fold more somatic NUMTs than matched normal genomes. Women colorectal tumors contained more NUMT than men. NUMT abundance in tumor predicted parallel abundance in blood. NUMT abundance positively correlated with GC content and gene density. Increased numtogenesis was observed with higher mortality. We identified YME1L1, a human homolog of yeast YME1 (yeast mitochondrial DNA escape 1) to be frequently mutated in colorectal tumors. YME1L1 was also mutated in tumors derived from other tissues. We show that inactivation of YME1L1 results in increased transfer of mtDNA in the nuclear genome. Conclusions: Our study demonstrates increased somatic transfer of mtDNA in colorectal tumors. Our study also reveals sex-based differences in frequency of NUMT occurrence and that NUMT in blood reflects NUMT in tumors, suggesting NUMT may be used as a biomarker for tumorigenesis. We identify YME1L1 as the first NUMT suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. Our study reveals that numtogenesis plays an important role in the development of cancer. C1 [Srinivasainagendra, Vinodh; Sandel, Michael W.; Sundaresan, Aishwarya; Tiwari, Hemant K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostatist, Birmingham, AL 35294 USA. [Singh, Bhupendra; Mooga, Ved P.; Bajpai, Prachi] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Genet, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Pathol, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Environm Hlth, Birmingham, AL 35294 USA. [Singh, Keshav K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Singh, Keshav K.] Univ Alabama Birmingham, Sch Med, Dept Genet, Kaul Genet Bldg,Suite 620,720 20th St South, Birmingham, AL 35294 USA. [Sandel, Michael W.] Univ West Alabama, Sch Nat Sci & Math, Dept Biol & Environm Sci, Livingston, NJ USA. RP Tiwari, HK (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostatist, Birmingham, AL 35294 USA.; Singh, KK (reprint author), Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Genet, Birmingham, AL 35294 USA.; Singh, KK (reprint author), Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Pathol, Birmingham, AL 35294 USA.; Singh, KK (reprint author), Univ Alabama Birmingham, Ctr Aging & UAB Comprehens Canc Ctr, Ctr Free Radical Biol, Dept Environm Hlth, Birmingham, AL 35294 USA.; Singh, KK (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA.; Singh, KK (reprint author), Univ Alabama Birmingham, Sch Med, Dept Genet, Kaul Genet Bldg,Suite 620,720 20th St South, Birmingham, AL 35294 USA. EM htiwari@uab.edu; kksingh@uab.edu FU Veterans Administration [1I01BX001716]; NCTN-LAPS Program Translational Research Award; [T32HL072757] FX This study was supported by grants from the Veterans Administration 1I01BX001716 and a NCTN-LAPS Program Translational Research Award to KKS and T32HL072757 (PI: HKT) to MWS. NR 88 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 1756-994X J9 GENOME MED JI Genome Med. PD MAR 29 PY 2017 VL 9 AR 31 DI 10.1186/s13073-017-0420-6 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA EP9ZA UT WOS:000397730300001 PM 28356157 ER PT J AU Carnicelli, AP De Caterina, R Halperin, JL Renda, G Ruff, CT Trevisan, M Nordio, F Mercuri, MF Antman, E Giugliano, RP AF Carnicelli, Anthony P. De Caterina, Raffaele Halperin, Jonathan L. Renda, Giulia Ruff, Christian T. Trevisan, Marco Nordio, Francesco Mercuri, Michele F. Antman, Elliott Giugliano, Robert P. CA ENGAGE AF-TIMI 48 Investigators TI Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves SO CIRCULATION LA English DT Letter DE anticoagulation; atrial fibrillation; bioprosthetic valve; edoxaban; warfarin ID WARFARIN C1 [Carnicelli, Anthony P.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [De Caterina, Raffaele; Renda, Giulia] Univ G DAnnunzio, Inst Cardiol, Chieti, Italy. [De Caterina, Raffaele; Renda, Giulia] Univ G DAnnunzio, Ctr Excellence Aging, Chieti, Italy. [Halperin, Jonathan L.] Icahn Sch Med Mt Sinai, Mt Sinai Hosp, New York, NY 10029 USA. [Ruff, Christian T.; Trevisan, Marco; Nordio, Francesco; Antman, Elliott; Giugliano, Robert P.] TIMI Study Grp Throm Bolysis Myocardial Infarct, Boston, MA USA. Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM rgiugliano@partners.org FU Daiichi Sankyo FX The ENGAGE AF-TIMI 48 trial was supported by a research grant from Daiichi Sankyo to the Brigham and Women's Hospital. All analyses were conducted independently by the Thrombolysis In Myocardial Infarction (TIMI) Study Group, and all authors had full access to the data. The authors are fully responsible for the study design, data collection, analysis and interpretation of the data, and the writing of the manuscript. The sponsor played no role in the decision to submit the manuscript for publication. 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 MAR 28 PY 2017 VL 135 IS 13 BP 1273 EP 1275 DI 10.1161/CIRCULATIONAHA.116.026714 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EP4YY UT WOS:000397387200020 PM 28209729 ER PT J AU El-Jawahri, A Temel, JS AF El-Jawahri, Areej Temel, Jennifer S. TI Inpatient Palliative Care After Hematopoietic Stem Cell Transplantation In Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID BONE-MARROW-TRANSPLANTATION C1 [El-Jawahri, Areej; Temel, Jennifer S.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP El-Jawahri, A (reprint author), Dept Hematol, Oncol Bone Marrow Transplant Program, 55 Fruit St,Cox 120, Boston, MA 02114 USA. EM ael-jawahri@partners.org NR 5 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 MAR 28 PY 2017 VL 317 IS 12 BP 1276 EP 1276 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EP7KX UT WOS:000397557800028 PM 28350921 ER PT J AU Lau, ES Braunwald, E Murphy, SA Wiviott, SD Bonaca, MP Husted, S James, SK Wallentin, L Clemmensen, P Roe, MT Ohman, EM Harrington, RA Mega, JL Bhatt, DL Sabatine, MS O'Donoghue, ML AF Lau, Emily S. Braunwald, Eugene Murphy, Sabina A. Wiviott, Stephen D. Bonaca, Marc P. Husted, Steen James, Stefan K. Wallentin, Lars Clemmensen, Peter Roe, Matthew T. Ohman, E. Magnus Harrington, Robert A. Mega, Jessica L. Bhatt, Deepak L. Sabatine, Marc S. O'Donoghue, Michelle L. TI Potent P2Y(12) Inhibitors in Men Versus Women A Collaborative Meta-Analysis of Randomized Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ACUTE CORONARY SYNDROMES; GLYCOPROTEIN IIB/IIIA INHIBITORS; RAPID RISK STRATIFICATION; SUPPRESS ADVERSE OUTCOMES; PLATELET INHIBITION; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; EARLY IMPLEMENTATION; CLINICAL-TRIALS; SEX-DIFFERENCES AB BACKGROUND Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain. OBJECTIVES The study investigated the efficacy and safety of the potent P2Y(12) inhibitors in patients with coronary artery disease. METHODS A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y(12) inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial. RESULTS Potent P2Y(12) inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y(12) inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62). CONCLUSIONS In randomized trials, the efficacy and safety of the potent P2Y(12) inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y(12) inhibitors. (C) 2017 by the American College of Cardiology Foundation. C1 [Lau, Emily S.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Braunwald, Eugene; Murphy, Sabina A.; Wiviott, Stephen D.; Bonaca, Marc P.; Bhatt, Deepak L.; Sabatine, Marc S.; O'Donoghue, Michelle L.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 60 Fenwood Rd,7th Floor, Boston, MA 02115 USA. [Husted, Steen] Arhus Univ Hosp, Dept Cardiol, Aarhus, Denmark. [James, Stefan K.; Wallentin, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [James, Stefan K.; Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Clemmensen, Peter] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Clemmensen, Peter] Univ Southern Denmark, Nykoebing Hosp F, Dept Med, Odense, Denmark. [Roe, Matthew T.; Ohman, E. Magnus] Duke Clin Res Inst, Div Cardiol, Durham, NC USA. [Harrington, Robert A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Mega, Jessica L.] Verily Life Sci, Mountain View, CA USA. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 60 Fenwood Rd,7th Floor, Boston, MA 02115 USA. EM modonoghue@partners.org FU Eli Lilly; Daiichi-Sankyo; AstraZeneca; Medicines Company; Novartis; Merck; GlaxoSmithKline; Amgen; Arena; Bristol-Myers Squibb; Eisai; Janssen; Sanofi; Bayer; Boehringer Ingelheim; Pfizer; Janssen/Bayer; Roche; Schering-Plough; Bristol-Myers Squibb/Pfizer; Abbott; Aventis; Fibrex; Myogen; Medtronic; Nycomed; Organon; Pharmacia; Regado; Sarle; Servier; Gilead Sciences; Janssen Pharmaceuticals; CSL; Johnson Johnson; Portola; Amarin; Ethicon; Forest Laboratories; Ischemix; Critical Diagnostics; Intarcia; Poxel; Janssen Research Development; MedImmune FX The TRITON-TIMI 38 trial was funded by grant support through Eli Lilly and Daiichi-Sankyo. The PLATO trial was funded by AstraZeneca. The TRILOGY-ACS trial was funded by grant support through Eli Lilly and Daiichi-Sankyo. The CHAMPION PHOENIX trial was funded by The Medicines Company. The PEGASUS-TIMI 54 trial was funded by AstraZeneca. Dr. Braunwald has received research grant support from Eli Lilly, AstraZeneca, Novartis, Merck, Daiichi-Sankyo, and GlaxoSmithKline; uncompensated consultancies and lectures with Merck and Novartis; and consultancies with The Medicines Company and Theravance. Dr. Wiviott has received research funding from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; has been a consultant for Arena, Aegerion, Allergan, Angelmed, Aralez, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Icon Clinical, Janssen, Lexicon, and Xoma. Dr. Bonaca serves as a consultant for AstraZeneca, Merck, Bayer, and Roche Diagnostics. Dr. Husted has received consulting fees, honoraria, or both from AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer; and grant support from GlaxoSmithKline. Dr. James has received institutional research grants from AstraZeneca and The Medicines Company; and honoraria from AstraZeneca and Janssen/Bayer. Dr. Wallentin has received research grants to his institution from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck, Roche, and Schering-Plough; has been a consultant for Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; receives lecture fees and travel support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; and holds patents involving GDF-15. Dr. Clemmensen has received research funding from Abbott, AstraZeneca, Aventis, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Fibrex, Janssen, Merck, Myogen, Medtronic, The Medicines Company, Nycomed, Organon, Pfizer, Pharmacia, Regado, Sanofi, Sarle, and Servier; speaker fees from Abbott, AstraZeneca, Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck, Medtronic, The Medicines Company, Nycomed, Pfizer, Pharmacia, Sanofi, and Servier; and served on advisory boards for AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, DaiichiSankyo, Eli Lilly, Evolva, Merck, Medtronic, Mitsubishi Pharma, TheMedicines Company, Nycomed, Pfizer, Pharmacia, Sanofi, and Servier. Dr. Roe has received research grants or contracts from AstraZeneca, Eli Lilly & Company, Janssen Pharmaceuticals, Sanofi, Daiichi-Sankyo, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals; has lectured for Amgen and Bristol-Myers Squibb; and has served as a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Merck & Co., Daiichi-Sankyo, Elsevier Publishers, PriMed, and MyoKardia. Dr. Ohman has received research grants from Daiichi-Sankyo, Gilead Sciences, and Janssen Pharmaceuticals; and has been a consultant for Abiomed, Abbott Vascular, AstraZeneca, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Faculty Connection, Merck, St. Jude Medical, Stealth Peptides, The Medicines Company, and Medscape. Dr.; Harrington has received research grants from AstraZeneca, Bristol-Myers Squibb, CSL, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Portola, Sanofi, The Medicines Company, Regado, and Janssen Pharmaceuticals; and has been a consultant/advisor for Amgen, Bristol-Myers Squibb, Gilead, Johnson & Johnson, Merck, MyoKardia, The Medicines Company, and WebMD. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; has served on the boards of directors of the Boston VA Research Institute and Society of Cardiovascular Patient Care; has chaired the American Heart Association Quality Oversight Committee; has served on the data monitoring committees of the Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (vice-chair), VA CART Research and Publications Committee (chair); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company (including for his role as co-chair of the CHAMPION PHOENIX trial); has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); has served as site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Sabatine has received research grants to his institution from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi, Takeda, Novartis, Poxel, Janssen Research Development, and MedImmune; and has been a consultant for Alnylam, AstraZeneca, CVS Caremark, Merck, and Ionis. Dr. O'Donoghue has received research grant support from GlaxoSmithKline, Eisai, Merck, Janssen, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of the paper to disclose. Stephen Ellis, MD, served as Guest Editor for this paper. NR 36 TC 1 Z9 1 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 MAR 28 PY 2017 VL 69 IS 12 BP 1549 EP 1559 DI 10.1016/j.jacc.2017.01.028 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO5JW UT WOS:000396730200005 PM 28335837 ER PT J AU Cheezum, MK Liberthson, RR Shah, NR Villines, TC O'Gara, PT Landzberg, MJ Blankstein, R AF Cheezum, Michael K. Liberthson, Richard R. Shah, Nishant R. Villines, Todd C. O'Gara, Patrick T. Landzberg, Michael J. Blankstein, Ron TI Anomalous Aortic Origin of a Coronary Artery From the Inappropriate Sinus of Valsalva SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE anomalous coronary artery; interarterial; management; outcomes; prevalence; sudden cardiac death ID AMERICAN-HEART-ASSOCIATION; COLLEGE-OF-CARDIOLOGY; SUDDEN CARDIAC DEATH; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; CARDIOVASCULAR MAGNETIC-RESONANCE; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; OPPOSITE SINUS; TASK-FORCE; SCIENTIFIC STATEMENT; INTERARTERIAL COURSE AB Anomalous aortic origin of a coronary artery (AAOCA) from the inappropriate sinus of Valsalva is increasingly recognized by cardiac imaging. Although most AAOCA subtypes are benign, autopsy studies report an associated risk of sudden death with interarterial anomalous left coronary artery (ALCA) and anomalous right coronary artery (ARCA). Despite efforts to identify high-risk ALCA and ARCA patients who may benefit from surgical repair, debate remains regarding their classification, prevalence, risk stratification, and management. We comprehensively reviewed 77 studies reporting the prevalence of AAOCA among >1 million patients, and 20 studies examining outcomes of interarterial ALCA/ARCA patients. Observational data suggests that interarterial ALCA is rare (weighted prevalence = 0.03%; 95% confidence interval [CI]: 0.01% to 0.04%) compared with interarterial ARCA (weighted prevalence = 0.23%; 95% CI: 0.17% to 0.31%). Recognizing the challenges in managing these patients, we review cardiac tests used to examine AAOCA and knowledge gaps in management. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Cheezum, Michael K.; O'Gara, Patrick T.; Blankstein, Ron] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Cheezum, Michael K.; O'Gara, Patrick T.; Blankstein, Ron] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Dept Radiol, Boston, MA USA. [Cheezum, Michael K.] Ft Belvoir Community Hosp, Serv Cardiol, Dept Med, Ft Belvoir, VA USA. [Liberthson, Richard R.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [Shah, Nishant R.] Brown Univ, Dept Med, Alpert Sch Med, Lifespan Cardiovasc Inst,Div Cardiovasc Med, Providence, RI 02912 USA. [Villines, Todd C.] Walter Reed Natl Mil Med Ctr, Serv Cardiol, Dept Med, Bethesda, MD USA. [Landzberg, Michael J.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. RP Cheezum, MK (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM mcheezum@gmail.com NR 102 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 MAR 28 PY 2017 VL 69 IS 12 BP 1592 EP 1608 DI 10.1016/j.jacc.2017.01.031 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO5JW UT WOS:000396730200011 PM 28335843 ER PT J AU Toribio, M Fitch, KV Sanchez, L Burdo, TH Williams, KC Sponseller, CA Pate, MM Aberg, JA Zanni, MV Grinspoon, SK AF Toribio, Mabel Fitch, Kathleen V. Sanchez, Laura Burdo, Tricia H. Williams, Kenneth C. Sponseller, Craig A. Pate, Mary McCurdy Aberg, Judith A. Zanni, Markella V. Grinspoon, Steven K. TI Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV SO AIDS LA English DT Article DE atherosclerosis; cardiovascular disease; HIV; inflammation; statin ID LOW-DENSITY-LIPOPROTEIN; ANTIRETROVIRAL THERAPY; MONOCYTE ACTIVATION; PHOSPHOLIPASE A(2); INFECTED PATIENTS; T-CELL; VASCULAR INFLAMMATION; CORONARY PLAQUE; STATIN THERAPY; SOLUBLE CD163 AB Objective: Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population. Design: Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites. Methods: Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4mg daily vs. pravastatin 40mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials. gov (NCT01301066). Results: One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 +/- 0.2 copies/ml, and CD4(+) cell count was 580 (439, 794) cells/mu l. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P=0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P-0.005) (pitavastatin vs. pravastatin). Conclusion: Fifty-two weeks of pitavastatin 4mg daily (vs. pravastatin 40mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Toribio, Mabel; Fitch, Kathleen V.; Sanchez, Laura; Zanni, Markella V.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr & Metab, Boston, MA 02114 USA. [Toribio, Mabel; Fitch, Kathleen V.; Sanchez, Laura; Zanni, Markella V.; Grinspoon, Steven K.] Harvard Med Sch, Boston, MA USA. [Burdo, Tricia H.; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Burdo, Tricia H.] Temple Univ, Sch Med, Dept Neurosci, Philadelphia, PA USA. [Aberg, Judith A.] Icahn Sch Med Mt Sinai, Div Infect Dis, Mt Sinai Dept Med, New York, NY 10029 USA. [Sponseller, Craig A.; Pate, Mary McCurdy] KOWA Pharmaceut Amer Inc, Montgomery, AL USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 5 Longfellow Pl,Room 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU KOWA Pharmaceuticals America, Inc.; NIH the Nutrition Obesity Research Center at Harvard [P30 DK040561]; National Institutes of Health [T32DK007028-41] FX This study was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and NIH P30 DK040561 the Nutrition Obesity Research Center at Harvard. M.T. was supported by the National Institutes of Health [T32DK007028-41]. NR 32 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2017 VL 31 IS 6 BP 797 EP 806 DI 10.1097/QAD.0000000000001427 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4UW UT WOS:000396003400008 PM 28252528 ER PT J AU Patra, A Chen, XD Sadowska, GB Zhang, JY Lim, YP Padbury, JF Banks, WA Stonestreet, BS AF Patra, Aparna Chen, Xiaodi Sadowska, Grazyna B. Zhang, Jiyong Lim, Yow-Pin Padbury, James F. Banks, William A. Stonestreet, Barbara S. TI NEUTRALIZING ANTI-INTERLEUKIN-1 beta ANTIBODIES REDUCE ISCHEMIA-RELATED INTERLEUKIN-1 beta TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER IN FETAL SHEEP SO NEUROSCIENCE LA English DT Article DE blood-brain barrier; cytokines; interleukin-1 beta; fetus; hypoxia-ischemia; sheep ID EXTREMELY PRETERM INFANTS; NECROSIS-FACTOR-ALPHA; WHITE-MATTER INJURY; IN-OVINE FETUSES; NEONATAL ENCEPHALOPATHY; INFLAMMATORY CYTOKINES; PROTEIN EXPRESSION; CEREBRAL-ISCHEMIA; ENDOTHELIAL-CELLS; TNF-ALPHA AB Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1 beta (IL-1 beta) is a key mediator of inflammatory responses and elevated IL-1b levels in brain correlate with adverse neuro developmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1 beta monoclonal antibody (mAb) reduce IL-1 beta transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo-or anti-IL-1 beta mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1 beta protein expressed from IL-1 beta pGEX-2T vectors in Escherichia coli (E.coli) BL-21 cells was produced, purified, and radiolabeled with (125) I. BBB permeability was quantified using the blood-to-brain transfer constant (K-i) with I-125-radiolabeled-IL-1 beta. Increases in antiIL-1 beta mAb were observed in the brain of the mAb-treated group (P < 0.001). Blood-to-brain transport of I-125-IL-1 beta was lower (P < 0.04) across brain regions in the anti-IL-1 beta mAb-treated than placebo-treated ischemic fetuses. Plasma I-125-IL-1 beta counts were higher (P < 0.001) in the anti-IL-1 beta mAb-than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1 beta mAb reduce IL-1 beta transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic proinflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Patra, Aparna; Chen, Xiaodi; Sadowska, Grazyna B.; Zhang, Jiyong; Padbury, James F.; Stonestreet, Barbara S.] Brown Univ, Women & Infants Hosp Rhode Isl, Alpert Med Sch, Pediat, Providence, RI 02905 USA. [Lim, Yow-Pin] ProThera Biol, Providence, RI 02903 USA. [Banks, William A.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98104 USA. [Patra, Aparna] Univ Kentucky, Dept Pediat, 138 Leader Ave,Room 10C, Lexington, KY 40508 USA. RP Stonestreet, BS (reprint author), Brown Univ, Women & Infants Hosp Rhode Isl, Alpert Med Sch, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM aparna.patra@uky.edu; bstonestreet@wihri.org FU National Institute of General Medical Sciences of the National Institutes of Health [1R01-HD-057100, P20 RR018728, P20GM103537]; American Heart Association [13POST16860015] FX Research summarized in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number 1R01-HD-057100, by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 RR018728 and P20GM103537, and by a postdoctoral fellowship award (J.Z.) from the American Heart Association under grant number 13POST16860015. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 65 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 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 27 PY 2017 VL 346 BP 113 EP 125 DI 10.1016/j.neuroscience.2016.12.051 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EN1SK UT WOS:000395790100011 PM 28089577 ER PT J AU Cai, WK Sakaguchi, M Kleinridders, A Gonzalez-Del Pino, G Dreyfuss, JM O'Neill, BT Ramirez, AK Pan, H Winnay, JN Boucher, J Eck, MJ Kahn, CR AF Cai, Weikang Sakaguchi, Masaji Kleinridders, Andre Gonzalez-Del Pino, Gonzalo Dreyfuss, Jonathan M. O'Neill, Brian T. Ramirez, Alfred K. Pan, Hui Winnay, Jonathon N. Boucher, Jeremie Eck, Michael J. Kahn, C. Ronald TI Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression SO NATURE COMMUNICATIONS LA English DT Article ID GROWTH-FACTOR-I; JUXTAMEMBRANE REGION; CYTOPLASMIC DOMAINS; MICROARRAY ANALYSIS; LIGAND-BINDING; BETA-SUBUNIT; INTERNALIZATION; KINASE; MICE; SHC AB Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation. Strikingly, replacement of leucine(973) in the juxtamembrane region of IR to phenylalanine, which is present in IGF1R, mimics many of these signalling and gene expression responses. Overall, we show that the distinct activities of the closely related IR and IGF1R are mediated by their intracellular juxtamembrane region and substrate binding to this region. C1 [Cai, Weikang; Sakaguchi, Masaji; Kleinridders, Andre; O'Neill, Brian T.; Ramirez, Alfred K.; Winnay, Jonathon N.; Boucher, Jeremie; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Cai, Weikang; Sakaguchi, Masaji; Kleinridders, Andre; O'Neill, Brian T.; Ramirez, Alfred K.; Winnay, Jonathon N.; Boucher, Jeremie; Kahn, C. Ronald] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Kleinridders, Andre] German Inst Human Nutr, Cent Regulat Metab, D-14558 Potsdam, Nuthetal, Germany. [Kleinridders, Andre] Natl Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Gonzalez-Del Pino, Gonzalo; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Gonzalez-Del Pino, Gonzalo; Eck, Michael J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.; Pan, Hui] Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.; Ramirez, Alfred K.; Pan, Hui] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [O'Neill, Brian T.] Univ Iowa, Dept Endocrinol & Metab, Fraternal Order Eagles Diabet Res Ctr, Carver Coll Med, Iowa City, IA 52242 USA. [Boucher, Jeremie] AstraZeneca R&D, IMED Cardiovasc & Metab Dis, S-43183 Molndal, Sweden. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.; Kahn, CR (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu OI Dreyfuss, Jonathan/0000-0001-7242-3991 FU NIH [R01 DK031036, R01 DK033201, T32 DK007260-37, K08 DK100543]; Manpei Suzuki Diabetes Foundation; Japan Society for the Promotion of Science; German Research Foundation (DFG) [Kl2399-4/1]; Federal Ministry of Education and Research (German Center for Diabetes Research) [01GI092]; The Joslin Diabetes Center DRC Genomics and Bioinformatics Core [P30 DK36836] FX This work was supported by NIH Grants R01 DK031036 and R01 DK033201 (to C.R.K.) and Sanofi. M.S. was supported by Manpei Suzuki Diabetes Foundation and a fellowship from the Japan Society for the Promotion of Science. A.K. was supported by a German Research Foundation (DFG) fellowship Kl2399-1/1 and 4/1 grant and by the Federal Ministry of Education and Research (German Center for Diabetes Research, Grant No 01GI092). A.K.R. was supported by NIH Grant T32 DK007260-37. B.T.O. was supported by NIH Grant K08 DK100543. The Joslin Diabetes Center DRC Genomics and Bioinformatics Core (P30 DK36836) also provided important help. NR 51 TC 0 Z9 0 U1 0 U2 0 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 MAR 27 PY 2017 VL 8 AR 14892 DI 10.1038/ncomms14892 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP5ER UT WOS:000397402300001 PM 28345670 ER PT J AU Cameron, D Piccart-Gebhart, MJ Gelber, RD Procter, M Goldhirsch, A de Azambuja, E Castro, G Untch, M Smith, I Gianni, L Baselga, J Al-Sakaff, N Lauer, S McFadden, E Leyland-Jones, B Bell, R Dowsett, M Jackisch, C AF Cameron, David Piccart-Gebhart, Martine J. Gelber, Richard D. Procter, Marion Goldhirsch, Aron de Azambuja, Evandro Castro, Gilberto, Jr. Untch, Michael Smith, Ian Gianni, Luca Baselga, Jose Al-Sakaff, Nedal Lauer, Sabine McFadden, Eleanor Leyland-Jones, Brian Bell, Richard Dowsett, Mitch Jackisch, Christian CA Herceptin Adjuvant HERA Trial TI 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial SO LANCET LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; OPEN-LABEL; PHASE-3 TRIAL; MULTICENTER; PERTUZUMAB; SYSTEM AB Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1: 1: 1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10.09-11.53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0.76, 95% CI 0.68-0.86) and death (0.74, 0.64-0.86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1.02, 95% CI 0.89-1.17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7.3%) in the 2-years trastuzumab group, 74 (4.4%) in the 1-year trastuzumab group, and 15 (0.9%) in the observation group. Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. C1 [Cameron, David] Univ Edinburgh, Canc Res Ctr, Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Piccart-Gebhart, Martine J.] Univ Libre Bruxelles, Dept Med, Brussels, Belgium. [de Azambuja, Evandro] Univ Libre Bruxelles, Med Oncol Clin, Brussels, Belgium. Univ Libre Bruxelles, BrEAST Data Ctr, Inst Jules Bordet, Brussels, Belgium. [Gelber, Richard D.] Harvard TH Chan Sch Publ Hlth, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Harvard Med Sch, Boston, MA USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Procter, Marion] Frontier Sci Scotland Ltd, Kincraig, Kingussie, Scotland. [Goldhirsch, Aron] European Inst Oncol, Milan, Italy. [Castro, Gilberto, Jr.] Univ Sao Paulo, Clin Oncol, Inst Canc Estado Sao Paulo, Fac Med, Sao Paulo, Brazil. [Untch, Michael] Helios Klinikum Berlin Buch, Multidisciplinary Breast Canc Ctr, Berlin, Germany. [Smith, Ian; Dowsett, Mitch] Royal Marsden Hosp, Breast Unit, London, England. [Smith, Ian; Dowsett, Mitch] Inst Canc Res, London, England. [Gianni, Luca] Hosp San Raffaele, Dept Med Oncol, Inst Sci, Milan, Italy. [Baselga, Jose] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Al-Sakaff, Nedal; Lauer, Sabine] F Hoffmann La Roche, Basel, Switzerland. [McFadden, Eleanor] Frontier Sci Scotland Ltd, Kincraig, Kingussie, Scotland. [Leyland-Jones, Brian] Avera Canc Inst, Ctr Precis Oncol, Sioux Falls, SD USA. [Bell, Richard] Deakin Univ, Waurn Ponds, Vic, Australia. [Jackisch, Christian] Sana Klinikum Offenbach, Dept Gynecol & Obstet, Offenbach, Germany. RP Cameron, D (reprint author), Univ Edinburgh, Canc Res Ctr, Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. EM d.cameron@ed.ac.uk FU F Hoffmann-La Roche (Roche) FX F Hoffmann-La Roche (Roche). 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 25 PY 2017 VL 389 IS 10075 BP 1195 EP 1205 DI 10.1016/S0140-6736(16)32616-2 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EP1KL UT WOS:000397143700032 PM 28215665 ER PT J AU Kang, SL Li, QJ Chen, Q Zhou, YG Park, S Lee, G Grimes, B Krysan, K Yu, M Wang, W Alber, F Sun, FZ Dubinett, SM Li, WY Zhou, XHJ AF Kang, Shuli Li, Qingjiao Chen, Quan Zhou, Yonggang Park, Stacy Lee, Gina Grimes, Brandon Krysan, Kostyantyn Yu, Min Wang, Wei Alber, Frank Sun, Fengzhu Dubinett, Steven M. Li, Wenyuan Zhou, Xianghong Jasmine TI CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA SO GENOME BIOLOGY LA English DT Article DE Cell-free DNA; Liquid biopsy; DNA methylation; Next-generation sequencing; Cancer diagnosis ID COPY NUMBER ABERRATIONS; PLASMA DNA; COLORECTAL-CANCER; HYPOMETHYLATION; CLASSIFIERS; BIOMARKERS; CARCINOMA; PATTERNS AB We propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. CancerLocator outperforms two established multi-class classification methods on simulations and real data, even with the low proportion of tumor-derived DNA in the cell-free DNA scenarios. CancerLocator also achieves promising results on patient plasma samples with low DNA methylation sequencing coverage. C1 [Kang, Shuli; Li, Qingjiao; Chen, Quan; Alber, Frank; Sun, Fengzhu] Univ Southern Calif, Mol & Computat Biol, Los Angeles, CA 90089 USA. [Zhou, Yonggang; Dubinett, Steven M.; Li, Wenyuan; Zhou, Xianghong Jasmine] Univ Calif Los Angeles, Dept Pathol & Lab Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Zhou, Yonggang; Zhou, Xianghong Jasmine] Univ Calif Los Angeles, Inst Quantitat & Computat Biosci, Los Angeles, CA 90095 USA. [Park, Stacy; Grimes, Brandon; Krysan, Kostyantyn] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm Crit Care Med Clin Immunol & Allergy, Los Angeles, CA 90095 USA. [Lee, Gina] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Yu, Min] Univ Southern Calif, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA. [Yu, Min] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Wang, Wei] Zhejiang Prov Tongde Hosp, Clin Lab, Hangzhou, Zhejiang, Peoples R China. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Dubinett, SM; Li, WY; Zhou, XHJ (reprint author), Univ Calif Los Angeles, Dept Pathol & Lab Med, David Geffen Sch Med, Los Angeles, CA 90095 USA.; Zhou, XHJ (reprint author), Univ Calif Los Angeles, Inst Quantitat & Computat Biosci, Los Angeles, CA 90095 USA.; Dubinett, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA.; Dubinett, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA.; Dubinett, SM (reprint author), Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. EM sdubinett@mednet.ucla.edu; WenyuanLi@mednet.ucla.edu; XJZhou@mednet.ucla.edu FU NHLBI MAPGEN [U01HL108634]; NIH/NCI [1U01CA214182-01, 1U01CA196408-01]; National Institutes of Health (NIH) [NHLBI MAPGEN] [U01HL108634] FX This work was supported by the NHLBI MAPGEN U01HL108634 grant to X.J.Z., the NIH/NCI 1U01CA214182-01 and the NIH/NCI 1U01CA196408-01 to S.M.D. Funding for open access charge: National Institutes of Health (NIH) [NHLBI MAPGEN U01HL108634 to X.J.Z.]. The authors greatly acknowledge Dr. Yuk Ming Dennis Lo and his circulating nucleic acids research group in the Chinese University of Hong Kong for his cfDNA data [19, 21]. We also thank Wing Hung Wong for his constructive input for the manuscript. NR 29 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 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAR 24 PY 2017 VL 18 AR 53 DI 10.1186/s13059-017-1191-5 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EP0ZI UT WOS:000397114800001 PM 28335812 ER PT J AU Toska, E Osmanbeyoglu, HU Castel, P Chan, C Hendrickson, RC Elkabets, M Dickler, MN Scaltriti, M Leslie, CS Armstrong, SA Baselga, J AF Toska, Eneda Osmanbeyoglu, Hatice U. Castel, Pau Chan, Carmen Hendrickson, Ronald C. Elkabets, Moshe Dickler, Maura N. Scaltriti, Maurizio Leslie, Christina S. Armstrong, Scott A. Baselga, Jose TI CANCER THERAPY PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D SO SCIENCE LA English DT Article ID H3K4 MONOMETHYLATION; COMPASS FAMILY; PHASE-I; INHIBITOR; FOXA1; METHYLTRANSFERASE; METHYLATION; DISRUPTION; MLL3/MLL4; ENHANCERS AB Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase alpha (PI3K alpha), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Ka inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3K alpha inhibition. We found that PI3Ka inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3K alpha inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer. C1 [Toska, Eneda; Castel, Pau; Chan, Carmen; Elkabets, Moshe; Scaltriti, Maurizio; Baselga, Jose] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA. [Osmanbeyoglu, Hatice U.; Leslie, Christina S.] Computat Biol Program, Mem Sloan Kettering Canc Ctr, 1275 York Ave,Box 460, New York, NY 10065 USA. [Castel, Pau] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1450 3rd St, San Francisco, CA 94158 USA. [Hendrickson, Ronald C.] Mem Sloan Kettering Canc Ctr, Microchemistry & Prote Core Lab, New York, NY 10065 USA. [Elkabets, Moshe] Ben Gurion Univ Negev, Shraga Segal Dept Microbiol, Immunol & Genet, Fac Hlth Sci, IL-84105 Beer Sheva, Israel. [Dickler, Maura N.; Baselga, Jose] Dept Med, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Scaltriti, Maurizio] Dept Pathol, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Armstrong, Scott A.] Canc Biol & Genet Program, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Armstrong, Scott A.] Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Baselga, J (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA.; Baselga, J (reprint author), Dept Med, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.; Armstrong, SA (reprint author), Canc Biol & Genet Program, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.; Armstrong, SA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM scott_armstrong@dfci.harvard.edu; baselgaj@mskcc.org FU NIH [RO1CA190642-01A1, CA66996, CA140575]; Breast Cancer Research Foundation; Geoffrey Beene Cancer Research Center; National Cancer Institute (NCI) Cancer Center Support Grant [P30CA08748]; NCI [K99 CA207871]; Novartis Pharmaceuticals; Epizyme; Imago Biosciences; Vitae Pharmaceuticals FX We are grateful to L. Pasqualucci, who provided the pCMV-HA-KMT2D and the corresponding mutants, the N5437S and R5432W KMT2D plasmids. We also thank A. Shilatifard, who provided the KMT2D antibody for our preliminary experiments; P. Giresi, A. Krivtsov, and Y. Li for help with ATAC-seq; Y. Zou for help with ChIP-seq; N. Morse for help with xenograft establishment; and N. Socci for help with microarray analysis. This work was supported by NIH grant RO1CA190642-01A1, the Breast Cancer Research Foundation, and the Geoffrey Beene Cancer Research Center (to J. B.); National Cancer Institute (NCI) Cancer Center Support Grant P30CA08748 to the Microchemistry and Proteomics Core Laboratory of the Memorial Sloan Kettering Cancer Center; and NIH grants CA66996 and CA140575 to S. A. A. We are also grateful for the support of T. and B. Weinstein. E. T. holds a fellowship from the Terri Brodeur Breast Cancer Foundation. H. U. O. is supported by NCI award K99 CA207871. J. B. and M. N. D. are paid consultants for Novartis Pharmaceuticals. S. A. A. is a paid consultant for Epizyme, Imago Biosciences, and Vitae Pharmaceuticals. Memorial Sloan Kettering Cancer Center and the authors (E. T., S. A. A., and J. B.) have filed a patent application (U. S. patent registration number 62/420324) related to KMT2D inhibition as a treatment for breast cancer. The sequencing data have been deposited in the Gene Expression Omnibus database under accession numbers GEO GSE84515, GSE84593, GSE84594, and GSE95366. NR 33 TC 0 Z9 0 U1 2 U2 2 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 MAR 24 PY 2017 VL 355 IS 6331 BP 1324 EP 1329 DI 10.1126/science.aah6893 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP0NB UT WOS:000397082900042 PM 28336670 ER PT J AU Ritter, ML Guo, W Samuels, JF Wang, Y Nestadt, PS Krasnow, J Greenberg, BD Fyer, AJ McCracken, JT Geller, DA Murphy, DL Knowles, JA Grados, MA Riddle, MA Rasmussen, SA McLaughlin, NC Nurmi, EL Askland, KD Cullen, B Piacentini, J Pauls, DL Bienvenu, J Stewart, E Goes, FS Maher, B Pulver, AE Mattheisen, M Qian, J Nestadt, G Shugart, YY AF Ritter, McKenzie L. Guo, Wei Samuels, Jack F. Wang, Ying Nestadt, Paul S. Krasnow, Janice Greenberg, Benjamin D. Fyer, Abby J. McCracken, James T. Geller, Daniel A. Murphy, Dennis L. Knowles, James A. Grados, Marco A. Riddle, Mark A. Rasmussen, Steven A. McLaughlin, Nicole C. Nurmi, Erika L. Askland, Kathleen D. Cullen, Bernadette Piacentini, John Pauls, David L. Bienvenu, Joseph Stewart, Evelyn Goes, Fernando S. Maher, Brion Pulver, Ann E. Mattheisen, Manuel Qian, Ji Nestadt, Gerald Shugart, Yin Yao TI Genome Wide Association Study (GWAS) between Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD) SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE ADHD; OCD; GWAS; meta-analysis; polygenic score; protein-protein link analysis; eQTL ID DEFICIT/HYPERACTIVITY DISORDER; PSYCHOMETRIC PROPERTIES; K-SADS; CHILDREN; METAANALYSIS; RELIABILITY; IV; SCHIZOPHRENIA; ADOLESCENTS; COMORBIDITY AB Objective: The aim of this study was to identify any potential genetic overlap between attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). We hypothesized that since these disorders share a sub-phenotype, they may share common risk alleles. In this manuscript, we report the overlap found between these two disorders. Methods: A meta-analysis was conducted between ADHD and OCD, and polygenic risk scores (PRS) were calculated for both disorders. In addition, a protein-protein analysis was completed in order to examine the interactions between proteins; p-values for the protein-protein interaction analysis was calculated using permutation. Conclusion: None of the single nucleotide polymorphisms (SNPs) reached genome wide significance and there was little evidence of genetic overlap between ADHD and OCD. C1 [Ritter, McKenzie L.; Guo, Wei; Shugart, Yin Yao] NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA. [Samuels, Jack F.; Wang, Ying; Krasnow, Janice; Grados, Marco A.; Riddle, Mark A.; Cullen, Bernadette; Bienvenu, Joseph; Goes, Fernando S.; Pulver, Ann E.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Nestadt, Paul S.; Maher, Brion] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Greenberg, Benjamin D.; Rasmussen, Steven A.; McLaughlin, Nicole C.; Askland, Kathleen D.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Fyer, Abby J.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [McCracken, James T.; Nurmi, Erika L.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Geller, Daniel A.; Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Geller, Daniel A.; Pauls, David L.] Harvard Med Sch, Boston, MA USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Bldg 10, Bethesda, MD 20892 USA. [Knowles, James A.] Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Stewart, Evelyn] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] Aarhus Univ, Ctr Integrated Sequencing iSEQ, Aarhus, Denmark. [Mattheisen, Manuel] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, Bonn, Germany. [Qian, Ji] Fudan Univ, Inst Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China. RP Shugart, YY (reprint author), NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA.; Nestadt, G (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM gnestadt@jhmi.edu; kay1yao@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [MH002930-06] FX MLR and YYS and WG acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and grant number MH002930-06. The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 49 TC 0 Z9 0 U1 0 U2 0 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 MAR 23 PY 2017 VL 10 AR 83 DI 10.3389/fnmol.2017.00083 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EP0NU UT WOS:000397084800001 PM 28386217 ER PT J AU Xie, H Li, XY Peng, JP Chen, Q Gao, ZJ Song, XZ Li, WY Xiao, JQ Li, CH Zhang, T Gusella, JF Zhong, JM Chen, XL AF Xie, Hua Li, Xiaoyan Peng, Jiping Chen, Qian Gao, ZhiJie Song, Xiaozhen Li, WeiYu Xiao, Jianqiu Li, Caihua Zhang, Ting Gusella, James F. Zhong, Jianmin Chen, Xiaoli TI A complex intragenic rearrangement of ERCC8 lein Chinese siblings with Cockayne syndrome SO SCIENTIFIC REPORTS LA English DT Article ID SYNDROME GROUP-A; HUMAN GENOME; COPY-NUMBER; STRUCTURAL VARIATION; DELETION; REPAIR; SCALE; CSA; GUIDELINES; DISORDERS AB Cockayne syndrome is an autosomal recessive disorder principally characterized by postnatal growth failure and progressive neurological dysfunction, due primarily to mutations in ERCC6 and ERCC8. Here, we report our diagnostic experience for two patients in a Chinese family suspected on clinical grounds to have Cockayne syndrome. Using multiple molecular techniques, including whole exome sequencing, array comparative genomic hybridization and quantitative polymerase chain reaction, we identified compound heterozygosity for a maternal splicing variant (chr5: 60195556, NM_000082: c.618-2A > G) and a paternal complex deletion/inversion/deletion rearrangement removing exon 4 of ERCC8, confirming the suspected pathogenesis in these two subjects. Microhomology (TAA and AGCT) at the breakpoints indicated that microhomology-mediated FoSTeS events were involved in this complex ERCC8 rearrangement. This diagnostic experience illustrates the value of high-throughput genomic technologies combined with detailed phenotypic assessment in clinical genetic diagnosis. C1 [Xie, Hua; Peng, Jiping; Song, Xiaozhen; Zhang, Ting; Chen, Xiaoli] Capital Inst Pediat, Beijing Municipal Key Lab Child Dev & Nutri, Beijing, Peoples R China. [Li, Xiaoyan; Zhong, Jianmin] Childrens Hosp Jiangxi Prov, Dept Neurol, Nanchang, Jiangxi, Peoples R China. [Chen, Qian; Gao, ZhiJie] Affiliated Childrens Hosp Capital Inst Pediat, Dept Neurol, Beijing, Peoples R China. [Li, WeiYu; Xiao, Jianqiu] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China. [Li, WeiYu; Xiao, Jianqiu] Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai, Peoples R China. [Li, Caihua] Genesky Biotechnol, Shanghai, Peoples R China. [Gusella, James F.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Gusella, James F.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. RP Chen, XL (reprint author), Capital Inst Pediat, Beijing Municipal Key Lab Child Dev & Nutri, Beijing, Peoples R China.; Zhong, JM (reprint author), Childrens Hosp Jiangxi Prov, Dept Neurol, Nanchang, Jiangxi, Peoples R China. EM zhongjm@163.com; cxlwx@sina.com FU Capital Health Research and Development of Special [2014-2-1131]; National Nature Science Fund [31671310, 81370708, 81401207]; Beijing Natural Science Foundation [7162029]; Beijing nova program interdisciplinary collaborative project [xxjc201717]; NIH [P01GM061354]; CAMS Initiative for Innovative Medicine [CAMS-I2M]; advanced Personnel Training Program of Beijing Municipal Health Bureau FX This work is partially funded by the Capital Health Research and Development of Special [2014-2-1131], the National Nature Science Fund [31671310 and 81370708 to XLC, 81401207 to HX], and Beijing Natural Science Foundation [7162029 to XLC] and the advanced Personnel Training Program of Beijing Municipal Health Bureau and Beijing nova program interdisciplinary collaborative project [xxjc201717], and NIH grant [P01GM061354 to JFG] as well as the CAMS Initiative for Innovative Medicine [CAMS-I2M]. NR 40 TC 0 Z9 0 U1 0 U2 0 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 MAR 23 PY 2017 VL 7 AR 44271 DI 10.1038/srep44271 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP1SC UT WOS:000397163600001 PM 28333167 ER PT J AU Fajgenbaum, DC Uldrick, TS Bagg, A Frank, D Wu, D Srkalovic, G Simpson, D Liu, AY Menke, D Chandrakasan, S Lechowicz, MJ Wong, RSM Pierson, S Paessler, M Rossi, JF Ide, M Ruth, J Croglio, M Suarez, A Krymskaya, V Chadburn, A Colleoni, G Nasta, S Jayanthan, R Nabel, CS Casper, C Dispenzieri, A Fossa, A Kelleher, D Kurzrock, R Voorhees, P Dogan, A Yoshizaki, K van Rhee, F Oksenhendler, E Jaffe, ES Elenitoba-Johnson, KSJ Lim, MS AF Fajgenbaum, David C. Uldrick, Thomas S. Bagg, Adam Frank, Dale Wu, David Srkalovic, Gordan Simpson, David Liu, Amy Y. Menke, David Chandrakasan, Shanmuganathan Lechowicz, Mary Jo Wong, Raymond S. M. Pierson, Sheila Paessler, Michele Rossi, Jean-Francois Ide, Makoto Ruth, Jason Croglio, Michael Suarez, Alexander Krymskaya, Vera Chadburn, Amy Colleoni, Gisele Nasta, Sunita Jayanthan, Raj Nabel, Christopher S. Casper, Corey Dispenzieri, Angela Fossa, Alexander Kelleher, Dermot Kurzrock, Razelle Voorhees, Peter Dogan, Ahmet Yoshizaki, Kazuyuki van Rhee, Frits Oksenhendler, Eric Jaffe, Elaine S. Elenitoba-Johnson, Kojo S. J. Lim, Megan S. TI International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease SO BLOOD LA English DT Article ID LYMPH-NODE HYPERPLASIA; LUPUS-ERYTHEMATOSUS PATIENTS; TAFRO SYNDROME; IGG4-RELATED DISEASE; HERPESVIRUS; LESIONS; HIV; INTERLEUKIN-6; SILTUXIMAB; PATHOLOGY AB Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases ofMCDand can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic featuresmay include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevatedC-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research. C1 [Fajgenbaum, David C.; Liu, Amy Y.; Pierson, Sheila; Suarez, Alexander] Univ Pennsylvania, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA USA. [Uldrick, Thomas S.; Jaffe, Elaine S.] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. [Bagg, Adam; Lim, Megan S.] Univ Pennsylvania, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA. [Wu, David] Univ Washington, Dept Lab Med, Seattle, WA USA. [Srkalovic, Gordan] Edward Sparrow Hosp Assoc, Sparrow Canc Ctr, Lansing, MI USA. [Simpson, David] North Shore Hosp, Div Haematol, Auckland, New Zealand. [Menke, David] Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA. [Menke, David] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Chandrakasan, Shanmuganathan; Lechowicz, Mary Jo] Emory Univ Sch Med, Dept Med, Atlanta, GA USA. [Wong, Raymond S. M.] Chinese Univ Hong Kong, Prince Wales Hosp, Sir K Pao Ctr Canc, Hong Kong, Peoples R China. [Wong, Raymond S. M.] Chinese Univ Hong Kong, Dept Med Therapeut, Hong Kong, Peoples R China. [Paessler, Michele] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA USA. [Rossi, Jean-Francois] Hop St Eloi Univ Hosp, Dept Hematol, Montpellier, France. [Ide, Makoto] Takamatsu Red Cross Hosp, Dept Hematol, Takamatsu, Kagawa, Japan. [Ruth, Jason] Dana Farber Canc Inst, Harvard Med Sch, Dept Med Oncol, Boston, MA USA. [Croglio, Michael] SUNY Stony Brook, Sch Med, Stony Brook, NY USA. [Krymskaya, Vera] Univ Penn, Perelman Sch Med, Div Pulm Allergy & Crit Care, Philadelphia, PA USA. [Chadburn, Amy] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Colleoni, Gisele] Univ Fed Sao Paulo, Dept Oncol Clin Expt, Sao Paulo, Brazil. [Nasta, Sunita] Univ Pennsylvania, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA USA. [Jayanthan, Raj] Texas Childrens Hosp, Dept Pediat, Houston, TX USA. [Nabel, Christopher S.] Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Casper, Corey] Fred Hutchinson Canc Ctr, Vaccine & Infect Dis Div, Seattle, WA USA. [Dispenzieri, Angela] Mayo Clin, Div Hematol Oncol, Rochester, MN USA. [Fossa, Alexander] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, Oslo, Norway. [Kelleher, Dermot] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Kurzrock, Razelle] UC San Diego Moores Canc Ctr, Ctr Personalized Therapy, La Jolla, CA USA. [Voorhees, Peter] Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Carolinas HealthCare Syst, Charlotte, NC USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Pathol, Lab Med, New York, NY USA. [Yoshizaki, Kazuyuki] Osaka Univ, Inst Sci & Ind Res, Dept Organ Fine Chem, Osaka, Japan. [van Rhee, Frits] Univ Arkansas Med Sci, Myeloma Inst, Little Rock, AR USA. [Oksenhendler, Eric] Hop St Louis, Dept Clin Immunol, Paris, France. RP Fajgenbaum, DC (reprint author), Hosp Univ Penn, 3400 Spruce St,Suite S05094, Philadelphia, PA 19104 USA.; Uldrick, TS; Jaffe, ES (reprint author), Natl Canc Inst, Ctr Canc Res, Bldg 10,Room 3S235, Bethesda, MD USA.; Elenitoba-Johnson, KSJ; Lim, MS (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol, 609 Stellar Chance, Philadelphia, PA 19104 USA. EM megan.lim@uphs.upenn.edu FU CDCN; Penn Orphan Disease Center; Intramural Research Program of the National Institutes of Health FX The authors thank the CDCN and Penn Orphan Disease Center for logistical and funding support and Janssen Pharmaceuticals for providing extensive, deidentified datasets and lymph node slides from clinical trial NCT01024036. All funding from the CDCN and the Penn Orphan Disease Center was provided without fur ther input into the work conduct, results interpretation, and manuscript preparation. The authors also thank Hayley Williamson and Melanie Kier for their assistance with coordinating the meeting and performing preliminary data analyses, Arthur Rubenstein for his guidance, and Noriko Iwaki and Yasuharu Sato for contributing clinical and histopathologic data toward the evidence base for this criteria.; This study was supported, in part, by the Intramural Research Program of the National Institutes of Health. NR 57 TC 2 Z9 2 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 MAR 23 PY 2017 VL 129 IS 12 BP 1646 EP 1657 DI 10.1182/blood-2016-10-746933 PG 12 WC Hematology SC Hematology GA EP3QR UT WOS:000397297300015 PM 28087540 ER PT J AU Zhang, XW Yosef, N AF Zhang, Xiuwei Yosef, Nir TI A new way to build cell lineages SO ELIFE LA English DT Article ID GENOMICS C1 [Zhang, Xiuwei; Yosef, Nir] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Zhang, Xiuwei; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA. [Zhang, Xiuwei; Yosef, Nir] MIT & Harvard, Ragon Inst, Massachusetts Gen Hosp, Cambridge, MA 02139 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, Ragon Inst, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. EM niryosef@berkeley.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 23 PY 2017 VL 6 AR e25654 DI 10.7554/eLife.25654 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EP8RS UT WOS:000397643100001 ER PT J AU Xiang, Y Laurent, B Hsu, CH Nachtergaele, S Lu, ZK Sheng, WQ Xu, CY Hen, HC Jian, OY Wang, SQ Ling, D Hsu, PH Zou, L Jambhekar, A Iie, C Shi, Y AF Xiang, Yang Laurent, Benoit Hsu, Chih-Hung Nachtergaele, Sigrid Lu, Zhike Sheng, Wanqiang Xu, Chuanyun Hen, Hao C. Jian, Ouyang Wang, Siqing Ling, Dominic Hsu, Pang-Hung Zou, Lee Jambhekar, Ashwini IIe, Chuan Shi, Yang TI RNA m(6)A methylation regulates the ultraviolet-induced DNA damage response SO NATURE LA English DT Article ID NUCLEAR-RNA; POLYMERASE-KAPPA; HUMAN-CELLS; POL-KAPPA; N-6-METHYLADENOSINE; REPAIR; N6-METHYLADENOSINE; TRANSCRIPTION; LOCALIZATION; TRANSLATION AB Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m(6)A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) 1 and the demethylase FTO (fat mass and obesity-associated protein) 2. In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m(6)A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway3, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase(4). DNA polymerase. (Pol.), which has been implicated in both nucleotide excision repair and trans-lesion synthesis(5,6), required the catalytic activity of METTL3 for immediate localization to ultravioletinduced DNA damage sites. Importantly, Pol. overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m(6)A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m(6)A RNA serves as a beacon for the selective, rapid recruitment of Pol. to damage sites to facilitate repair and cell survival. C1 [Xiang, Yang; Laurent, Benoit; Hsu, Chih-Hung; Sheng, Wanqiang; Xu, Chuanyun; Hen, Hao C.; Wang, Siqing; Ling, Dominic; Jambhekar, Ashwini; Shi, Yang] Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA. [Xiang, Yang; Laurent, Benoit; Hsu, Chih-Hung; Sheng, Wanqiang; Xu, Chuanyun; Hen, Hao C.; Wang, Siqing; Ling, Dominic; Jambhekar, Ashwini; Shi, Yang] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Dept Chem, Chicago, IL 60637 USA. [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Inst Biophys Dynam, 929 East 57th St, Chicago, IL 60637 USA. [Nachtergaele, Sigrid; Lu, Zhike; IIe, Chuan] Univ Chicago, Howard Hughes Med Inst, 929 East 57th St, Chicago, IL 60637 USA. [Jian, Ouyang; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02109 USA. [Jian, Ouyang; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Dept Pathol, Boston, MA 02109 USA. [Hsu, Pang-Hung] Natl Taiwan Ocean Univ, Dept Biosci & Biotechnol, Keelung 202, Taiwan. [Wang, Siqing] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. RP Xiang, Y; Laurent, B; Hsu, CH (reprint author), Boston Childrens Hosp, Dept Med, Div Newborn Med & Epigenet Program, Boston, MA 02115 USA.; Xiang, Y; Laurent, B; Hsu, CH (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. EM yshi@hms.harvard.edu FU Association pour la Recherche sur le Cancer (ARC) (France); National Institutes of Health [4 T32 HD 7466-20, R01 CA118487]; Boston Children's Hospital FX We thank members of the Shi laboratory for discussions. We are especially indebted to L. Li for advice, discussion, and sharing reagents; to R. Meganck and A. Sancar for providing reagents and discussions; to F. Huetz for the cell-cycle analysis, S. Elledge for advice, and L. Izhar in the Elledge laboratory for teaching Y.X. how to perform laser micro-irradiation; and to L. Kraus for reagents and advice. We thank Abclonal Biotechnology and Santa Cruz Biotechnology for providing antibodies, and N. Mosammaparast and B. Sleckman for the H2A.X KO mouse embryonic fibroblast (MEF) cells. B. L. was supported by a fellowship from Association pour la Recherche sur le Cancer (ARC) (France) and National Institutes of Health 4 T32 HD 7466-20. This work was supported by a grant from the National Institutes of Health to Y.S. (R01 CA118487) and funds from Boston Children's Hospital. Y.S. is an American Cancer Society Research Professor. NR 35 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 23 PY 2017 VL 543 IS 7646 BP 573 EP + DI 10.1038/nature21671 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9OM UT WOS:000397018000056 PM 28297716 ER PT J AU Hnisz, D Shrinivas, K Young, RA Chakraborty, AK Sharp, PA AF Hnisz, Denes Shrinivas, Krishna Young, Richard A. Chakraborty, Arup K. Sharp, Phillip A. TI A Phase Separation Model for Transcriptional Control SO CELL LA English DT Review ID RNA-POLYMERASE-II; STOCHASTIC GENE-EXPRESSION; COVALENT CDK7 INHIBITOR; NEGATIVE BREAST-CANCER; EMBRYONIC STEM-CELLS; SUPER-ENHANCER; BETA ENHANCEOSOME; MAMMALIAN GENES; IDENTITY GENES; EARLY PROMOTER AB Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals. C1 [Hnisz, Denes; Young, Richard A.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Shrinivas, Krishna; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Young, Richard A.; Sharp, Phillip A.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Shrinivas, Krishna; Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Shrinivas, Krishna; Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Shrinivas, Krishna; Chakraborty, Arup K.] Harvard Univ, Cambridge, MA 02139 USA. [Sharp, Phillip A.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA. RP Young, RA (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Young, RA; Sharp, PA (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.; Chakraborty, AK (reprint author), Harvard Univ, Cambridge, MA 02139 USA.; Sharp, PA (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA. EM young@wi.mit.edu; arupc@mit.edu; sharppa@mit.edu FU NIH [HG002668, P01-CA042063]; Austrian Science Fund FWF [J3490]; Margaret and Herman Sokol Postdoctoral Award; National Cancer Institute [P30-CA14051] FX P.A.S. and R.A.Y. thank the MIT students in their course "Structure and Functions of the Nucleus'' for discussions. We are grateful to Mehran Kardar, Steve McKnight, Ben Sabari, and Tony Lee for comments. The work was supported by an NIH grant (HG002668) (to R.A.Y.), an Erwin Schrodinger Fellowship (J3490) from the Austrian Science Fund FWF (to D.H.), a Margaret and Herman Sokol Postdoctoral Award (to D.H.), and an NIH grant (P01-CA042063) (to P.A.S.). This work was supported, in part, by a Koch Institute Support (core) grant (P30-CA14051) from the National Cancer Institute (to P.A.S). R.A.Y. is a founder of Syros Pharmaceuticals and Marauder Therapeutics. NR 81 TC 0 Z9 0 U1 2 U2 2 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 MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.02.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000004 PM 28340338 ER PT J AU Manolio, TA Fowler, DM Starita, LM Haendel, MA MacArthur, DG Biesecker, LG Worthey, E Chisholm, RL Green, ED Jacob, HJ McLeod, HL Roden, D Rodriguez, LL Williams, MS Cooper, GM Cox, NJ Herman, GE Kingsmore, S Lo, C Lutz, C MacRae, CA Nussbaum, RL Ordovas, JM Ramos, EM Robinson, PN Rubinstein, WS Seidman, C Stranger, BE Wang, HY Westerfield, M Bult, C AF Manolio, Teri A. Fowler, Douglas M. Starita, Lea M. Haendel, Melissa A. MacArthur, Daniel G. Biesecker, Leslie G. Worthey, Elizabeth Chisholm, Rex L. Green, Eric D. Jacob, Howard J. McLeod, Howard L. Roden, Dan Rodriguez, Laura Lyman Williams, Marc S. Cooper, Gregory M. Cox, Nancy J. Herman, Gail E. Kingsmore, Stephen Lo, Cecilia Lutz, Cathleen MacRae, Calum A. Nussbaum, Robert L. Ordovas, Jose M. Ramos, Erin M. Robinson, Peter N. Rubinstein, Wendy S. Seidman, Christine Stranger, Barbara E. Wang, Haoyi Westerfield, Monte Bult, Carol TI Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research SO CELL LA English DT Editorial Material ID VARIANTS; ASSOCIATION; DISORDERS; GENETICS; DISEASES AB Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant- phenotype databases, adopting phenotype description standards, and promoting data sharing. C1 [Manolio, Teri A.; Biesecker, Leslie G.; Green, Eric D.; Rodriguez, Laura Lyman; Ramos, Erin M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Fowler, Douglas M.; Starita, Lea M.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Haendel, Melissa A.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. [MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Worthey, Elizabeth; Jacob, Howard J.; Cooper, Gregory M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Chisholm, Rex L.] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [McLeod, Howard L.] H Lee Moffitt Canc Ctr & Res Inst, DeBartolo Family Personalized Med Inst, Tampa, FL 33612 USA. [Roden, Dan] Vanderbilt Univ, Med Ctr, Dept Med Pharmacol & Biomed Informat, Nashville, TN 37203 USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA 17822 USA. [Cox, Nancy J.] Vanderbilt Univ, Med Ctr, Div Med Genet, Nashville, TN 37203 USA. [Herman, Gail E.] Nationwide Childrens Hosp, Res Inst, Inst Genom Med, Columbus, OH 43205 USA. [Kingsmore, Stephen] Rady Childrens Inst Genom Med, San Diego, CA 92123 USA. [Lo, Cecilia] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 1526 USA. [Lutz, Cathleen] Jackson Lab Mammalian Genet, Rare & Orphan Dis Ctr, Bar Harbor, ME 04609 USA. [MacRae, Calum A.] Brigham & Womens Hosp, Network Med & Genet, Div Cardiovasc Med, Boston, MA 02115 USA. [Nussbaum, Robert L.] Invitae Genet Informat & Testing Co, San Francisco, CA 94107 USA. [Ordovas, Jose M.] Tufts Univ, JM USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Robinson, Peter N.] Jackson Lab Genom Med, Farmington, CT 06032 USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Seidman, Christine] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Seidman, Christine] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Seidman, Christine] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Stranger, Barbara E.] Univ Chicago, Ctr Data Intens Sci, Inst Genom & Syst Biol, Dept Med,Sect Genet Med, Chicago, IL 60637 USA. [Wang, Haoyi; Bult, Carol] Jackson Lab Mammalian Genet, Bar Harbor, ME 04609 USA. [Westerfield, Monte] Univ Oregon, Dept Biol, Portland, OR 97403 USA. RP Manolio, TA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM manolio@nih.gov FU NIH HHS [R24 OD011883] NR 15 TC 0 Z9 0 U1 0 U2 0 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 MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.03.005 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000003 PM 28340351 ER PT J AU Sharabi, K Lin, H Tavares, CDJ Dominy, JE Camporez, JP Perry, RJ Schilling, R Rines, AK Lee, J Hickey, M Bennion, M Palmer, M Nag, PP Bittker, JA Perez, J Jedrychowski, MP Ozcan, U Gygi, SP Kamenecka, TM Shulman, GI Schreiber, SL Griffin, PR Puigserver, P AF Sharabi, Kfir Lin, Hua Tavares, Clint D. J. Dominy, John E. Camporez, Joao Paulo Perry, Rachel J. Schilling, Roger Rines, Amy K. Lee, Jaemin Hickey, Marc Bennion, Melissa Palmer, Michelle Nag, Partha P. Bittker, Joshua A. Perez, Jose Jedrychowski, Mark P. Ozcan, Umut Gygi, Steve P. Kamenecka, Theodore M. Shulman, Gerald I. Schreiber, Stuart L. Griffin, Patrick R. Puigserver, Pere TI Selective Chemical Inhibition of PGC-1 alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes SO CELL LA English DT Article ID CONTROLS GLUCOSE-METABOLISM; HEPATIC INSULIN-RESISTANCE; IN-VIVO; PHOSPHOENOLPYRUVATE CARBOXYKINASE; COACTIVATOR PGC-1; EXPRESSION; RECEPTOR; KINASE; LIVER; MICE AB Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1 alpha acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platformto quantify PGC-1 alpha acetylation in cells and identified small molecules that increase PGC-1 alpha acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. Onthe basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D. C1 [Sharabi, Kfir; Tavares, Clint D. J.; Dominy, John E.; Rines, Amy K.; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Sharabi, Kfir; Tavares, Clint D. J.; Dominy, John E.; Rines, Amy K.; Jedrychowski, Mark P.; Gygi, Steve P.; Puigserver, Pere] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Lin, Hua; Kamenecka, Theodore M.; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Camporez, Joao Paulo; Perry, Rachel J.; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Lee, Jaemin; Ozcan, Umut] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02130 USA. [Schilling, Roger; Hickey, Marc; Bennion, Melissa; Palmer, Michelle; Nag, Partha P.; Bittker, Joshua A.; Perez, Jose; Schreiber, Stuart L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. 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 02115 USA. EM pere_puigserver@dfci.harvard.edu FU AHA [15POST22880002]; ADA [1-16-PDF-111, 7-12-MN-68]; NIH/NIDDK [F32 DK102293-01, R24DK080261, R01DK-40936 9, 2U2CDK059635]; NIH [U54HG005032]; [R03DA032468]; [R01 DK069966] FX K.S. was partially funded by a post-doctoral fellowship from the AHA (15POST22880002). C.D.J.T. was partially funded by a post-doctoral fellowship from the ADA (1-16-PDF-111). A.K.R. received a post-doctoral fellowship from NIH/NIDDK (F32 DK102293-01). The HTS was funded by a grant from NIH to the Broad Institute as a MLPCN Center (S.L.S.) (U54HG005032). P.P. and P.R.G. were funded by the NIH/NIDDK (R24DK080261). G.I.S. was funded by NIH/NIDDK (R01DK-40936 9 and 2U2CDK059635). P.P. was funded by R03DA032468, R01 DK069966, and the ADA (7-12-MN-68). NR 46 TC 0 Z9 0 U1 1 U2 1 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 MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.03.001 PG 28 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000015 PM 28340340 ER PT J AU Longhurst, H Cicardi, M Craig, T Bork, K Grattan, C Baker, J Li, HH Reshef, A Bonner, J Bernstein, JA Anderson, J Lumry, WR Farkas, H Katelaris, CH Sussman, GL Jacobs, J Riedl, M Manning, ME Hebert, J Keith, PK Kivity, S Neri, S Levy, DS Baeza, ML Nathan, R Schwartz, LB Caballero, T Yang, W Crisan, I Hernandez, MD Hussain, I Tarzi, M Ritchie, B Kralickova, P Guilarte, M Rehman, SM Banerji, A Gower, RG Bensen-Kennedy, D Edelman, J Feuersenger, H Lawo, JP Machnig, T Pawaskar, D Pragst, I Zuraw, BL AF Longhurst, H. Cicardi, M. Craig, T. Bork, K. Grattan, C. Baker, J. Li, H. H. Reshef, A. Bonner, J. Bernstein, J. A. Anderson, J. Lumry, W. R. Farkas, H. Katelaris, C. H. Sussman, G. L. Jacobs, J. Riedl, M. Manning, M. E. Hebert, J. Keith, P. K. Kivity, S. Neri, S. Levy, D. S. Baeza, M. L. Nathan, R. Schwartz, L. B. Caballero, T. Yang, W. Crisan, I. Hernandez, M. D. Hussain, I. Tarzi, M. Ritchie, B. Kralickova, P. Guilarte, M. Rehman, S. M. Banerji, A. Gower, R. G. Bensen-Kennedy, D. Edelman, J. Feuersenger, H. Lawo, J. -P. Machnig, T. Pawaskar, D. Pragst, I. Zuraw, B. L. CA COMPACT Investigators TI Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHASE-II; CONCENTRATE; C1-INHIBITOR; PROPHYLAXIS; DEFICIENCY; PATHOPHYSIOLOGY; RECOMMENDATIONS; MANAGEMENT; BRADYKININ AB BACKGROUND Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (= 50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P< 0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. C1 [Longhurst, H.] Barts Hlth NHS Trust, London, England. [Grattan, C.] Guys Hosp, St Johns Inst Dermatol, London, England. [Tarzi, M.] Royal Sussex Cty Hosp, Clin Invest & Res, Brighton, E Sussex, England. [Cicardi, M.] UO Med Gen, Osped Luigi Sacco, Milan, Italy. [Neri, S.] Univ Catania, Dept Internal Med, Catania, Italy. [Craig, T.] Penn State Hershey Allergy Asthma & Immunol, Dept Med & Pediat, Hershey, PA USA. [Bensen-Kennedy, D.; Edelman, J.; Pawaskar, D.] CSL Behring, King Of Prussia, PA USA. [Bork, K.] Johannes Gutenberg Univ Mainz, Dept Dermatol, Mainz, Germany. [Feuersenger, H.; Lawo, J. -P.; Machnig, T.; Pragst, I.] CSL Behring, Marburg, Germany. [Baker, J.] Baker Allergy Asthma & Dermatol Res Ctr, Portland, OR USA. [Li, H. H.] Inst Asthma & Allergy, Chevy Chase, MD USA. [Reshef, A.] Chaim Sheba Med Ctr, Allergy & Immunol Unit, Tel Hashomer, Israel. [Kivity, S.] Tel Aviv Sourasky Med Ctr, Allergy & Immunol Unit, Tel Aviv, Israel. [Bonner, J.; Anderson, J.] Clin Res Ctr Alabama, Birmingham, AL USA. [Bernstein, J. A.] Univ Cincinnati, Coll Med, Dept Internal Med, Allergy Sect Cincinnati, Cincinnati, OH USA. [Rehman, S. M.] Toledo Inst Clin Res, Toledo, OH USA. [Lumry, W. R.] Allergy Asthma Res Associates Res Ctr, Dallas, TX USA. [Farkas, H.] Semmelweis Univ, Dept Internal Med 3, Hungarian Angioedema Ctr, Budapest, Hungary. [Katelaris, C. H.] Campbelltown Hosp, Dept Med Immunol & Allergy, Campbelltown, NSW, Australia. [Sussman, G. L.] St Michaels Hosp, Dept Clin Immunol & Allergy, Toronto, ON, Canada. [Hebert, J.] Ctr Rech Appl Allergie Quebec, Quebec City, PQ, Canada. [Keith, P. K.] McMaster Univ, Hamilton, ON, Canada. [Yang, W.] Ottawa Allergy Res, Ottawa, ON, Canada. [Yang, W.] Univ Ottawa, Sch Med, Ottawa, ON, Canada. [Ritchie, B.] Univ Alberta Hosp, Edmonton, AB, Canada. [Jacobs, J.] Allergy & Asthma Clin Res, Walnut Creek, CA USA. [Riedl, M.; Zuraw, B. L.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Levy, D. S.] 705 W La Veta Ave,Suite 101, Orange, CA USA. [Manning, M. E.] Med Res Arizona, Scottsdale, AZ USA. [Baeza, M. L.] Hosp Gen Univ Gregorio Maranon, Gregorio Maranon, Spain. [Baeza, M. L.] Inst Hlth Res, Biomed Res Network Rare Diseases U761, Gregorio Maranon, Spain. [Caballero, T.] Hosp La Paz, Inst Hlth Res, Biomed Res Network Rare Dis, Allergy Dept, Madrid, Spain. [Hernandez, M. D.] Univ La Fe, IIS Hosp, Dept Allergy, Valencia, Spain. [Guilarte, M.] Hosp Univ Vall dHebron, Barcelona, Spain. [Nathan, R.] Asthma & Allergy Assoc, Colorado Springs, CO USA. [Schwartz, L. B.] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23284 USA. [Crisan, I.] Spitalul Clin Municipal, Cluj Napoca, Romania. [Hussain, I.] Vital Prospects Clin Res Inst, Tulsa, OK USA. [Kralickova, P.] Univ Hosp, Inst Clin Immunol & Allergol, Hradec Kralove, Czech Republic. [Banerji, A.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Gower, R. G.] Marycliff Allergy Specialists, Spokane, WA USA. RP Longhurst, H (reprint author), Longhurst Barts Hlth NHS Trust, Pathol & Pharm Bldg,80 Newark St, London E1 2ES, England. EM hilary.longhurst@bartshealth.nhs.uk FU CSL Behring FX Supported by CSL Behring. NR 19 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 MAR 23 PY 2017 VL 376 IS 12 BP 1131 EP 1140 DI 10.1056/NEJMoa1613627 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300009 PM 28328347 ER PT J AU Nagarur, A Axelrod, L Dighe, AS AF Nagarur, Amulya Axelrod, Lloyd Dighe, Anand S. TI Case 9-2017: A 27-Year-Old Woman with Nausea, Vomiting, Confusion, and Hyponatremia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ADRENAL INSUFFICIENCY; VASOPRESSIN RELEASE; ADDISONS-DISEASE; EDEMATOUS DISORDERS; WATER-EXCRETION; SECRETION; HORMONE; HEALTH; WOMEN; RISK C1 [Nagarur, Amulya; Axelrod, Lloyd] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Dighe, Anand S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Nagarur, Amulya; Axelrod, Lloyd] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Dighe, Anand S.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Nagarur, A (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Nagarur, A (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 21 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 MAR 23 PY 2017 VL 376 IS 12 BP 1159 EP 1167 DI 10.1056/NEJMcpc1616024 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300013 PM 28328333 ER PT J AU Bertagnolli, MM Sartor, O Chabner, BA Rothenberg, ML Khozin, S Hugh-Jones, C Reese, DM Murphy, MJ AF Bertagnolli, Monica M. Sartor, Oliver Chabner, Bruce A. Rothenberg, Mace L. Khozin, Sean Hugh-Jones, Charles Reese, David M. Murphy, Martin J. TI Advantages of a Truly Open-Access Data-Sharing Model SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PROSTATE-CANCER C1 [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Chabner, Bruce A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Sartor, Oliver] Tulane Med Sch, New Orleans, LA USA. [Rothenberg, Mace L.] Pfizer, New York, NY USA. [Hugh-Jones, Charles] Carmine Res, New York, NY USA. [Khozin, Sean] US FDA, Silver Spring, MD USA. [Reese, David M.] Amgen Inc, Thousand Oaks, CA USA. [Murphy, Martin J.] Project Data Sphere, Cary, NC USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 8 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 MAR 23 PY 2017 VL 376 IS 12 BP 1178 EP 1181 DI 10.1056/NEJMsb1702054 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300018 PM 28328337 ER PT J AU Khera, AV Emdin, CA Kathiresan, S AF Khera, Amit V. Emdin, Connor A. Kathiresan, Sekar TI Fish Oil in Pregnancy and Asthma in Offspring REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Khera, Amit V.; Emdin, Connor A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM skathiresan1@mgh.harvard.edu NR 2 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 MAR 23 PY 2017 VL 376 IS 12 BP 1194 EP 1195 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300028 PM 28328341 ER PT J AU Sohn, K Merchant, FM Sayadi, O Puppala, D Doddamani, R Sahani, A Singh, JP Heist, EK Isselbacher, EM Armoundas, AA AF Sohn, Kwanghyun Merchant, Faisal M. Sayadi, Omid Puppala, Dheeraj Doddamani, Rajiv Sahani, Ashish Singh, Jagmeet P. Heist, E. Kevin Isselbacher, Eric M. Armoundas, Antonis A. TI A Novel Point-of-Care Smartphone Based System for Monitoring the Cardiac and Respiratory Systems SO SCIENTIFIC REPORTS LA English DT Article ID ELECTROCARDIOGRAPHIC SIGNALS IMPLICATIONS; ESTIMATING MINUTE VENTILATION; CHEYNE-STOKES RESPIRATION; CONGESTIVE-HEART-FAILURE; OPTIMIZED METHOD; SLEEP; VARIABILITY; IMPEDANCE; ADULTS; RISK AB Cardio- respiratory monitoring is one of the most demanding areas in the rapidly growing, mobiledevice, based health care delivery. We developed a 12-lead smartphone-based electrocardiogram ( ECG) acquisition and monitoring system ( called " cvrPhone"), and an application to assess underlying ischemia, and estimate the respiration rate (RR) and tidal volume (TV) from analysis of electrocardiographic (ECG) signals only. During in- vivo swine studies (n = 6), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. Ischemic indices calculated from each lead showed statistically significant (p < 0.05) increase within 2 min of occlusion compared to baseline. Following myocardial infarction, spontaneous ventricular tachycardia episodes ( n = 3) were preceded by significant ( p < 0.05) increase of the ischemic index 1- 4 min prior to the onset of the tachyarrhythmias. In order to assess the respiratory status during apnea, the mechanical ventilator was paused for up to 2 min during normal breathing. We observed that the RR and TV estimation algorithms detected apnea within 7.9 +/- 1.1 sec and 5.5 +/- 2.2 sec, respectively, while the estimated RR and TV values were 0 breaths/ min and less than 100 ml, respectively. In conclusion, the cvrPhone can be used to detect myocardial ischemia and periods of respiratory apnea using a readily available mobile platform. C1 [Sohn, Kwanghyun; Sayadi, Omid; Puppala, Dheeraj; Doddamani, Rajiv; Sahani, Ashish; Armoundas, Antonis A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Singh, Jagmeet P.; Heist, E. Kevin] Massachusetts Gen Hosp, Div Cardiol, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Healthcare Transformat Lab, Boston, MA 02114 USA. [Armoundas, Antonis A.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Armoundas, AA (reprint author), MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. EM aarmoundas@partners.org NR 38 TC 0 Z9 0 U1 0 U2 0 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 MAR 22 PY 2017 VL 7 DI 10.1038/srep44946 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9BU UT WOS:000396985000001 ER PT J AU Singh, JA Cleveland, J AF Singh, Jasvinder A. Cleveland, John TI Allopurinol and the risk of ventricular arrhythmias in the elderly: a study using US Medicare data SO BMC MEDICINE LA English DT Article DE Allopurinol; Ventricular arrhythmias; Risk factor; Elderly; Medicare ID XANTHINE-OXIDASE INHIBITION; SUDDEN CARDIAC DEATH; REPERFUSION-INDUCED ARRHYTHMIAS; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; ATRIAL-FIBRILLATION; CARDIOVASCULAR-DISEASE; HEART-DISEASE; RACIAL-DIFFERENCES; BLOOD-PRESSURE AB Background: There are no published human studies investigating whether the use of allopurinol, the most commonly used medication for the treatment of hyperuricemia in gout, the most common type of inflammatory arthritis in adults, has any beneficial effects on ventricular electrophysiology. The objective of our study was to assess whether allopurinol use is associated with a reduction in the risk of ventricular arrhythmias (VA). Methods: We used the 5% random sample of Medicare beneficiaries from 2006-2012 to examine new allopurinol use and the risk of incident VA. Multivariable Cox regression analyses were adjusted for demographics (age, race, sex), comorbidity, cardiac medications, and conditions associated with VA. We calculated hazard ratios (HR) and 95% confidence intervals (CI). Results: Of the 28,755 episodes of new allopurinol use, 2538 were associated with incident VA (8.8%). Among patients with incident VA, 54% were male, 78% were White, 75% had gout as the underlying diagnosis, and the mean Charlson-Romano comorbidity score was 4.8. The crude incidence of VA per 1,000,000 person-days declined as the duration of allopurinol use increased: 1-180 days, 151; 181 days to 2 years, 105; and > 2 years, 85. In multivariableadjusted analyses, compared to non-use, allopurinol use was associated with lower HR of VA of 0.82 (95% CI, 0.76-0.90). Compared to allopurinol non-use, longer allopurinol use durations were significantly associated with lower multivariable-adjusted HR for VA: 1-180 days, 0.96 (95% CI, 0.85-1.08); 181 days to 2 years, 0.76 (95% CI, 0.68-0.85); and > 2 years, 0.72 (95% CI, 0.60-0.87). Multiple sensitivity analyses adjusting for cardiac conditions, anti-arrhythmic drugs and alternate definitions confirmed our findings with minimal/no attenuation of estimates. Conclusion: Allopurinol use and use duration of more than 6 months were independently associated with a lower risk of VA. Future studies need to assess the pathophysiology of this potential benefit. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. [Singh, Jasvinder A.; Cleveland, John] UAB, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Cleveland, John] UAB, Div Epidemiol, Sch Publ Hlth, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. [Singh, Jasvinder A.; Cleveland, John] Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA.; Singh, JA (reprint author), UAB, Sch Med, Dept Med, Birmingham, AL 35294 USA.; Singh, JA (reprint author), UAB, Div Epidemiol, Sch Publ Hlth, Birmingham, AL 35294 USA. EM jasvinder.md@gmail.com FU UAB Division of Rheumatology FX This material is the result of work supported by research funds from the UAB Division of Rheumatology and the resources and use of facilities at the Birmingham VA Medical Center. Role of Funding Agencies: The funding agencies played no role in study design, collection, analysis, interpretation of data, writing of the manuscript, or in the decision to submit the paper for publication. They accept no responsibility for the contents. NR 54 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 1741-7015 J9 BMC MED JI BMC Med. PD MAR 22 PY 2017 VL 15 AR 59 DI 10.1186/s12916-017-0816-6 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EP9FA UT WOS:000397678300001 PM 28327188 ER PT J AU Kanakasabapathy, MK Sadasivam, M Singh, A Preston, C Thirumalaraju, P Venkataraman, M Bormann, CL Draz, MS Petrozza, JC Shafiee, H AF Kanakasabapathy, Manoj Kumar Sadasivam, Magesh Singh, Anupriya Preston, Collin Thirumalaraju, Prudhvi Venkataraman, Maanasa Bormann, Charles L. Draz, Mohamed Shehata Petrozza, John C. Shafiee, Hadi TI An automated smartphone-based diagnostic assay for point-of-care semen analysis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MALE-INFERTILITY; SPERM MOTILITY; QUANTIFICATION; SYSTEM; DEVICE AB Male infertility affects up to 12% of the world's male population and is linked to various environmental and medical conditions. Manual microscope-based testing and computer-assisted semen analysis (CASA) are the current standard methods to diagnose male infertility; however, these methods are labor-intensive, expensive, and laboratory-based. Cultural and socially dominated stigma against male infertility testing hinders a large number of men from getting tested for infertility, especially in resource-limited African countries. We describe the development and clinical testing of an automated smartphone-based semen analyzer designed for quantitative measurement of sperm concentration and motility for point-of-care male infertility screening. Using a total of 350 clinical semen specimens at a fertility clinic, we have shown that our assay can analyze an unwashed, unprocessed liquefied semen sample with <5-s mean processing time and provide the user a semen quality evaluation based on the World Health Organization (WHO) guidelines with similar to 98% accuracy. The work suggests that the integration of microfluidics, optical sensing accessories, and advances in consumer electronics, particularly smartphone capabilities, can make remote semen quality testing accessible to people in both developed and developing countries who have access to smartphones. C1 [Kanakasabapathy, Manoj Kumar; Sadasivam, Magesh; Singh, Anupriya; Preston, Collin; Thirumalaraju, Prudhvi; Venkataraman, Maanasa; Draz, Mohamed Shehata; Shafiee, Hadi] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Engn Med, Boston, MA 02139 USA. [Bormann, Charles L.; Petrozza, John C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Boston, MA 02114 USA. [Shafiee, Hadi] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Shafiee, H (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Engn Med, Boston, MA 02139 USA.; Shafiee, H (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM hshafiee@bwh.harvard.edu FU Brigham Research Institute Pilot Grant; Bright Futures Prize; Innovation Evergreen Fund; Fund to Sustain Research Excellence (Brigham Research Institute, Brigham and Women's Hospital, Harvard Medical School); NIH [1R01AI118502, P30ES000002]; Harvard National Institute of Environmental Health Sciences Grant; American Society of Reproductive Medicine Award (American Board of Obstetrics and Gynecology, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and Society for Reproductive Endocrinology and Infertility) FX This work is supported by the Brigham Research Institute Pilot Grant, the Bright Futures Prize, the Innovation Evergreen Fund, and the Fund to Sustain Research Excellence (Brigham Research Institute, Brigham and Women's Hospital, Harvard Medical School), NIH grants (1R01AI118502 and P30ES000002), a Harvard National Institute of Environmental Health Sciences Grant (Harvard T.H.Chan School of Public Health, Harvard Center for Environmental Health), and an American Society of Reproductive Medicine Award (American Board of Obstetrics and Gynecology, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and Society for Reproductive Endocrinology and Infertility). NR 39 TC 0 Z9 0 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 MAR 22 PY 2017 VL 9 IS 382 AR eaai7863 DI 10.1126/scitranslmed.aai7863 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EP0UK UT WOS:000397102000004 ER PT J AU Anstey, MH Wibrow, B Thevathasan, T Roberts, B Chhangani, K Ng, PY Levine, A DiBiasio, A Sarge, T Eikermann, M AF Anstey, Matthew H. Wibrow, Bradley Thevathasan, Tharusan Roberts, Brigit Chhangani, Khushi Ng, Pauline Yeung Levine, Alexander DiBiasio, Alan Sarge, Todd Eikermann, Matthias TI Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial) SO BMC ANESTHESIOLOGY LA English DT Article DE Midodrine; Alpha adrenergic agonist; Vasopressor; Hypotension; Intensive care unit; High dependency unit ID NEUROGENIC ORTHOSTATIC HYPOTENSION; ORAL MIDODRINE; DOUBLE-BLIND; APPROVAL AB Background: Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital. Methods: The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration. Discussion: Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine. C1 [Anstey, Matthew H.; Wibrow, Bradley; Roberts, Brigit] Sir Charles Gairdner Hosp, Perth, WA, Australia. [Anstey, Matthew H.; Wibrow, Bradley] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Thevathasan, Tharusan; Chhangani, Khushi; Ng, Pauline Yeung; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Thevathasan, Tharusan; Chhangani, Khushi; Ng, Pauline Yeung; Eikermann, Matthias] Harvard Med Sch, Boston, MA 02115 USA. [Levine, Alexander] Univ St Joseph, Dept Pharm Practice & Adm, Hartford, CT USA. [DiBiasio, Alan] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Sarge, Todd] Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, Boston, MA 02215 USA. [Eikermann, Matthias] Univ Duisburg Essen, Klin Anaesthesiol & Intens Med, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.; Eikermann, M (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Eikermann, M (reprint author), Univ Duisburg Essen, Klin Anaesthesiol & Intens Med, Essen, Germany. EM meikermann@partners.org FU Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital; research at Sir Charles Gairdner Hospital FX This research is funded by the Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, as well as Jeff and Judy Buzen (philanthropic funding). Internal departmental funding supports the research at Sir Charles Gairdner Hospital. The funding body or funders have no role in study design, collection, analysis, and interpretation of data, or in manuscript preparation. NR 14 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 1471-2253 J9 BMC ANESTHESIOL JI BMC Anesthesiol. PD MAR 21 PY 2017 VL 17 AR 47 DI 10.1186/s12871-017-0339-x PG 7 WC Anesthesiology SC Anesthesiology GA EP0RG UT WOS:000397093800001 PM 28327122 ER PT J AU Chen, JY Newcomb, B Zhou, C Pondick, JV Ghoshal, S York, SR Motola, DL Coant, N Yi, JK Mao, CG Tanabe, KK Bronova, I Berdyshev, EV Fuchs, BC Hannun, Y Chung, RT Mullen, AC AF Chen, Jennifer Y. Newcomb, Benjamin Zhou, Chan Pondick, Joshua V. Ghoshal, Sarani York, Samuel R. Motola, Daniel L. Coant, Nicolas Yi, Jae Kyo Mao, Cungui Tanabe, Kenneth K. Bronova, Irina Berdyshev, Evgeny V. Fuchs, Bryan C. Hannun, Yusuf Chung, Raymond T. Mullen, Alan C. TI Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells SO SCIENTIFIC REPORTS LA English DT Article ID LIVER FIBROSIS; ACID SPHINGOMYELINASE; SERINE PALMITOYLTRANSFERASE; SPHINGOLIPID METABOLISM; SPHINGOSINE KINASE-1; TUMOR-GROWTH; RAT-LIVER; INHIBITION; ACTIVATION; EXPRESSION AB Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide. C1 [Chen, Jennifer Y.; Zhou, Chan; Pondick, Joshua V.; York, Samuel R.; Motola, Daniel L.; Chung, Raymond T.; Mullen, Alan C.] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Newcomb, Benjamin; Coant, Nicolas; Yi, Jae Kyo; Mao, Cungui; Hannun, Yusuf] SUNY Stony Brook, Hlth Sci Ctr, Stony Brook, NY 11794 USA. [Ghoshal, Sarani; Tanabe, Kenneth K.; Fuchs, Bryan C.] Harvard Med Sch, Massachusetts Gen Hosp, Div Surg Oncol, Ctr Canc, Boston, MA USA. [Bronova, Irina; Berdyshev, Evgeny V.] Natl Jewish Hlth, Denver, CO USA. [Mullen, Alan C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Chung, RT; Mullen, AC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA.; Mullen, AC (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM Chung.Raymond@mgh.harvard.edu; acmullen@mgh.harvard.edu FU Research Scholars Program at MGH; MGH Department of Medicine Transformative Scholar Award; [F32DK10719701A1]; [T32DK007191] FX We thank the Institute of Chemistry and Chemical Biology (ICCB) Longwood Screening Facility at Harvard Medical School for help with assay development and optimization. We acknowledge David Dombkowski and the Center for Regenerative Medicine at Massachusetts General Hospital (MGH) for assistance with flow cytometry (1S10RR020936-01, Dept Path LSR2) and the MGH Program in Membrane Biology for use of the confocal microscope. We thank Russell Jenkins for his helpful advice. This project was supported by F32DK107197-01A1 and T32DK007191 (JYC), the Research Scholars Program at MGH (RTC), and the MGH Department of Medicine Transformative Scholar Award (ACM). NR 74 TC 0 Z9 0 U1 0 U2 0 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 MAR 21 PY 2017 VL 7 AR 44867 DI 10.1038/srep44867 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7FC UT WOS:000396855600001 PM 28322247 ER PT J AU Yoo, B Kavishwar, A Wang, P Ross, A Pantazopoulos, P Dudley, M Moore, A Medarova, Z AF Yoo, Byunghee Kavishwar, Amol Wang, Ping Ross, Alana Pantazopoulos, Pamela Dudley, Michael Moore, Anna Medarova, Zdravka TI Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer SO SCIENTIFIC REPORTS LA English DT Article ID MIR-B-10; REJECTION; MIGRATION; INVASION; CELLS AB Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b- a master regulator of metastatic cell viability - leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche. C1 [Yoo, Byunghee; Kavishwar, Amol; Wang, Ping; Ross, Alana; Pantazopoulos, Pamela; Moore, Anna; Medarova, Zdravka] Massachusetts Gen Hosp, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA. [Yoo, Byunghee; Kavishwar, Amol; Wang, Ping; Ross, Alana; Pantazopoulos, Pamela; Moore, Anna; Medarova, Zdravka] Harvard Med Sch, Boston, MA 02129 USA. [Dudley, Michael] TransCode Therapeut Inc, Boston, MA 02124 USA. RP Moore, A; Medarova, Z (reprint author), Massachusetts Gen Hosp, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA.; Moore, A; Medarova, Z (reprint author), Harvard Med Sch, Boston, MA 02129 USA. EM amoore@helix.mgh.harvard.edu; zmedarova@partners.org NR 14 TC 0 Z9 0 U1 0 U2 0 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 MAR 21 PY 2017 VL 7 AR 45060 DI 10.1038/srep45060 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7DO UT WOS:000396851600001 PM 28322342 ER PT J AU Scarfo, I Maus, MV AF Scarfo, Irene Maus, Marcela V. TI Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Review DE Chimeric antigen receptor T-cells; Adoptive immunotherapy; Tumor microenvironment ID FIBROBLAST ACTIVATION PROTEIN; CHIMERIC ANTIGEN RECEPTORS; CHECKPOINT BLOCKADE; ANTITUMOR EFFICACY; STROMAL CELLS; THERAPY; CANCER; IL-12; INTERLEUKIN-12; EXPRESSION AB Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches. C1 [Maus, Marcela V.] Massachusetts Gen Hosp, Cellular Immunotherapy Program, Ctr Canc, 149 13th St,Room 7-219, Boston, MA 02129 USA. [Maus, Marcela V.] Harvard Med Sch, 149 13th St,Room 7-219, Boston, MA 02129 USA. RP Maus, MV (reprint author), Massachusetts Gen Hosp, Cellular Immunotherapy Program, Ctr Canc, 149 13th St,Room 7-219, Boston, MA 02129 USA. EM mvmaus@mgh.harvard.edu FU American-Italian Cancer Foundation Post-Doctoral Research Fellowship; NIH [NCI K08CA166039]; Gabrielle's Angel Foundation; V Foundation FX Irene Scarfo receives support from American-Italian Cancer Foundation Post-Doctoral Research Fellowship. Marcela Maus receives support from the NIH (NCI K08CA166039), the Gabrielle's Angel Foundation, and the V Foundation. NR 54 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 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAR 21 PY 2017 VL 5 AR 28 DI 10.1186/s40425-017-0230-9 PG 8 WC Oncology SC Oncology GA EO8CT UT WOS:000396917300001 PM 28331617 ER PT J AU Charidimou, A Boulouis, G Pasi, M Auriel, E van Etten, ES Haley, K Ayres, A Schwab, KM Martinez-Ramirez, S Goldstein, JN Rosand, J Viswanathan, A Greenberg, SM Gurol, ME AF Charidimou, Andreas Boulouis, Gregoire Pasi, Marco Auriel, Eitan van Etten, Ellis S. Haley, Kellen Ayres, Alison Schwab, Kristin M. Martinez-Ramirez, Sergi Goldstein, Joshua N. Rosand, Jonathan Viswanathan, Anand Greenberg, Steven M. Gurol, M. Edip TI MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy SO NEUROLOGY LA English DT Article ID SMALL VESSEL DISEASE; CORTICAL SUPERFICIAL SIDEROSIS; VIRCHOW-ROBIN SPACES; INTRACEREBRAL HEMORRHAGE; ALZHEIMERS-DISEASE; PREVALENCE; PATHOLOGY; SEVERITY; INSIGHTS; MARKERS AB Objective: To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). Methods: Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 < 10, 2 = 11-20, 3 = 21-40, and 4 > 40 EPVS). We tested associations of predefined highdegree (score > 2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance ( i. e.,CSO-EPVS. BG-EPVS) and BG-EPVS predominance pattern ( i. e., BG-EPVS. CSO-EPVS) in adjusted multinomial logistic regression ( reference group, BG-EPVS= CSO-EPVS). Results: We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO- EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10-1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30-3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75-4.64, p, 0.0001) and higher WMH volume ( OR 1.02, 95% CI 1.01-1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO- EPVS-predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0001). CSO- PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. Conclusions: Different patterns ofMRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH. C1 [Charidimou, Andreas; Boulouis, Gregoire; Pasi, Marco; Auriel, Eitan; van Etten, Ellis S.; Haley, Kellen; Ayres, Alison; Schwab, Kristin M.; Martinez-Ramirez, Sergi; Viswanathan, Anand; Greenberg, Steven M.; Gurol, M. Edip] Harvard Med Sch, Hemorrhag Stroke Res Program, Massachusetts Gen Hosp, Dept Neurol,Stroke Res Ctr, Boston, MA 02115 USA. [Boulouis, Gregoire] Univ Paris 05, Ctr Hosp St Anne, INSERM, UMR 894,Dept Neuroradiol, Paris, France. [Goldstein, Joshua N.; Rosand, Jonathan] Harvard Med Sch, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA USA. RP Charidimou, A (reprint author), Harvard Med Sch, Hemorrhag Stroke Res Program, Massachusetts Gen Hosp, Dept Neurol,Stroke Res Ctr, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk FU NIH [5K23NS083711, R01 NS070834, 2R01 AG26484]; Bodossaki Foundation postdoctoral research scheme FX This study was supported by the following NIH grants: 5K23NS083711 (M.E.G.), R01 NS070834, and 2R01 AG26484 (S.M.G.). A Charidimou is supported by the Bodossaki Foundation postdoctoral research scheme. NR 35 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 MAR 21 PY 2017 VL 88 IS 12 BP 1157 EP 1164 DI 10.1212/WNL.0000000000003746 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EP4XK UT WOS:000397383000015 PM 28228568 ER PT J AU Fanola, CL Giugliano, RP Ruff, CT Trevisan, M Nordio, F Mercuri, MF Antman, EM Braunwald, E AF Fanola, Christina L. Giugliano, Robert P. Ruff, Christian T. Trevisan, Marco Nordio, Francesco Mercuri, Michele F. Antman, Elliott M. Braunwald, Eugene TI A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Atrial fibrillation; Anticoagulants; Stroke; Warfarin; Edoxaban ID VITAMIN-K ANTAGONIST; CLASSIFICATION SCHEMES; ORAL ANTICOAGULANTS; NATIONAL REGISTRY; SAME-TT2R2 SCORE; WARFARIN; STROKE; EDOXABAN; RIVAROXABAN; VALIDATION AB Aims The choice between initiating a non-vitamin K antagonist oral anticoagulant (NOAC) and a vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) may be challenging. To assist in this decision, we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted. Methods and results ENGAGE AF-TIMI 48 was a randomized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF. Cox proportional hazard models identified factors associated with a serious net clinical outcome (NCO) of disabling stroke, life-threatening bleeding, and all-cause mortality in VKA naive patients from the warfarin arm. These were used to develop an integer risk score. Performance was assessed by C-indices and validation by bootstrapping. KaplanMeier analyses were stratified by three score categories and treatment arm. Over a median of 2.7 years, 457 NCO events occurred in 2898 patients with a total person-time of 7549.5 years (6.05%/ year). The risk prediction model (C = 0.693) for the NCO was translated into a 17-point integer score, with annualized event rates for the low, intermediate, and high-risk categories in the warfarin arm of 3.5%, 9.9%, and 20.8%, respectively. Therapeutic benefit of higher-and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate- risk, with equal benefit in the low-risk categories ( P-interaction 0.008 and 0.014, respectively). Conclusion In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA. C1 [Fanola, Christina L.; Giugliano, Robert P.; Ruff, Christian T.; Trevisan, Marco; Nordio, Francesco; Antman, Elliott M.; Braunwald, Eugene] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Cardiovasc,TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. [Mercuri, Michele F.] Daiichi Sankyo Pharma Dev, 399 Thornall St, Edison, NJ 08837 USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Cardiovasc,TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM ebraunwald@partners.org FU Daiichi Sankyo. FX The ENGAGE AF-TIMI 48 study was supported by a research grant from Daiichi Sankyo. NR 28 TC 2 Z9 2 U1 0 U2 0 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 MAR 21 PY 2017 VL 38 IS 12 BP 888 EP 896 DI 10.1093/eurheartj/ehw565 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP1LK UT WOS:000397146200011 ER PT J AU Harris, JA Byhoff, E Perumalswami, CR Langa, KM Wright, AA Griggs, JJ AF Harris, John A. Byhoff, Elena Perumalswami, Chithra R. Langa, Kenneth M. Wright, Alexi A. Griggs, Jennifer J. TI The Relationship of Obesity to Hospice Use and Expenditures A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID OF-LIFE CARE; PALLIATIVE CARE; MEDICARE BENEFICIARIES; FAMILY PERSPECTIVES; MENTAL-HEALTH; OLDER-ADULTS; RISK-FACTORS; END; CANCER; PATIENT AB Background: Obesity complicates medical, nursing, and informal care in severe illness, but its effect on hospice use and Medicare expenditures is unknown. Objective: To describe the associations between body mass index (BMI) and hospice use and Medicare expenditures in the last 6 months of life. Design: Retrospective cohort. Setting: The HRS (Health and Retirement Study). Participants: 5677 community-dwelling Medicare fee-forservice beneficiaries who died between 1998 and 2012. Measurements: Hospice enrollment, days enrolled in hospice, in-home death, and total Medicare expenditures in the 6 months before death. Body mass index was modeled as a continuous variable with a quadratic functional form. Results: For decedents with BMI of 20 kg/m(2), the predicted probability of hospice enrollment was 38.3% (95% CI, 36.5% to 40.2%), hospice duration was 42.8 days (CI, 42.3 to 43.2 days), probability of in-home death was 61.3% (CI, 59.4% to 63.2%), and total Medicare expenditures were $ 42 803 (CI, $ 41 085 to $ 44 521). When BMI increased to 30 kg/m2, the predicted probability of hospice enrollment decreased by 6.7 percentage points (CI, -9.3 to -4.0 percentage points), hospice duration decreased by 3.8 days (CI, -4.4 to -3.1 days), probability of in-home death decreased by 3.2 percentage points (CI, -6.0 to -0.4 percentage points), and total Medicare expenditures increased by $ 3471 (CI, $ 955 to $ 5988). For morbidly obese decedents (BMI = 40 kg/m2), the predicted probability of hospice enrollment decreased by 15.2 percentage points (CI, -19.6 to -10.9 percentage points), hospice duration decreased by 4.3 days (CI, -5.7 to -2.9 days), and in-home death decreased by 6.3 percentage points (CI, -11.2 to -1.5 percentage points) versus decedents with BMI of 20 kg/m(2). Limitation: Baseline data were self-reported, and the interval between reported BMI and time of death varied. Conclusion: Among community-dwelling decedents in the HRS, increasing obesity was associated with reduced hospice use and in-home death and higher Medicare expenditures in the last 6 months of life. C1 [Byhoff, Elena; Perumalswami, Chithra R.] Univ Michigan, Dept Med, Inst Healthcare Policy & Innovat, 2800 Plymouth Rd,Bldg 10,Room G100, Ann Arbor, MI 48109 USA. [Langa, Kenneth M.] Univ Michigan, Inst Gerontol, Inst Healthcare Policy & Innovat, 2800 Plymouth Rd,Bldg 16,Room 444E, Ann Arbor, MI 48109 USA. [Griggs, Jennifer J.] Univ Michigan, Sch Publ Hlth, Dept Med & Hlth Management & Policy, Div Hematol & Oncol, 2800 Plymouth Rd,Bldg 16,Room 116W, Ann Arbor, MI 48109 USA. [Wright, Alexi A.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Harris, JA (reprint author), Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, 300 Halket St,Suite 2328, Pittsburgh, PA 15213 USA. EM harrisja@mail.magee.edu FU National Institute on Aging [U01 AG009740, P30 AG024824]; Robert Wood Johnson Foundation; U.S. Department of Veterans Affairs; National Cancer Institute [K07 CA166210] FX The Health and Retirement Study is funded by the National Institute on Aging (U01 AG009740) and performed at the Institute for Social Research, University of Michigan. Drs. Harris and Byhoff were supported by the Robert Wood Johnson Foundation at the time the manuscript was originally submitted. Dr. Byhoff was supported by the U.S. Department of Veterans Affairs. Dr. Perumalswami is supported by the Robert Wood Johnson Foundation and the U.S. Department of Veterans Affairs. Dr. Langa is supported by the U.S. Department of Veterans Affairs and the National Institute on Aging (P30 AG024824). Dr. Wright is supported by the National Cancer Institute (K07 CA166210). NR 53 TC 0 Z9 0 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 MAR 21 PY 2017 VL 166 IS 6 BP 381 EP + DI 10.7326/M16-0749 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA EO9RM UT WOS:000397025800013 PM 28166546 ER PT J AU Rodrigues, AR Yakushiji-Kaminatsui, N Atsuta, Y Andrey, G Schorderet, P Duboule, D Tabin, CJ AF Rodrigues, Alan R. Yakushiji-Kaminatsui, Nayuta Atsuta, Yuji Andrey, Guillaume Schorderet, Patrick Duboule, Denis Tabin, Clifford J. TI Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Sonic hedgehog; fibroblast growth factor; Hox genes; limb development ID APICAL ECTODERMAL RIDGE; DEEP-SEQUENCING DATA; SONIC-HEDGEHOG; VERTEBRATE LIMB; FEEDBACK LOOP; MAMMALIAN LIMB; CHICK LIMB; GROWTH; BUD; SPECIFICATION AB During embryonic development, fields of progenitor cells form complex structures through dynamic interactions with external signaling molecules. How complex signaling inputs are integrated to yield appropriate gene expression responses is poorly understood. In the early limb bud, for instance, Sonic hedgehog (Shh) is expressed in the distal posterior mesenchyme, where it acts as a mediator of anterior to posterior (AP) patterning, whereas fibroblast growth factor 8 (Fgf8) is produced by the apical ectodermal ridge (AER) at the distal tip of the limb bud to direct outgrowth along the proximal to distal (PD) axis. Here we use cultured limb mesenchyme cells to assess the response of the target Hoxd genes to these two factors. We find that they act synergistically and that both factors are required to activate Hoxd13 in limb mesenchymal cells. However, the analysis of the enhancer landscapes flanking the HoxD cluster reveals that the bimodal regulatory switch observed in vivo is only partially achieved under these in vitro conditions, suggesting an additional requirement for other factors. C1 [Rodrigues, Alan R.; Atsuta, Yuji; Tabin, Clifford J.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Yakushiji-Kaminatsui, Nayuta; Andrey, Guillaume; Schorderet, Patrick; Duboule, Denis] Fed Inst Technol, Lab Dev Genom, CH-1015 Lausanne, Switzerland. [Duboule, Denis] Univ Geneva, Dept Genet & Evolut, CH-1205 Geneva, Switzerland. [Andrey, Guillaume] Max Planck Inst Mol Genet, RG Dev & Dis, D-14195 Berlin, Germany. [Schorderet, Patrick] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Tabin, CJ (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Duboule, D (reprint author), Fed Inst Technol, Lab Dev Genom, CH-1015 Lausanne, Switzerland.; Duboule, D (reprint author), Univ Geneva, Dept Genet & Evolut, CH-1205 Geneva, Switzerland. EM denis.duboule@epfl.ch; tabin@genetics.med.harvard.edu OI Andrey, Guillaume/0000-0002-0911-4907 FU NIH [HD032443]; Swiss National Science Foundation [310030B_138662] FX We thank Drs. John F. Fallon for providing the chicken Ozd mutant embryos and Jean-Marc Matter for sharing materials. This work was supported by NIH Grant HD032443 (to C. J. T.) and Swiss National Science Foundation Grant 310030B_138662 (to D. D.). NR 51 TC 0 Z9 0 U1 2 U2 2 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 MAR 21 PY 2017 VL 114 IS 12 BP 3139 EP 3144 DI 10.1073/pnas.1620767114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7TS UT WOS:000396893600063 PM 28270602 ER PT J AU Pishesha, N Bilate, AM Wibowo, MC Huang, NJ Li, ZY Dhesycka, R Bousbaine, D Li, HJ Patterson, HC Dougan, SK Maruyama, T Lodish, HF Ploegh, HL AF Pishesha, Novalia Bilate, Angelina M. Wibowo, Marsha C. Huang, Nai-Jia Li, Zeyang Dhesycka, Rhogerry Bousbaine, Djenet Li, Hojun Patterson, Heide C. Dougan, Stephanie K. Maruyama, Takeshi Lodish, Harvey F. Ploegh, Hidde L. TI Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sortase; engineered red blood cells; antigen-specific tolerance; autoimmune diseases ID RED-BLOOD-CELLS; REGULATORY T-CELLS; CENTRAL-NERVOUS-SYSTEM; DENDRITIC CELLS; IMMUNE TOLERANCE; ORAL TOLERANCE; MOUSE MODEL; IN-VIVO; B-CELLS; ENCEPHALOMYELITIS AB Current therapies for autoimmune diseases rely on traditional immunosuppressive medications that expose patients to an increased risk of opportunistic infections and other complications. Immunoregulatory interventions that act prophylactically or therapeutically to induce antigen-specific tolerance might overcome these obstacles. Here we use the transpeptidase sortase to covalently attach diseaseassociated autoantigens to genetically engineered and to unmodified red blood cells as a means of inducing antigen-specific tolerance. This approach blunts the contribution to immunity of major subsets of immune effector cells (B cells, CD4(+) and CD8(+) T cells) in an antigenspecific manner. Transfusion of red blood cells expressing self-antigen epitopes can alleviate and even prevent signs of disease in experimental autoimmune encephalomyelitis, as well as maintain normoglycemia in a mouse model of type 1 diabetes. C1 [Pishesha, Novalia; Bilate, Angelina M.; Wibowo, Marsha C.; Huang, Nai-Jia; Li, Zeyang; Dhesycka, Rhogerry; Bousbaine, Djenet; Li, Hojun; Patterson, Heide C.; Dougan, Stephanie K.; Maruyama, Takeshi; Lodish, Harvey F.; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Pishesha, Novalia; Dhesycka, Rhogerry; Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02142 USA. [Pishesha, Novalia; Li, Zeyang; Bousbaine, Djenet; Ploegh, Hidde L.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wibowo, Marsha C.; Bousbaine, Djenet; Lodish, Harvey F.; Ploegh, Hidde L.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Ploegh, Hidde L.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Lodish, HF; Ploegh, HL (reprint author), Whitehead Inst Biomed Res, Cambridge, MA 02142 USA.; Lodish, HF (reprint author), MIT, Dept Biol Engn, Cambridge, MA 02142 USA.; Ploegh, HL (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Lodish, HF; Ploegh, HL (reprint author), MIT, Dept Biol, Cambridge, MA 02142 USA.; Ploegh, HL (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM lodish@wi.mit.edu; hidde.ploegh@childrens.harvard.edu FU Defense Advanced Research Projects Agency Contract [HR0011-12-2-0015]; Schlumberger Foundation Faculty for the Future; Howard Hughes Medical Institute International Student Research Fellowship; Siebel Scholarship FX We thank members of the H. F. L. and H. L. P. laboratories, especially Lenka Kundrat and Jiahai Shi, for discussions; Jessica R. Ingram and Yushu Xie for critical reading of the manuscript; Marko Knoll and Leif S. Ludwig for providing reagents; John Jackson, Tony Chavarria, and Ferenc Reinhardt for mouse husbandry; Tom DiCesare for assistance with illustrations; and Prathapan Thiru and George W. Bell in Bioinformatics and Research Computing (Whitehead Institute) for assistance with statistical analyses. This work was supported by Defense Advanced Research Projects Agency Contract HR0011-12-2-0015 (to H. L. P. and H. F. L.) and grants from the Schlumberger Foundation Faculty for the Future, the Howard Hughes Medical Institute International Student Research Fellowship, and the Siebel Scholarship (to N. P.). NR 55 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 MAR 21 PY 2017 VL 114 IS 12 BP 3157 EP 3162 DI 10.1073/pnas.1701746114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7TS UT WOS:000396893600066 PM 28270614 ER PT J AU Bierie, B Pierce, SE Kroeger, C Stover, DG Pattabiraman, DR Thiru, P Donaher, JL Reinhardt, F Chaffer, CL Keckesova, Z Weinberg, RA AF Bierie, Brian Pierce, Sarah E. Kroeger, Cornelia Stover, Daniel G. Pattabiraman, Diwakar R. Thiru, Prathapan Donaher, Joana Liu Reinhardt, Ferenc Chaffer, Christine L. Keckesova, Zuzana Weinberg, Robert A. TI Integrin-beta 4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; heterogeneity; EMT; mesenchymal; ITGB4 ID HYBRID EPITHELIAL/MESENCHYMAL PHENOTYPE; HUMAN BREAST-CANCER; EPITHELIAL-CELLS; MICROARRAY DATA; TRANSITION; EXPRESSION; BETA-4; SUBTYPES; SURVIVAL; EMT AB Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-beta 4 (ITGB4), can be used to enable stratification of mesenchymal like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4(+) cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63 alpha (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC. C1 [Bierie, Brian; Kroeger, Cornelia; Pattabiraman, Diwakar R.; Thiru, Prathapan; Donaher, Joana Liu; Reinhardt, Ferenc; Chaffer, Christine L.; Keckesova, Zuzana; Weinberg, Robert A.] Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. [Pierce, Sarah E.] Brown Univ, Dept Biol, Providence, RI 02912 USA. [Stover, Daniel G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Weinberg, Robert A.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Weinberg, Robert A.] MIT, Ludwig Ctr Mol Oncol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Weinberg, RA (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA.; Weinberg, RA (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA.; Weinberg, RA (reprint author), MIT, Ludwig Ctr Mol Oncol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM weinberg@wi.mit.edu FU US Department of Defense Breast Cancer Research Program [W81XWH-10-1-0647]; National Health and Medical Research Council of Australia [NHMRC APP1071853]; NIH/ National Cancer Institute (NCI) [1K99CA201574-01A1]; NCI [5R01CA078461-17, 5P01CA080111-18]; American Cancer Society Research Professor; Foundation Cancer Research Professor FX We thank Richard Goldsby, Arthur Lambert, Jordan Krall, Anushka Dongre, Asaf Spiegel, Sonia Iyer, Tsukasa Shibue, Xin Ye, Julia Frose, Jasmine DeCock, and Yun Zhang for essential comments and suggestions during the course of this work, as well as the Flow Cytometry Core Facility at the Whitehead Institute for Biomedical Research. This work was funded by grants from the US Department of Defense Breast Cancer Research Program (W81XWH-10-1-0647 to B. B.), C. J. Martin Overseas Biomedical Fellowship from the National Health and Medical Research Council of Australia (NHMRC APP1071853 to D.R.P.), K99/R00 Pathway to Independence Award [NIH/ National Cancer Institute (NCI) 1K99CA201574-01A1 to D.R.P.], and NCI (5R01CA078461-17 and 5P01CA080111-18 to R.A.W.). R. A. W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Foundation Cancer Research Professor. NR 48 TC 0 Z9 0 U1 0 U2 0 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 MAR 21 PY 2017 VL 114 IS 12 BP E2337 EP E2346 DI 10.1073/pnas.1618298114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7TS UT WOS:000396893600012 PM 28270621 ER PT J AU Niu, B Paulson, JN Zheng, XQ Kolter, R AF Niu, Ben Paulson, Joseph Nathaniel Zheng, Xiaoqi Kolter, Roberto TI Simplified and representative bacterial community of maize roots SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE maize; synthetic community; community assembly; biological control ID MICROBIAL COMMUNITIES; RHIZOSPHERE MICROBIOME; SEQUENCING DATA; PLANT HEALTH; SOIL; DIVERSITY; INVASION; SHAPE; BIOGEOGRAPHY; SELECTION AB Plant-associated microbes are important for the growth and health of their hosts. As a result of numerous prior studies, we know that host genotypes and abiotic factors influence the composition of plant microbiomes. However, the high complexity of these communities challenges detailed studies to define experimentally the mechanisms underlying the dynamics of community assembly and the beneficial effects of such microbiomes on plant hosts. In this work, from the distinctive microbiota assembled by maize roots, through host-mediated selection, we obtained a greatly simplified synthetic bacterial community consisting of seven strains (Enterobacter cloacae, Stenotrophomonas maltophilia, Ochrobactrum pituitosum, Herbaspirillum frisingense, Pseudomonas putida, Curtobacterium pusillum, and Chryseobacterium indologenes) representing three of the four most dominant phyla found in maize roots. By using a selective culture-dependent method to track the abundance of each strain, we investigated the role that each plays in community assembly on roots of axenic maize seedlings. Only the removal of E. cloacae led to the complete loss of the community, and C. pusillum took over. This result suggests that E. cloacae plays the role of keystone species in this model ecosystem. In planta and in vitro, this model community inhibited the phytopathogenic fungus Fusarium verticillioides, indicating a clear benefit to the host. Thus, combined with the selective culture-dependent quantification method, our synthetic seven-species community representing the root microbiome has the potential to serve as a useful system to explore how bacterial interspecies interactions affect root microbiome assembly and to dissect the beneficial effects of the root microbiota on hosts under laboratory conditions in the future. C1 [Niu, Ben; Kolter, Roberto] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Paulson, Joseph Nathaniel; Zheng, Xiaoqi] Dana Farber Canc Inst, Dept Biostatist & Computat Biol, Boston, MA 02115 USA. [Paulson, Joseph Nathaniel] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Zheng, Xiaoqi] Shanghai Normal Univ, Dept Math, Shanghai 200234, Peoples R China. RP Kolter, R (reprint author), Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA. EM roberto_kolter@hms.harvard.edu FU China Green Health Agriculture Postdoctoral Fellowship; NIH [5R01-HL111759, 1U01-CA190234, GM58218] FX We thank Koji Yasuda for data analysis; Dr. Charles Bacon for his generous gift of F. verticillioides strains; Dr. Scott Chimileski for the imaging analyses of fungal growth inhibition; Dr. Alejandro Reyes and Dr. Meng Wu for valuable advice on data analysis and comments on the manuscript; and Dr. Nicholas Griffin, Dr. Kornelia Smalla, Dr. Ching-Hong Yang, and members of the R.K. laboratory for valuable advice. B.N. was supported, in part, by a China Green Health Agriculture Postdoctoral Fellowship. J.N.P. was supported by NIH Grants 5R01-HL111759 and 1U01-CA190234 (to John Quackenbush). This work was supported by NIH Grant GM58218 (to R.K.). NR 88 TC 0 Z9 0 U1 7 U2 7 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 MAR 21 PY 2017 VL 114 IS 12 BP E2450 EP E2459 DI 10.1073/pnas.1616148114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7TS UT WOS:000396893600024 PM 28275097 ER PT J AU Capoulade, R Bowdish, M Kron, IL Smith, P Hung, J AF Capoulade, Romain Bowdish, Michael Kron, Irving L. Smith, Peter Hung, Judy TI Response by Capoulade et al to Letter Regarding Article, "Impact of Left Ventricular to Mitral Valve Ring Mismatch on Recurrent Ischemic Mitral Regurgitation After Ring Annuloplasty" SO CIRCULATION LA English DT Letter C1 [Capoulade, Romain; Hung, Judy] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Bowdish, Michael] USC, Keck Sch Med, Dept Surg, Los Angeles, CA USA. [Kron, Irving L.] Univ Virginia Hlth Syst, Dept Surg, Heart & Vasc Ctr, Charlottesville, VA USA. [Smith, Peter] Duke Univ Med, Dept Surg, Durham, NC USA. RP Capoulade, R (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. 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 MAR 21 PY 2017 VL 135 IS 12 BP 785 EP 786 DI 10.1161/CIRCULATIONAHA.117.026957 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO5LA UT WOS:000396733400006 ER PT J AU Renda, G Ricci, F Giugliano, RP De Caterina, R AF Renda, Giulia Ricci, Fabrizio Giugliano, Robert P. De Caterina, Raffaele TI Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atrial fibrillation; bleeding; death; major bleeding; stroke; systemic embolism; valvular heart disease ID VALVE DISEASE; WARFARIN; TRIAL; EPIDEMIOLOGY; RIVAROXABAN; DABIGATRAN; STROKE; APIXABAN AB BACKGROUND Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. OBJECTIVES This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. METHODS We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. RESULTS Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR: 1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). CONCLUSIONS High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD. (J Am Coll Cardiol 2017; 69: 1363-71) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). C1 [Renda, Giulia; Ricci, Fabrizio; De Caterina, Raffaele] Univ G DAnnunzio, Inst Cardiol, Chieti, Italy. [Renda, Giulia; Ricci, Fabrizio; De Caterina, Raffaele] Univ G DAnnunzio, Ctr Excellence Aging, Chieti, Italy. [Giugliano, Robert P.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. RP Giugliano, RP (reprint author), TIMI Study Off, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA.; De Caterina, R (reprint author), Univ G DAnnunzio, Osped SS Annunziata, Inst Cardiol, Via Vestini, I-66013 Chieti, Italy. EM rgiugliano@partners.org; rdecater@unich.it FU Boehringer Ingelheim; Daiichi-Sankyo; Bayer; Merck; Bristol-Myers Squibb; Portola; Pfizer; Bristol-Myers Squibb/Pfizer; Roche FX Dr. Renda has received consultant and speaker fees from Boehringer Ingelheim, Daiichi-Sankyo, and Bayer. Dr. Giugliano has received research grants from Daiichi-Sankyo and Merck; honoraria from Daiichi-Sankyo and the American College of Cardiology; and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Merck, Portola, and Pfizer. Dr. De Caterina has received research grant support from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, and Roche; and honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, AstraZeneca, Merck, Lilly, and Novartis. Dr. Ricci has reported that he has no relationships relevant to the contents of this paper to disclose. NR 27 TC 1 Z9 1 U1 8 U2 8 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 MAR 21 PY 2017 VL 69 IS 11 BP 1363 EP 1371 DI 10.1016/j.jacc.2016.12.038 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AU UT WOS:000396361500002 PM 28302287 ER PT J AU De Caterina, R Renda, G Carnicelli, AP Nordio, F Trevisan, M Mercuri, MF Ruff, CT Antman, EM Braunwald, E Giugliano, RP AF De Caterina, Raffaele Renda, Giulia Carnicelli, Anthony P. Nordio, Francesco Trevisan, Marco Mercuri, Michele F. Ruff, Christian T. Antman, Elliott M. Braunwald, Eugene Giugliano, Robert P. TI Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulation; atrial fibrillation; edoxaban; NOACs; valvular heart disease; warfarin ID NONVALVULAR ATRIAL-FIBRILLATION; VALVE DISEASE; DABIGATRAN; ANTICOAGULATION; EPIDEMIOLOGY; RIVAROXABAN; DEFINITION; PREVENTION; APIXABAN; EVENTS AB BACKGROUND The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest. OBJECTIVES This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. METHODS Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. RESULTS After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.26 to 1.56; p < 0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p < 0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [p(int)] = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; p(int) = 0.57). CONCLUSIONS The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391) (J Am Coll Cardiol 2017; 69: 1372-82) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [De Caterina, Raffaele; Renda, Giulia] Univ G DAnnunzio, Inst Cardiol, Chieti, Italy. [De Caterina, Raffaele; Renda, Giulia] Univ G DAnnunzio, Ctr Excellence Aging, Chieti, Italy. [Carnicelli, Anthony P.; Nordio, Francesco; Trevisan, Marco; Ruff, Christian T.; Antman, Elliott M.; Braunwald, Eugene; Giugliano, Robert P.] Brigham & Womens Hosp, Cardiovasc Med Div, 75 Francis St, Boston, MA 02115 USA. [Mercuri, Michele F.] Daiichi Sankyo, Pharma Dev, Parsippany, NJ USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org FU Daiichi-Sankyo; Boehringer Ingelheim; Bayer; Bristol-Myers Squibb/Pfizer; Roche; AstraZeneca; Eisai; Intarcia; GlaxoSmithKline; Novartis; Duke University; Merck; American College of Cardiology FX The ENGAGE AF-TIMI 48 trial was supported by a research grant from Daiichi-Sankyo to the Brigham and Women's Hospital. Dr. De Caterina has received research grants through his institution from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, and Roche; and has received honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Lilly, AstraZeneca, Merck, Eli Lilly, and Novartis. Dr. Renda is a compensated consultant and speaker for Boehringer Ingelheim, Daiichi-Sankyo, and Bayer. Drs. Nordio, Trevisan, and Antman have received grant support through their institutions from Daiichi-Sankyo. Dr. Mercuri is an employee of Daiichi-Sankyo; and holds a pending patent related to clinical properties of edoxaban. Dr. Ruff has received grant support through his institution from Daiichi-Sankyo, AstraZeneca, Eisai, Intarcia, and GlaxoSmithKline; and is a consultant for and received honoraria from Daiichi-Sankyo, Boehringer Ingelheim, Bayer, and Portola. Dr. Braunwald has received grant support through his institution from Daiichi-Sankyo, AstraZeneca, Novartis, Duke University, Merck, and GlaxoSmithKline; is an uncompensated consultant and lecturer for Merck and Novartis; and is a consultant for The Medicines Company, Sanofi, and Theravance; and is a compensated lecturer for Daiichi-Sankyo, Menarini International, Bayer, and Medscape. Dr. Giugliano has received research grants and honoraria for CME programs from Daiichi-Sankyo and the American College of Cardiology; and is a compensated consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Merck, Portola, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 28 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 21 PY 2017 VL 69 IS 11 BP 1372 EP 1382 DI 10.1016/j.jacc.2016.12.031 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AU UT WOS:000396361500003 PM 28302288 ER PT J AU Konstam, MA Kiernan, M Chandler, A Dhingra, R Mody, FV Eisen, H Haught, WH Wagoner, L Gupta, D Patten, R Gordon, P Korr, K Fileccia, R Pressler, SJ Gregory, D Wedge, P Dowling, D Romeling, M Konstam, JM Massaro, JM Udelson, JE AF Konstam, Marvin A. Kiernan, Michael Chandler, Arthur Dhingra, Ravi Mody, Freny Vaghaiwalla Eisen, Howard Haught, W. Herbert Wagoner, Lynne Gupta, Divya Patten, Richard Gordon, Paul Korr, Kenneth Fileccia, Russell Pressler, Susan J. Gregory, Douglas Wedge, Patricia Dowling, Douglas Romeling, Matthew Konstam, Jeremy M. Massaro, Joseph M. Udelson, James E. CA SECRET CHF Investigators TI Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE clinical trials; diuresis; dyspnea; jugular venous pressure; vasopressin antagonism ID WORSENING RENAL-FUNCTION; VASOPRESSIN ANTAGONIST; CONTROLLED-TRIAL; CLINICAL-COURSE; ORAL TOLVAPTAN; OUTCOMES; DECONGESTION; DYSFUNCTION; CHF AB BACKGROUND In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments. OBJECTIVES It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response. METHODS In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m(2); 2) hyponatremia; or 3) diuretic resistance (urine output <= 125 ml/h following intravenous furosemide >= 40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach. RESULTS We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 +/- 2.1 kg vs. -0.9 +/- 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings. CONCLUSIONS Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [ SECRET of CHF]; NCT01584557) (J Am Coll Cardiol 2017; 69: 1409-19) (C) 2017 by the American College of Cardiology Foundation. C1 [Konstam, Marvin A.; Kiernan, Michael; Udelson, James E.] Tufts Med Ctr, Cardiovasc Ctr, Box 108,800 Washington St, Boston, MA 02111 USA. [Chandler, Arthur] Univ Cardiol Associates, Augusta, GA USA. [Dhingra, Ravi] Univ Wisconsin, Cardiovasc Div, Madison, WI USA. [Mody, Freny Vaghaiwalla] VA Greater Los Angeles, Div Cardiol, Los Angeles, CA USA. [Eisen, Howard] Drexel Univ, Div Cardiol, Philadelphia, PA 19104 USA. [Haught, W. Herbert] Heart Ctr Res, Huntsville, AL USA. [Wagoner, Lynne] Mercy Hosp, Inst Heart, Fairfield, OH USA. [Gupta, Divya] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Patten, Richard] Lahey Med Ctr, Cardiovasc Med, Burlington, MA USA. [Gordon, Paul; Korr, Kenneth] Miriam Hosp, Cardiovasc Inst, Providence, RI 02906 USA. [Fileccia, Russell] Adv Cardiovasc Specialists, Shreveport, LA USA. [Pressler, Susan J.] Indiana Univ, Sch Nursing, Ctr Enhancing Qual Life Chron Dis, Indianapolis, IN 46204 USA. [Gregory, Douglas; Wedge, Patricia; Dowling, Douglas; Romeling, Matthew; Konstam, Jeremy M.] Cardiovasc Clin Sci Fdn, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Konstam, MA (reprint author), Tufts Med Ctr, Cardiovasc Ctr, Box 108,800 Washington St, Boston, MA 02111 USA. EM mkonstam@tuftsmedicalcenter.org FU Otsuka Pharmaceuticals Co., Rockville, Maryland; Otsuka Pharmaceuticals; Otsuka FX This investigation was an investigator-initiated study funded by Otsuka Pharmaceuticals Co., Rockville, Maryland. Each of the authors and/or their organizations received support originating from Otsuka Pharmaceuticals to support this research. Dr. Gupta has received additional research support from Otsuka. Drs. M.A. Konstam and Wagoner have received honoraria from Otsuka. Randall Starling, MD, served as Guest Editor for this paper. NR 22 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 MAR 21 PY 2017 VL 69 IS 11 BP 1409 EP 1419 DI 10.1016/j.jacc.2016.12.035 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AU UT WOS:000396361500009 PM 28302292 ER PT J AU Gerhard-Herman, MD Gornik, HL Barrett, C Barshes, NR Corriere, MA Drachman, DE Fleisher, LA Fowkes, FGR Hamburg, NM Kinlay, S Lookstein, R Misra, S Mureebe, L Olin, JW Patel, RAG Regensteiner, JG Schanzer, A Shishehbor, MH Stewart, KJ Treat-Jacobson, D Walsh, ME AF Gerhard-Herman, Marie D. Gornik, Heather L. Barrett, Coletta Barshes, Neal R. Corriere, Matthew A. Drachman, Douglas E. Fleisher, Lee A. Fowkes, Francis Gerry R. Hamburg, Naomi M. Kinlay, Scott Lookstein, Robert Misra, Sanjay Mureebe, Leila Olin, Jeffrey W. Patel, Rajan A. G. Regensteiner, Judith G. Schanzer, Andres Shishehbor, Mehdi H. Stewart, Kerry J. Treat-Jacobson, Diane Walsh, M. Eileen TI 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC/AHA Clinical Practice Guideline; acute limb ischemia; antiplatelet agents; bypass surgery; claudication; critical limb ischemia; endovascular procedures; limb salvage; peripheral artery disease; smoking cessation; supervised exercise ID CRITICAL LIMB ISCHEMIA; ANKLE-BRACHIAL INDEX; RANDOMIZED-CONTROLLED-TRIAL; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; FOOT INFECTION WIFI; ULTRASOUND-ACCELERATED THROMBOLYSIS; DIGITAL-SUBTRACTION-ANGIOGRAPHY; PERFUSION-PRESSURE MEASUREMENT; COMMON FEMORAL ENDARTERECTOMY; SUPERVISED EXERCISE THERAPY C1 [Gerhard-Herman, Marie D.] Harvard Med Sch, Boston, MA 02115 USA. [Gornik, Heather L.] Cleveland Clin Fdn, Cardiovasc Med, Noninvas Vasc Lab, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Barrett, Coletta] Our Lady Lake Reg Med Ctr, Baton Rouge, LA USA. [Barshes, Neal R.] Baylor Coll Med, Div Vasc Surg & Endovasc Therapy, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Corriere, Matthew A.] Univ Michigan, Cardiovasc Surg, Ann Arbor, MI 48109 USA. [Corriere, Matthew A.] Univ Michigan, Surg, Ann Arbor, MI 48109 USA. [Drachman, Douglas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fleisher, Lee A.] Univ Penn Hlth Syst, Dept Anesthesiol & Crit Care, Philadelphia, PA USA. [Fowkes, Francis Gerry R.] Univ Edinburgh, Epidemiol, Edinburgh, Midlothian, Scotland. [Hamburg, Naomi M.] Boston Univ, Sch Med, Cardiovasc Med Sect, Med, Boston, MA 02215 USA. [Kinlay, Scott] VA Boston Healthcare Syst, Cardiac Catheterizat Lab & Vasc Med, Boston, MA USA. [Lookstein, Robert] Mt Sinai Med Ctr, Intervent Radiol, New York, NY 10029 USA. [Lookstein, Robert] Mt Sinai Med Ctr, Radiol & Surg, New York, NY 10029 USA. [Lookstein, Robert] Mt Sinai Med Ctr, Dept Radiol, New York, NY 10029 USA. [Misra, Sanjay] Mayo Clin, Div Vasc & Intervent Radiol, Minneapolis, MN USA. [Misra, Sanjay] Mayo Clin, Dept Radiol, Minneapolis, MN USA. [Mureebe, Leila] Duke Univ, Med Ctr, Surg, Div Vasc Surg, Durham, NC 27706 USA. [Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Olin, Jeffrey W.] Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, Med, Cardiol, New York, NY USA. [Olin, Jeffrey W.] Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, Vasc Med, New York, NY USA. [Patel, Rajan A. G.] Univ Queensland, John Ochsner Heart & Vasc Ctr, Ochsner Clin Sch, Sch Med, Brisbane, Qld, Australia. [Regensteiner, Judith G.] Univ Colorado, Hlth Sci Ctr, Div Cardiol, Med, Boulder, CO 80309 USA. [Schanzer, Andres] Univ Massachusetts, Sch Med, Surg & Quantitat Hlth Sci, Amherst, MA 01003 USA. [Schanzer, Andres] Univ Massachusetts, Sch Med, Vasc Surg Residency, Amherst, MA 01003 USA. [Shishehbor, Mehdi H.] Cleveland Clin, Intervent Cardiol & Vasc Med, Endovasc Serv, Cleveland, OH 44106 USA. [Stewart, Kerry J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Stewart, Kerry J.] Johns Hopkins Bayview Med Ctr, Med, Baltimore, MD USA. [Stewart, Kerry J.] Johns Hopkins Bayview Med Ctr, Clin & Res Exercise Physiol, Baltimore, MD USA. [Treat-Jacobson, Diane] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Walsh, M. Eileen] Univ Toledo, Coll Nursing, 2801 W Bancroft St, Toledo, OH 43606 USA. RP Gerhard-Herman, MD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 323 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 MAR 21 PY 2017 VL 69 IS 11 BP 1465 EP + DI 10.1016/j.jacc.2016.11.008 PG 44 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AU UT WOS:000396361500014 PM 27851991 ER PT J AU Gerhard-Herman, MD Gerhard-Herman, MD Gornik, HL Barrett, C Barshes, NR Corriere, MA Drachman, DE Fleisher, LA Fowkes, FGR Hamburg, NM Kinlay, S Lookstein, R Misra, S Mureebe, L Olin, JW Patel, RAG Regensteiner, JG Schanzer, A Shishehbor, MH Stewart, KJ Treat-Jacobson, D Walsh, ME AF Gerhard-Herman, Marie D. Gerhard-Herman, Marie D. Gornik, Heather L. Barrett, Coletta Barshes, Neal R. Corriere, Matthew A. Drachman, Douglas E. Fleisher, Lee A. Fowkes, Francis Gerry R. Hamburg, Naomi M. Kinlay, Scott Lookstein, Robert Misra, Sanjay Mureebe, Leila Olin, Jeffrey W. Patel, Rajan A. G. Regensteiner, Judith G. Schanzer, Andres Shishehbor, Mehdi H. Stewart, Kerry J. Treat-Jacobson, Diane Walsh, M. Eileen CA Amer Coll Cardiology Amer Heart Assoc TI 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC/AHA Clinical Practice Guideline; acute limb ischemia; antiplatelet agents; bypass surgery; claudication; critical limb ischemia; endovascular procedures; limb salvage; peripheral artery disease; smoking cessation; supervised exercise ID CRITICAL LIMB ISCHEMIA; ANKLE-BRACHIAL INDEX; RANDOMIZED-CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; QUALITY-OF-LIFE; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; CLINICAL-PRACTICE GUIDELINES; FOOT INFECTION WIFI; ULTRASOUND-ACCELERATED THROMBOLYSIS; DUAL ANTIPLATELET THERAPY C1 [Gerhard-Herman, Marie D.] Harvard Med Sch, Boston, MA 02115 USA. [Gornik, Heather L.] Cleveland Clin Fdn, Cardiovasc Med, Noninvas Vasc Lab, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Barrett, Coletta] Our Lady Lake Reg Med Ctr, Baton Rouge, LA USA. [Barshes, Neal R.] Baylor Coll Med, Div Vasc Surg & Endovasc Therapy, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Corriere, Matthew A.] Univ Michigan, Cardiovasc Surg, Ann Arbor, MI 48109 USA. [Corriere, Matthew A.] Univ Michigan, Surg, Ann Arbor, MI 48109 USA. [Drachman, Douglas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fleisher, Lee A.] Univ Penn Hlth Syst, Dept Anesthesiol & Crit Care, Philadelphia, PA USA. [Fowkes, Francis Gerry R.] Univ Edinburgh, Epidemiol, Edinburgh, Midlothian, Scotland. [Hamburg, Naomi M.] Boston Univ, Sch Med, Cardiovasc Med Sect, Med, Boston, MA 02215 USA. [Kinlay, Scott] VA Boston Healthcare Syst, Cardiac Catheterizat Lab & Vasc Med, Boston, MA USA. [Lookstein, Robert] Mt Sinai Med Ctr, Intervent Radiol, New York, NY 10029 USA. [Lookstein, Robert] Mt Sinai Med Ctr, Radiol & Surg, New York, NY 10029 USA. [Lookstein, Robert] Mt Sinai Med Ctr, Dept Radiol, New York, NY 10029 USA. [Misra, Sanjay] Mayo Clin, Div Vasc & Intervent Radiol, Minneapolis, MN USA. [Misra, Sanjay] Mayo Clin, Dept Radiol, Minneapolis, MN USA. [Mureebe, Leila] Duke Univ, Med Ctr, Surg, Div Vasc Surg, Durham, NC 27706 USA. [Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Olin, Jeffrey W.] Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, Med, Cardiol, New York, NY USA. [Olin, Jeffrey W.] Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, Vasc Med, New York, NY USA. [Patel, Rajan A. G.] Univ Queensland, Sch Med, Ochsner Clin Sch, John Ochsner Heart & Vasc Ctr, Brisbane, Qld, Australia. [Regensteiner, Judith G.] Univ Colorado, Hlth Sci Ctr, Div Cardiol, Med, Boulder, CO 80309 USA. [Schanzer, Andres] Univ Massachusetts, Sch Med, Surg & Quantitat Hlth Sci, Amherst, MA 01003 USA. [Schanzer, Andres] Univ Massachusetts, Sch Med, Vasc Surg Residency, Amherst, MA 01003 USA. [Shishehbor, Mehdi H.] Cleveland Clin, Intervent Cardiol & Vasc Med, Endovasc Serv, Cleveland, OH 44106 USA. [Stewart, Kerry J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Stewart, Kerry J.] Johns Hopkins Bayview Med Ctr, Med, Baltimore, MD USA. [Stewart, Kerry J.] Johns Hopkins Bayview Med Ctr, Clin & Res Exercise Physiol, Baltimore, MD USA. [Treat-Jacobson, Diane] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Walsh, M. Eileen] Univ Toledo, Coll Nursing, 2801 W Bancroft St, Toledo, OH 43606 USA. RP Gerhard-Herman, MD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 408 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 21 PY 2017 VL 69 IS 11 BP E71 EP + DI 10.1016/j.jacc.2016.11.007 PG 56 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AU UT WOS:000396361500001 PM 27851992 ER PT J AU Ebert, BL Friedberg, JW AF Ebert, Benjamin L. Friedberg, Jonathan W. TI Introduction to Genomics in Hematologic Malignancy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material C1 [Ebert, Benjamin L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Ebert, Benjamin L.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Inst, Rochester, NY USA. RP Ebert, BL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Ebert, BL (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 14 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 MAR 20 PY 2017 VL 35 IS 9 BP 927 EP 928 DI 10.1200/JCO.2017.72.2827 PG 2 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600001 PM 28297621 ER PT J AU du Pont, SR Cleynen, A Fontan, C Attal, M Munshi, N Corre, J Avet-Loiseau, H AF du Pont, Sebastien Robiou Cleynen, Alice Fontan, Charlotte Attal, Michel Munshi, Nikhil Corre, Jill Avet-Loiseau, Herve TI Genomics of Multiple Myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID IN-SITU HYBRIDIZATION; CHROMOSOMAL TRANSLOCATIONS; INTRACLONAL HETEROGENEITY; MOLECULAR CLASSIFICATION; INTERGROUPE FRANCOPHONE; CELL LEUKEMIA; C-MAF; GENE; EXPRESSION; SIGNATURES AB Multiple myeloma (MM) is characterized by wide variability in the chromosomal/genetic changes present in tumor plasma cells. Genetically, MM can be divided into two groups according to ploidy and hyperdiploidy versus nonhyperdiploidy. Several studies in gene expression profiling attempted to identify subentities in MM without convincing results. These studies mostly confirmed the cytogenetic data and subclassified patients according to 14q32 translocations and ploidy. More-recent data that are based on whole-exome sequencing have confirmed this heterogeneity and show many gene mutations but without a unifying mutation. These newer studies have shown the frequent alteration of the mitogen-activated protein kinase pathway. The most interesting data have demonstrated subclonality in all patients with MM, including subclonal mutations of supposed driver genes KRAS, NRAS, and BRAF. (C) 2017 by American Society of Clinical Oncology C1 [du Pont, Sebastien Robiou; Fontan, Charlotte; Attal, Michel; Corre, Jill; Avet-Loiseau, Herve] Inst Univ Canc Oncopole, Toulouse, France. [Cleynen, Alice] CNRS, Montpellier, France. [Cleynen, Alice] Univ Montpellier, Montpellier, France. [Munshi, Nikhil] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Avet-Loiseau, H (reprint author), Inst Univ Canc Oncopole, Genom Myeloma Lab, 1 Av Irene Joliot Curie, F-31059 Toulouse, France. EM avet-loiseau.h@chu-toulouse.fr FU National Cancer Institute [CA100707-12]; CAPTOR (Cancer Pharmacology of Toulouse-Oncopole and Region) program FX Supported by a grant from the National Cancer Institute (CA100707-12) and the CAPTOR (Cancer Pharmacology of Toulouse-Oncopole and Region) program. Cancer Research Center of Toulouse Team 13 is labeled by Fondation ARC pour la Recherche sur le Cancer. NR 44 TC 1 Z9 1 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 MAR 20 PY 2017 VL 35 IS 9 BP 963 EP 967 DI 10.1200/JCO.2016.70.6705 PG 5 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600006 ER PT J AU Kennedy, JA Ebert, BL AF Kennedy, James A. Ebert, Benjamin L. TI Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; DRIVER SOMATIC MUTATIONS; CLONAL HEMATOPOIESIS; TP53 MUTATIONS; MOLECULAR MUTATIONS; DISEASE PROGRESSION; RING SIDEROBLASTS; DNMT3A MUTATIONS; COHESIN COMPLEX AB Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies have enabled the identification of a set of recurrently mutated genes central to the pathogenesis of MDS, which can be organized into a limited number of cellular processes, including RNA splicing, epigenetic and traditional transcriptional regulation, and signal transduction. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis to frank MDS, and, ultimately, to secondary AML. This detailed understanding of the molecular landscape of MDS, coupled with the emergence of cost-and time-effective methodologies for DNA sequencing has led to the introduction of genetic studies into the clinical realm. Here, we review recent advances in our genetic understanding of MDS, with a particular focus on the emerging role for mutational data in clinical management as a potential tool to assist in diagnosis, risk stratification, and therapeutic decision-making. (C) 2017 by American Society of Clinical Oncology C1 [Kennedy, James A.] Univ Hlth Network, Toronto, ON, Canada. [Kennedy, James A.; Ebert, Benjamin L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Ebert, Benjamin L.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ebert, BL (reprint author), Karp Family Res Labs, 5-211 1 Blackfan Circle, Boston, MA 02115 USA. EM bebert@partners.org FU National Institutes of Health [R01 HL082945, R24 DK099808]; US Department of Defense; Edward P. Evans Foundation; Leukemia & Lymphoma Society; STARR Cancer Consortium FX Supported by grants from the National Institutes of Health (Grants No. R01 HL082945, R24 DK099808), the US Department of Defense, the Edward P. Evans Foundation, the Leukemia & Lymphoma Society, and the STARR Cancer Consortium (all to B.L.E.). NR 71 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 MAR 20 PY 2017 VL 35 IS 9 BP 968 EP 974 DI 10.1200/JCO.2016.71.0806 PG 7 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600007 PM 28297619 ER PT J AU Lazarian, G Guieze, R Wu, CJ AF Lazarian, Gregory Guieze, Romain Wu, Catherine J. TI Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID IDENTIFIES RECURRENT MUTATIONS; PREVIOUSLY UNTREATED PATIENTS; CLONAL EVOLUTION; NOTCH1 MUTATIONS; SF3B1 MUTATIONS; FOLLOW-UP; GENE-MUTATIONS; PROGNOSTIC CLASSIFICATION; COMPLEX KARYOTYPES; RANDOMIZED-TRIAL AB Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter-and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein. (C) 2017 by American Society of Clinical Oncology C1 [Lazarian, Gregory; Guieze, Romain; Wu, Catherine J.] Dana Farber Canc Inst, Dana 520C,44 Binney St, Boston, MA 02115 USA. [Guieze, Romain; Wu, Catherine J.] Harvard Med Sch, Boston, MA USA. [Wu, Catherine J.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Guieze, Romain; Wu, Catherine J.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Lazarian, Gregory] INSERM, U978, Bobigny, France. [Lazarian, Gregory] Hop Avicenne, AP HP, Bobigny, France. [Guieze, Romain] Ctr Hosp Univ Clermont Ferrand, Clermont Ferrand, France. [Guieze, Romain] Univ Auvergne, Clermont Ferrand, France. RP Wu, CJ (reprint author), Dana Farber Canc Inst, Dana 520C,44 Binney St, Boston, MA 02115 USA. EM cwu@partners.org NR 101 TC 1 Z9 1 U1 2 U2 2 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 MAR 20 PY 2017 VL 35 IS 9 BP 984 EP 993 DI 10.1200/JCO.2016.71.0822 PG 10 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600009 PM 28297623 ER PT J AU Hunter, ZR Yang, G Xu, L Liu, X Castillo, JJ Treon, SP AF Hunter, Zachary R. Yang, Guang Xu, Lian Liu, Xia Castillo, Jorge J. Treon, Steven P. TI Genomics, Signaling, and Treatment of Waldenstrom Macroglobulinemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID MYD88 L265P MUTATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; B-CELL LYMPHOMA; MULTIPLE-MYELOMA; SOMATIC MUTATION; CXCR4 MUTATIONS; LYMPHOPROLIFERATIVE DISORDERS; LYMPHOPLASMACYTIC LYMPHOMA; INTERNATIONAL WORKSHOP AB Next-generation sequencing has revealed recurring somatic mutations in Waldenstrom macro-globulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor-kappa B, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non-chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling. (C) 2017 by American Society of Clinical Oncology C1 [Hunter, Zachary R.; Yang, Guang; Xu, Lian; Liu, Xia; Castillo, Jorge J.; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,450 Brookline Ave, Boston, MA 02215 USA. [Hunter, Zachary R.; Yang, Guang; Xu, Lian; Liu, Xia; Castillo, Jorge J.; Treon, Steven P.] Harvard Med Sch, Boston, MA USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,450 Brookline Ave, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu NR 72 TC 1 Z9 1 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 MAR 20 PY 2017 VL 35 IS 9 BP 994 EP 1001 DI 10.1200/JCO.2016.71.0814 PG 8 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600010 ER PT J AU Furutani, E Shimamura, A AF Furutani, Elissa Shimamura, Akiko TI Germline Genetic Predisposition to Hematologic Malignancy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SEVERE CONGENITAL NEUTROPENIA; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SHWACHMAN-DIAMOND SYNDROME; FANCONI-ANEMIA REGISTRY; BONE-MARROW FAILURE; MYELODYSPLASTIC SYNDROME; PEDIATRIC CANCER; GATA2 DEFICIENCY; GENOMIC ANALYSIS AB Development of hematologic malignancies is driven by mutations that may be somatic or germline. Availability of next-generation DNA sequencing technologies has facilitated the development of individualized diagnostic evaluations and tailored treatment strategies. Until now, such personalized medical approaches have largely centered on prognostic stratification and treatment strategies informed by acquired somatic mutations. The role of germline mutations in children and adults with hematologic malignancies was previously underappreciated. Diagnosis of an inherited predisposition to hematologic malignancy informs choice of therapy, risk of treatment-related complications, donor selection for hematopoietic stem cell transplantation, evaluation of comorbidities, and surveillance strategies to improve clinical outcomes. The recognition that patients with inherited hematologic malignancy syndromes may present without classic clinical stigmata or suspicious family history has led to increased reliance on genetic testing, which, in turn, has raised new diagnostic challenges. Genomic testing is a rapidly evolving field with an increasing number of choices for testing for the practicing clinician to navigate. This review will discuss general approaches to diagnosis and management of patients with germline predisposition to hematology malignancies and will consider applications and limitations of genomic testing in clinical practice. (C) 2017 by American Society of Clinical Oncology C1 [Furutani, Elissa; Shimamura, Akiko] Dana Farber Canc Ctr, Boston, MA USA. [Furutani, Elissa; Shimamura, Akiko] Boston Childrens Canc & Blood Disorders Ctr, Boston, MA USA. RP Shimamura, A (reprint author), 300 Longwood Ave,Karp 8210, Boston, MA 02115 USA. EM akiko.shimamura@childrens.harvard.edu NR 61 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 MAR 20 PY 2017 VL 35 IS 9 BP 1018 EP 1028 DI 10.1200/JCO.2016.70.8644 PG 11 WC Oncology SC Oncology GA EO0DX UT WOS:000396369600013 PM 28297620 ER PT J AU Low, CM Akthar, S Patel, DF Loser, S Wong, CT Jackson, PL Blalock, JE Hare, SA Lloyd, CM Snelgrove, RJ AF Low, Caroline M. Akthar, Samia Patel, Dhiren F. Loeser, Stephan Wong, Chi-Tung Jackson, Patricia L. Blalock, J. Edwin Hare, Stephen A. Lloyd, Clare M. Snelgrove, Robert J. TI The development of novel LTA(4)H modulators to selectively target LTB4 generation SO SCIENTIFIC REPORTS LA English DT Article ID LEUKOTRIENE A(4) HYDROLASE; OBSTRUCTIVE PULMONARY-DISEASE; PROLINE-GLYCINE-PROLINE; NEUTROPHILIC INFLAMMATION; AIRWAY INFLAMMATION; INHIBITOR; ENZYME; AMINOPEPTIDASE; DISCOVERY; EMPHYSEMA AB The pro-inflammatory mediator leukotriene B-4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A(4) hydrolase (LTA(4)H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA(4)H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA(4)H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA(4)H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA(4)H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA(4)H inhibitors for translation into the clinic. C1 [Low, Caroline M.] Computat Drug Design Consultant, London SE21 8LS, England. [Akthar, Samia; Patel, Dhiren F.; Loeser, Stephan; Lloyd, Clare M.; Snelgrove, Robert J.] Imperial Coll London, Natl Heart & Lung Inst, Inflammat Repair & Dev, London SW7 2AZ, England. [Wong, Chi-Tung; Hare, Stephen A.] Imperial Coll London, Dept Life Sci, London SW7 2AZ, England. [Jackson, Patricia L.; Blalock, J. Edwin] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Jackson, Patricia L.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Snelgrove, RJ (reprint author), Imperial Coll London, Natl Heart & Lung Inst, Inflammat Repair & Dev, London SW7 2AZ, England. EM robert.snelgrove@imperial.ac.uk FU Wellcome Trust Career Development Fellow [095707/Z/11/Z]; Asthma UK Innovations award [AUK-IG-2014-286]; Imperial College Biomedical Research Centre (BRC) Therapeutic Primer fund and MRC/Imperial College Confidence in Concept schemes; Wellcome Trust Senior Fellow in Basic Biomedical Sciences [086718/Z/08/Z]; MRC Career Development Fellow [G1100332]; National Heart, Lung and Blood Institute funds [HL077783, HL110950, HL114439, HL126596]; UAB Lung Health Center Pulmonary Proteomics Laboratory is funded through the UAB Health Service Foundation General Endowment Fund FX R.J.S. is a Wellcome Trust Career Development Fellow (095707/Z/11/Z) and is also funded through an Asthma UK Innovations award (AUK-IG-2014-286). Aspects of this work have been funded (through R.J.S.) by the Imperial College Biomedical Research Centre (BRC) Therapeutic Primer fund and MRC/Imperial College Confidence in Concept schemes. C.M.L. is a Wellcome Trust Senior Fellow in Basic Biomedical Sciences (086718/Z/08/Z). S.H. is an MRC Career Development Fellow (G1100332). The National Heart, Lung and Blood Institute funds J.E.B. (HL077783, HL110950, HL114439 and HL126596). The UAB Lung Health Center Pulmonary Proteomics Laboratory is funded through the UAB Health Service Foundation General Endowment Fund. We would like to thank Dr. Anna Caldwell and the Centre of Excellence for Mass Spectrometry at King's College London for the use of equipment and technical assistance, and the staff of beamline I02 at Diamond Light Source for facilitating X-ray crystallography studies. We would like to thank Jen Morton, Matt Tozer, David Leese, Stuart Cameron, Seb Hallworth and David Fengas (all Peakdale Molecular) for compound synthesis and ADMET studies. NR 47 TC 0 Z9 0 U1 0 U2 0 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 MAR 17 PY 2017 VL 7 AR 44449 DI 10.1038/srep44449 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO2PB UT WOS:000396537300001 PM 28303931 ER PT J AU Pan, YC Liu, HL Wang, YR Kang, XZ Liu, ZS Owzar, K Han, YH Su, L Wei, YY Hung, RJ Brhane, Y McLaughlin, J Brennan, P Bickeboller, H Rosenberger, A Houlston, RS Caporaso, N Landi, MT Heinrich, J Risch, A Wu, XF Ye, YQ Christiani, DC Amos, CI Wei, QY AF Pan, Yongchu Liu, Hongliang Wang, Yanru Kang, Xiaozheng Liu, Zhensheng Owzar, Kouros Han, Younghun Su, Li Wei, Yongyue Hung, Rayjean J. Brhane, Yonathan McLaughlin, John Brennan, Paul Bickeboeller, Heike Rosenberger, Albert Houlston, Richard S. Caporaso, Neil Landi, Maria Teresa Heinrich, Joachim Risch, Angela Wu, Xifeng Ye, Yuanqing Christiani, David C. Amos, Christopher I. Wei, Qingyi TI Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CHINESE POPULATION; COLON-CANCER; IDENTIFIES 2; ADENOCARCINOMA; MACHINERY; MUTATIONS; JAPANESE; SMOKING AB mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) <= 0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer. C1 [Pan, Yongchu; Liu, Hongliang; Wang, Yanru; Kang, Xiaozheng; Liu, Zhensheng; Owzar, Kouros; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27708 USA. [Pan, Yongchu] Nanjing Med Univ, Affiliated Hosp Stomatol, Nanjing, Jiangsu, Peoples R China. [Pan, Yongchu; Liu, Hongliang; Wang, Yanru; Kang, Xiaozheng; Liu, Zhensheng; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Han, Younghun] Dartmouth Coll, Geisel Sch Med, Dept Biomed Data Sci, Hanover, NH 03755 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] Georg August Univ Gottingen, Dept Genet Epidemiol, Univ Med Ctr, Gottingen, Germany. [Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London, England. [Caporaso, Neil; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Heinrich, Joachim] Helmholtz Ctr Munich, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, Salzburg, Austria. [Wu, Xifeng; Ye, Yuanqing] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Wei, QY (reprint author), Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27708 USA.; Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. EM qingyi.wei@duke.edu FU Duke Cancer Institute, P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute, Duke University Medical Center; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University; Transdisciplinary Research in Cancer of the Lung (TRICL), Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19-CA148127]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; 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]; 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]; Institute National du Cancer, France; European Community (Integrated Project DNA repair) [LSHG-CT-2005-512113]; Norwegian Cancer Association; 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; 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]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]; 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]; CPRIT grant [RP100443]; CIDR [HHSN268200782096C]; NIH (National Cancer Institute) [CA092824, CA090578, CA074386]; GENADDICT [LSHMCT-2004-005166]; National Institutes of Health [R01-DA017932] FX The authors thank the investigators and participants of all TRICL-ILCCO studies (i.e., ICR, MDACC, IARC, NCI, Toronto, GLC, Harvard and deCODE) for their important contributions. As Duke Cancer Institute members, QW and KO acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: NIH CA014236). QW was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. Yongchu Pan was sponsored by Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University. 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 and C1298/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 Institute 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 and RO1HL091172-01), 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, and 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). NR 38 TC 0 Z9 0 U1 0 U2 0 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 MAR 17 PY 2017 VL 7 AR 44634 DI 10.1038/srep44634 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9IE UT WOS:000397001600001 PM 28304396 ER PT J AU Rovithi, M Avan, A Funel, N Leon, LG Gomez, VE Wurdinger, T Griffioen, AW Verheul, HMW Giovannetti, E AF Rovithi, Maria Avan, Amir Funel, Niccola Leon, Leticia G. Gomez, Valentina E. Wurdinger, Thomas Griffioen, Arjan W. Verheul, Henk M. W. Giovannetti, Elisa TI Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing SO SCIENTIFIC REPORTS LA English DT Article ID DUCTAL ADENOCARCINOMA; MOUSE MODEL; ANGIOSTATIC TREATMENT; MICRORNA EXPRESSION; GEMCITABINE; CARCINOMA; IDENTIFICATION; PROGRESSION; FIBROBLASTS; XENOGRAFTS AB The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressing Firefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p< 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi) genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations. C1 [Rovithi, Maria; Gomez, Valentina E.; Griffioen, Arjan W.; Verheul, Henk M. W.; Giovannetti, Elisa] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands. [Rovithi, Maria] Agios Nikolaos Gen Hosp, Dept Internal Med, Agios Nikolaos, Crete, Greece. [Avan, Amir] Mashhad Univ Med Sci, Mol Med Grp, Dept Modern Sci & Technol, Mashhad, Iran. [Avan, Amir] Mashhad Univ Med Sci, Sch Med, Mashhad, Iran. [Funel, Niccola; Leon, Leticia G.; Giovannetti, Elisa] Univ Pisa, AIRC Start Up Unit, Canc Pharmacol Lab, Pisa, Italy. [Wurdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Neurosurg, Amsterdam, Netherlands. [Wurdinger, Thomas] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Boston, MA USA. [Wurdinger, Thomas] Harvard Med Sch, Neurosci Program, Boston, MA USA. RP Giovannetti, E (reprint author), Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam, Netherlands.; Giovannetti, E (reprint author), Univ Pisa, AIRC Start Up Unit, Canc Pharmacol Lab, Pisa, Italy. EM e.giovannetti@vumc.nl FU Nederlands Wetenschappelijk Onderzoek (NWO) Veni grant; Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up grant; Istituto Toscano Tumori; AIRC-iCARE Fellowship; European Community; Cancer Center Amsterdam (CCA) Foundation grant; MARF; "Bando FAS Salute - Regione Toscana" grant FX This work was partly supported by Nederlands Wetenschappelijk Onderzoek (NWO) Veni grant (to EG), Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up grant (to EG), Istituto Toscano Tumori (to EG and NF), AIRC-iCARE Fellowship, cofunded by European Community (to LGL), Cancer Center Amsterdam (CCA) Foundation grant (to EG), "The Law Offices of Peter G. Angelos Grant" from MARF (to EG), and the "Bando FAS Salute - Regione Toscana" grant (to NF and EG). NR 47 TC 0 Z9 0 U1 0 U2 0 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 MAR 17 PY 2017 VL 7 AR 44686 DI 10.1038/srep44686 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9IX UT WOS:000397003500001 PM 28304379 ER PT J AU Bramlet, M Olivieri, L Farooqi, K Ripley, B Coakley, M AF Bramlet, Matthew Olivieri, Laura Farooqi, Kanwal Ripley, Beth Coakley, Meghan TI Impact of Three-Dimensional Printing on the Study and Treatment of Congenital Heart Disease SO CIRCULATION RESEARCH LA English DT Article DE 3D printing; cardiac models; congenital heart disease; database; peer review; segmentation ID SIMULATION; MODELS AB Three-dimensional (3D) printing technology allows for the translation of a 2-dimensional medical imaging study into a physical replica of a patient's individual anatomy. 3D printed models can facilitate a deeper understanding of complex patient anatomy and can aid in presurgical decision-making.(1) Although there are 3D printing case reports in almost every subspecialty of medicine to date, the rate of adoption in the field of congenital heart disease (CHD) is particularly advanced.(2,3) This is due, in no small part, to the fact that the heart is a hollow organ, which makes it a perfect substrate for 3D printing. More importantly, medical decision-making in CHD is informed by assessment of the anatomic morphology of the heart because cardiac pathology is a direct manifestation of the underlying 3D structure. C1 [Bramlet, Matthew] Univ Illinois, Coll Med, Pediat Cardiol, 1306 N Berkeley Ave, Peoria, IL 61603 USA. [Bramlet, Matthew] Jump Trading Simulat & Educ Ctr, Adv Imaging & Modeling Initiat, 1306 N Berkeley Ave, Peoria, IL 61603 USA. [Olivieri, Laura] Childrens Natl Med Ctr, Div Cardiol, Washington, DC USA. [Farooqi, Kanwal] Univ Med & Dent New Jersey, Dept Pediat, Rutgers Div Pediat Cardiol, Newark, NJ USA. [Farooqi, Kanwal] Icahn Sch Med Mt Sinai, Dept Pediat, Div Pediat Cardiol, New York, NY USA. [Ripley, Beth] VA Puget Sound Hlth Care Syst, Radiol, Seattle, WA USA. [Ripley, Beth] Univ Washington, Sch Med, Seattle, WA USA. [Coakley, Meghan] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD USA. RP Bramlet, M (reprint author), Univ Illinois, Coll Med, Pediat Cardiol, 1306 N Berkeley Ave, Peoria, IL 61603 USA.; Bramlet, M (reprint author), Jump Trading Simulat & Educ Ctr, Adv Imaging & Modeling Initiat, 1306 N Berkeley Ave, Peoria, IL 61603 USA. EM Matthew.T.Bramlet@osfhealthcare.org FU National Institutes of Allergy and Infectious Diseases [GS35F0373X]; US Department of Health and Human Services through HHS Ignite program; US Department of Health and Human Services through HHS Ventures program FX The National Institutes of Health (NIH) 3D Print Exchange is operated by the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Resources are provided in part through BCBB Support Services Contract [GS35F0373X], funded by the National Institutes of Allergy and Infectious Diseases. Initial funding for the 3D Print Exchange was supplemented by the US Department of Health and Human Services through the HHS Ignite and HHS Ventures programs. NR 16 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 17 PY 2017 VL 120 IS 6 BP 904 EP 907 DI 10.1161/CIRCRESAHA.116.310546 PG 4 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EP4DL UT WOS:000397330700004 PM 28302738 ER PT J AU Zaidi, S Brueckner, M AF Zaidi, Samir Brueckner, Martina TI Genetics and Genomics of Congenital Heart Disease SO CIRCULATION RESEARCH LA English DT Article DE genetics; genome; human; life; technology ID COPY-NUMBER VARIANTS; DE-NOVO MUTATIONS; PRIMARY CILIARY DYSKINESIA; HYPOPLASTIC LEFT-HEART; LEFT-RIGHT ASYMMETRY; VENTRICULAR SEPTAL-DEFECTS; HIGH-RESOLUTION ANALYSIS; MITRAL-VALVE-PROLAPSE; WHOLE-EXOME CAPTURE; HOLT-ORAM SYNDROME AB Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. This review will focus on the evidence for genetic causes underlying CHD and discuss data supporting both monogenic and complex genetic mechanisms underlying CHD. The discoveries from CHD genetic studies draw attention to biological pathways that simultaneously open the door to a better understanding of cardiac development and affect clinical care of patients with CHD. Finally, we address clinical genetic evaluation of patients and families affected by CHD. C1 [Zaidi, Samir] Yale Univ, Sch Med, Dept Genet, New Haven, CT USA. [Brueckner, Martina] Yale Univ, Sch Med, Dept Pediat & Genet, 333 Cedar St, New Haven, CT 06520 USA. [Zaidi, Samir] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Brueckner, M (reprint author), Yale Univ, Sch Med, Dept Pediat & Genet, 333 Cedar St, New Haven, CT 06520 USA. EM martina.brueckner@yale.edu FU National Institutes of Health (NIH) [UM1HL098162-07]; NIH [RO1HL125885-01] FX We are grateful for the invaluable contribution to the article by Dr Richard P. Lifton, President of Rockefeller University. We also thank Dr Robert W. Elder, Yale University, Department of Pediatrics/ Cardiology for critical review of the article. M. Brueckner is supported by National Institutes of Health (NIH) UM1HL098162-07 and NIH RO1HL125885-01 NR 153 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 17 PY 2017 VL 120 IS 6 BP 923 EP 940 DI 10.1161/CIRCRESAHA.116.309140 PG 18 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EP4DL UT WOS:000397330700006 PM 28302740 ER PT J AU Haynes, BF Burton, DR AF Haynes, Barton F. Burton, Dennis R. TI HIV Developing an HIV vaccine What are the paths and obstacles to a practical vaccine? SO SCIENCE LA English DT Editorial Material ID BROADLY NEUTRALIZING ANTIBODIES; IG KNOCKIN MICE; DESIGN; INFECTION C1 [Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Duke Ctr HIV AIDS Vaccine Immunol Immunogen Disco, Durham, NC 27708 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbiol, Scripps Ctr HIV AIDS Vaccine Immunol Immunogen Di, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA. RP Haynes, BF (reprint author), Duke Univ, Sch Med, Duke Human Vaccine Inst, Duke Ctr HIV AIDS Vaccine Immunol Immunogen Disco, Durham, NC 27708 USA. EM barton.haynes@duke.edu; burton@scripps.edu FU National Institute of Allergy and Infectious Diseases; Division of AIDS, the Centers for HIV/AIDS Vaccine Immunology-Immunogen Discovery Grants at Duke School of Medicine, Durham, NC [AI000645]; Scripps Research Institute, La Jolla, CA [AI 100663]; Bill & Melinda Gates Foundation; Collaboration for AIDS Vaccine Discovery Grants [OPP52282, OPP1114721, OPP1094352, OPP1084519] FX This work was supported by the National Institute of Allergy and Infectious Diseases, the Division of AIDS, the Centers for HIV/AIDS Vaccine Immunology-Immunogen Discovery Grants at Duke School of Medicine, Durham, NC (AI000645) and at The Scripps Research Institute, La Jolla, CA (AI 100663); and the Bill & Melinda Gates Foundation with Collaboration for AIDS Vaccine Discovery Grants OPP52282, OPP1114721, and OPP1094352 to B.F.H., and OPP1084519 to D.R.B. Many important references were not cited because of space limitations. See the supplementary materials for additional references. NR 15 TC 0 Z9 0 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 MAR 17 PY 2017 VL 355 IS 6330 SI SI BP 1129 EP 1130 DI 10.1126/science.aan0662 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9WV UT WOS:000396351200022 PM 28302812 ER PT J AU Stern, AD Alexander, BM Chandra, A AF Stern, A. D. Alexander, B. M. Chandra, A. TI BIOMEDICAL INNOVATION How economics can shape precision medicines Innovation incentives, pricing, and access are critical SO SCIENCE LA English DT Editorial Material ID BREAST-CANCER; ADAPTIVE RANDOMIZATION; MARKET-SIZE; TRIAL C1 [Stern, A. D.; Chandra, A.] Harvard Sch Business, Boston, MA 02163 USA. [Stern, A. D.] Brigham & Womens Hosp, Ariadne Labs, Boston, MA 02215 USA. [Stern, A. D.] Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA. [Alexander, B. M.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Alexander, B. M.] Harvard Med Sch, Harvard Program Therapeut Sci, Boston, MA 02115 USA. [Chandra, A.] Harvard Kennedy Sch, Cambridge, MA 02138 USA. [Chandra, A.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Stern, AD (reprint author), Harvard Sch Business, Boston, MA 02163 USA.; Stern, AD (reprint author), Brigham & Womens Hosp, Ariadne Labs, Boston, MA 02215 USA.; Stern, AD (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA. EM astern@hbs.edu NR 16 TC 0 Z9 0 U1 2 U2 2 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 MAR 17 PY 2017 VL 355 IS 6330 SI SI BP 1131 EP 1133 DI 10.1126/science.aai8707 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9WV UT WOS:000396351200023 PM 28302813 ER PT J AU Zhao, S Yu, ZY Liu, Y Bai, Y Jiang, YH van Leyen, K Yang, YG Lok, JM Whalen, MJ Lo, EH Wang, XY AF Zhao, Song Yu, Zhanyang Liu, Yu Bai, Yang Jiang, Yinghua van Leyen, Klaus Yang, Yong-Guang Lok, Josephine M. Whalen, Michael J. Lo, Eng H. Wang, Xiaoying TI CD47 deficiency improves neurological outcomes of traumatic brain injury in mice SO NEUROSCIENCE LETTERS LA English DT Article DE CD47; Traumatic brain injury (TBI); Controlled cortical impact (CCI); Neutrophil infiltration; Vessel density; Vascular endothelial growth factor (VEGF); Angiopoietin 1 (Ang-1); Neurological severity score (NSS) ID CELL-DEATH; HISTOPATHOLOGY; MIGRATION AB CD47 is a receptor for signal -regulatory protein alpha (SIRPcs) in self -recognition by the innate immune system, and a receptor of thrombospondin-1 (TSP-1) contributing to vascular impairment in response to stress. However, the roles of CD47 in traumatic brain injury (TBI) have not been investigated. In this study we aimed to test our hypothesis that CD47 mediates early neutrophil brain infiltration and late brain vascular remodeling after TBI. Mice were subjected to TBI using a controlled cortical impact (CCI) device. We examined early phase neutrophil infiltration, and late phase brain vessel density, pro-angiogenic markers VEGF and Ang-1 protein expression, neurological function deficits and lesion volumes for up to three weeks after TBI. Our results show that mice deficient in CD47 (CD47 Knockout) had significantly less brain neutrophil infiltration at 24 h, upregulated VEGF expression in peri-lesion cortex at 7 and 14 days, and increased blood vessel density at 21 days after TBI, compared to wild type (WT) mice. CD47 knockout also significantly decreased sensorimotor function deficits and reduced brain lesion volume at 21 days after TBI. We conclude that CD47 may play pathological roles in brain neutrophil infiltration, progression of brain tissue damage, impairment of cerebrovascular remodeling and functional recovery after TBI. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Zhao, Song; Bai, Yang] Jilin Univ, Dept Orthoped, Bethune Hosp 1, Changchun, Jilin, Peoples R China. [Zhao, Song; Bai, Yang] Jilin Univ, Dept Neurosurg, Bethune Hosp 1, Changchun, Jilin, Peoples R China. [Zhao, Song; Yu, Zhanyang; Liu, Yu; Jiang, Yinghua; van Leyen, Klaus; Lok, Josephine M.; Lo, Eng H.; Wang, Xiaoying] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, 149 13th St,Room 2401, Charlestown, MA 02129 USA. [Zhao, Song; Yu, Zhanyang; Liu, Yu; Jiang, Yinghua; van Leyen, Klaus; Lok, Josephine M.; Lo, Eng H.; Wang, Xiaoying] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 149 13th St,Room 2401, Charlestown, MA 02129 USA. [Liu, Yu] Harbin Med Univ, Affiliated Hosp 2, Dept Neurol, Harbin, Heilongjiang, Peoples R China. [Yang, Yong-Guang] Columbia Univ Coll Phys & Surg, Dept Med, Columbia Ctr Translat Immunol, New York, NY USA. [Lok, Josephine M.; Whalen, Michael J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Pediat Crit Care Med, Charlestown, MA USA. RP Wang, XY (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 149 13th St,Room 2401, Charlestown, MA 02129 USA.; Wang, XY (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 149 13th St,Room 2401, Charlestown, MA 02129 USA. EM 33528276@qq.com; Yu.Zhanyang@mgh.harvard.edu; liuyuly1982@163.com; 1295915645@qq.com; yjiang6@mgh.harvard.edu; kvanleyen@mgh.harvard.edu; yy2324@columbia.edu; JLOK1@mgh.harvard.edu; mwhalen@mgh.harvard.edu; lo@helix.mgh.harvard.edu; wangxi@helix.mgh.harvard.edu FU NIH [R37-NS37074]; China Nature Science Foundation [81301035] FX This study was in part supported by NIH grant R37-NS37074, and China Nature Science Foundation grant 81301035. NR 21 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 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 16 PY 2017 VL 643 BP 125 EP 130 DI 10.1016/j.neulet.2016.12.006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EO8UN UT WOS:000396966100020 PM 27931776 ER PT J AU Ghita, M McMahon, SJ Taggart, LE Butterworth, KT Schettino, G Prise, KM AF Ghita, Mihaela McMahon, Stephen J. Taggart, Laura E. Butterworth, Karl T. Schettino, Giuseppe Prise, Kevin M. TI A mechanistic study of gold nanoparticle radiosensitisation using targeted microbeam irradiation SO SCIENTIFIC REPORTS LA English DT Article ID X-RAY MICROBEAM; RADIATION; CELLS; RADIOTHERAPY AB Gold nanoparticles (GNPs) have been demonstrated as effective radiosensitizing agents in a range of preclinical models using broad field sources of various energies. This study aimed to distinguish between these mechanisms by applying subcellular targeting using a soft X-ray microbeam in combination with GNPs. DNA damage and repair kinetics were determined following nuclear and cytoplasmic irradiation using a soft X-ray ( carbon K-shell, 278 eV) microbeam in MDA-MB-231 breast cancer and AG01522 fibroblast cells with and without GNPs. To investigate the mechanism of the GNP induced radiosensitization, GNP-induced mitochondrial depolarisation was quantified by TMRE staining, and levels of DNA damage were compared in cells with depolarised and functional mitochondria. Differential effects were observed following radiation exposure between the two cell lines. These findings were validated 24 hours after removal of GNPs by flow cytometry analysis of mitochondrial depolarisation. This study provides further evidence that GNP radiosensitisation is mediated by mitochondrial function and it is the first report applying a soft X-ray microbeam to study the radiobiological effects of GNPs to enable the separation of physical and biological effects. C1 [Ghita, Mihaela; McMahon, Stephen J.; Taggart, Laura E.; Butterworth, Karl T.; Prise, Kevin M.] Queens Univ Belfast, Ctr Canc Res & Cell Biol, 97 Lisburn Rd, Belfast BT7 9AE, Antrim, North Ireland. [McMahon, Stephen J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [McMahon, Stephen J.] Harvard Med Sch, Boston, MA 02114 USA. [Schettino, Giuseppe] Natl Phys Lab, London TW11 0LW, England. RP Ghita, M (reprint author), Queens Univ Belfast, Ctr Canc Res & Cell Biol, 97 Lisburn Rd, Belfast BT7 9AE, Antrim, North Ireland. EM m.ghita@qub.ac.uk FU European Commission Framework 7 Programme [608163] FX The authors acknowledge Prof. Stanley Botchway from the Functional Biosystems Imaging, part of the OCTOPUS imaging cluster at the Research Complex in Harwell, for the FLIM and fluorescent microscopy imaging. This work was funded in part by the European Commission Framework 7 Programme (grant number EC FP7 MC ITN - 608163 - ARGENT). NR 34 TC 0 Z9 0 U1 0 U2 0 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 MAR 16 PY 2017 VL 7 AR 44752 DI 10.1038/srep44752 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO2NY UT WOS:000396534400001 PM 28300190 ER PT J AU Wu, MD Atkinson, TM Lindner, JR AF Wu, Melinda D. Atkinson, Tamara M. Lindner, Jonathan R. TI Platelets and von Willebrand factor in atherogenesis SO BLOOD LA English DT Article ID PROTEIN DISULFIDE-ISOMERASE; HIGH-DENSITY-LIPOPROTEIN; ENDOTHELIAL-CELLS; GLYCOPROTEIN IB; P-SELECTIN; CORONARY ATHEROSCLEROSIS; VASCULAR INFLAMMATION; THROMBUS FORMATION; YOUNG-PATIENTS; IX COMPLEX AB The role of platelet adhesion, activation, and aggregation in acute atherothrombotic events such as myocardial infarction and strokeis wellestablished. Thereis increasing evidence that platelet-endothelial interactions also contribute to early atherosclerotic plaque initiation and growth. Through these interactions, platelet-derived factors can contribute to the proinflammatory and mitogenic status of resident mural cells. Among the many putative mechanisms for platelet-endothelial interactions, increased endothelial-associated von Willebrand factor, particularly in a multimerized form, which interacts with platelet glycoproteins and integrins, is a major factor and represents a therapeutic target in early atherogenesis. C1 [Wu, Melinda D.; Atkinson, Tamara M.; Lindner, Jonathan R.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Wu, Melinda D.; Atkinson, Tamara M.; Lindner, Jonathan R.] Oregon Hlth & Sci Univ, Dept Pediat, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA. [Atkinson, Tamara M.] Portland VA Med Ctr, Portland, OR USA. [Lindner, Jonathan R.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Portland, OR 97201 USA. RP Lindner, JR (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM lindnerj@ohsu.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [R01-HL078610, R01-HL111969, R01-HL120046, T32-HL094294, K08-HL133493]; National Space Biomedical Research Institute [14-14NSBRI10025] FX This work was supported by grants R01-HL078610, R01-HL111969, and R01-HL120046 (J.R.L.), T32-HL094294 (M.D.W. and T.M.A.), and K08-HL133493 (M.D.W.) from the National Heart, Lung, and Blood Institute of the National Institutes of Health, and 14-14NSBRI10025 from the National Space Biomedical Research Institute (J.R.L.). NR 84 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 MAR 16 PY 2017 VL 129 IS 11 BP 1415 EP 1419 DI 10.1182/blood-2016-07-692673 PG 5 WC Hematology SC Hematology GA EP3PR UT WOS:000397294700009 PM 28174163 ER PT J AU Burk, RD Chen, ZG Saller, C Tarvin, K Carvalho, AL Scapulatempo-Neto, C Silveira, HC Fregnani, JH Creighton, CJ Anderson, ML Castro, P Wang, SS Yau, C Benz, C Robertson, AG Mungall, K Lim, L Bowlby, R Sadeghi, S Brooks, D Sipahimalani, P Mar, R Ally, A Clarke, A Mungall, AJ Tam, A Lee, D Chuah, E Schein, JE Tse, K Kasaian, K Ma, Y Marra, MA Mayo, M Balasundaram, M Thiessen, N Dhalla, N Carlsen, R Moore, RA Holt, RA Jones, SJM Wong, TN Pantazi, A Parfenov, M Kucherlapati, R Hadjipanayis, A Seidman, J Kucherlapati, M Ren, XJ Xu, AW Yang, LX Park, PJ Lee, S Rabeno, B Huelsenbeck-Dill, L Borowsky, M Cadungog, M Iacocca, M Petrelli, N Swanson, P Ojesina, AI Le, X Sandusky, G Adebamowo, SN Akeredolu, T Adebamowo, C Reynolds, SM Shmulevich, I Shelton, C Crain, D Mallery, D Curley, E Gardner, J Penny, R Morris, S Shelton, T Liu, J Lolla, L Chudamani, S Wu, Y Birrer, M McLellan, MD Bailey, MH Miller, CA Wyczalkowski, MA Fulton, RS Fronick, CC Lu, C Mardis, ER Appelbaum, EL Schmidt, HK Fulton, LA Cordes, MG Li, TD Ding, L Wilson, RK Rader, JS Behmaram, B Uyar, D Bradley, W Wrangle, J Pastore, A Levine, DA Dao, F Gao, JJ Schultz, N Sander, C Ladanyi, M Einstein, M Teeter, R Benz, S Wentzensen, N Felau, I Zenklusen, JC Bodelon, C Demchok, JA Yang, LM Sheth, M Ferguson, ML Tarnuzzer, R Yang, HN Schiffman, M Zhang, JS Wang, ZN Davidsen, T Olaniyan, O Hutter, CM Sofia, HJ Gordenin, DA Chan, K Roberts, SA Klimczak, LJ Van Waes, C Chen, Z Saleh, AD Cheng, H Parfitt, J Bartlett, J Albert, M Arnaout, A Sekhon, H Gilbert, S Peto, M Myers, J Harr, J Eckman, J Bergsten, J Tucker, K Zach, LA Karlan, BY Lester, J Orsulic, S Sun, Q Naresh, R Pihl, T Wan, YH Zaren, H Sapp, J Miller, J Drwiega, P Ojesina, AI Murray, BA Zhang, HL Cherniack, AD Sougnez, C Pedamallu, CS Lichtenstein, L Meyerson, M Noble, MS Heiman, DI Voet, D Getz, G Saksena, G Kim, J Shih, J Cho, J Lawrence, MS Gehlenborg, N Lin, P Beroukhim, R Frazer, S Gabriel, SB Schumacher, SE Leraas, KM Lichtenberg, TM Zmuda, E Bowen, J Frick, J Gastier-Foster, JM Wise, L Gerken, M Ramirez, NC Danilova, L Cope, L Baylin, SB Salvesen, HB Vellano, CP Ju, ZL Diao, LX Zhao, H Chong, ZC Ryan, MC Martinez-Ledesma, E Verhaak, RG Byers, LA Yuan, Y Chen, K Ling, SY Mills, GB Lu, YL Akbani, R Seth, S Liang, H Wang, J Han, L Weinstein, JN Bristow, CA Zhang, W Mahadeshwar, HS Sun, HD Tang, JB Zhang, JH Song, XZ Protopopov, A Shaw, KRM Chin, L Olabode, O Ojesina, AI DiSaia, P Radenbaugh, A Haussler, D Zhu, JC Stuart, J Chalise, P Koestler, D Fridley, BL Godwin, AK Madan, R Ciriello, G Martinez, C Higgins, K Bocklage, T Auman, JT Perou, CM Tan, DH Parker, JS Hoadley, KA Wilkerson, MD Mieczkowski, PA Skelly, T Veluvolu, U Hayes, DN Rathmell, WK Hoyle, AP Simons, JV Wu, JY Mose, LE Soloway, MG Balu, S Meng, SW Jefferys, SR Bodenheimer, T Shi, Y Roach, J Thorne, LB Boice, L Huang, M Jones, CD Zuna, R Walker, J Gunderson, C Snowbarger, C Brown, D Moxley, K Moore, K Andrade, K Landrum, L Mannel, R McMeekin, S Johnson, S Nelson, T Elishaev, E Dhir, R Edwards, R Bhargava, R Tiezzi, DG Andrade, JM Noushmehr, H Carlotti, CG Tirapelli, DPD Weisenberger, DJ Van Den Berg, DJ Maglinte, DT Bootwalla, MS Lai, PH Triche, T Swisher, EM Agnew, KJ Shelley, CS Laird, PW Schwarz, J Grigsby, P Mutch, D AF Burk, Robert D. Chen, Zigui Saller, Charles Tarvin, Katherine Carvalho, Andre L. Scapulatempo-Neto, Cristovam Silveira, Henrique C. Fregnani, Jose H. Creighton, Chad J. Anderson, Matthew L. Castro, Patricia Wang, Sophia S. Yau, Christina Benz, Christopher Robertson, A. Gordon Mungall, Karen Lim, Lynette Bowlby, Reanne Sadeghi, Sara Brooks, Denise Sipahimalani, Payal Mar, Richard Ally, Adrian Clarke, Amanda Mungall, Andrew J. Tam, Angela Lee, Darlene Chuah, Eric Schein, Jacqueline E. Tse, Kane Kasaian, Katayoon Ma, Yussanne Marra, Marco A. Mayo, Michael Balasundaram, Miruna Thiessen, Nina Dhalla, Noreen Carlsen, Rebecca Moore, Richard A. Holt, Robert A. Jones, Steven J. M. Wong, Tina Pantazi, Angeliki Parfenov, Michael Kucherlapati, Raju Hadjipanayis, Angela Seidman, Jonathan Kucherlapati, Melanie Ren, Xiaojia Xu, Andrew W. Yang, Lixing Park, Peter J. Lee, Semin Rabeno, Brenda Huelsenbeck-Dill, Lori Borowsky, Mark Cadungog, Mark Iacocca, Mary Petrelli, Nicholas Swanson, Patricia Ojesina, Akinyemi I. Le, Xuan Sandusky, George Adebamowo, Sally N. Akeredolu, Teniola Adebamowo, Clement Reynolds, Sheila M. Shmulevich, Ilya Shelton, Candace Crain, Daniel Mallery, David Curley, Erin Gardner, Johanna Penny, Robert Morris, Scott Shelton, Troy Liu, Jia Lolla, Laxmi Chudamani, Sudha Wu, Ye Birrer, Michael McLellan, Michael D. Bailey, Matthew H. Miller, Christopher A. Wyczalkowski, Matthew A. Fulton, Robert S. Fronick, Catrina C. Lu, Charles Mardis, Elaine R. Appelbaum, Elizabeth L. Schmidt, Heather K. Fulton, Lucinda A. Cordes, Matthew G. Li, Tiandao Ding, Li Wilson, Richard K. Rader, Janet S. Behmaram, Behnaz Uyar, Denise Bradley, William Wrangle, John Pastore, Alessandro Levine, Douglas A. Dao, Fanny Gao, Jianjiong Schultz, Nikolaus Sander, Chris Ladanyi, Marc Einstein, Mark Teeter, Randall Benz, Stephen Wentzensen, Nicolas Felau, Ina Zenklusen, Jean C. Bodelon, Clara Demchok, John A. Yang, Liming Sheth, Margi Ferguson, Martin L. Tarnuzzer, Roy Yang, Hannah Schiffman, Mark Zhang, Jiashan Wang, Zhining Davidsen, Tanja Olaniyan, Olayinka Hutter, Carolyn M. Sofia, Heidi J. Gordenin, Dmitry A. Chan, Kin Roberts, Steven A. Klimczak, Leszek J. Van Waes, Carter Chen, Zhong Saleh, Anthony D. Cheng, Hui Parfitt, Jeremy Bartlett, John Albert, Monique Arnaout, Angel Sekhon, Harman Gilbert, Sebastien Peto, Myron Myers, Jerome Harr, Jodi Eckman, John Bergsten, Julie Tucker, Kelinda Zach, Leigh Anne Karlan, Beth Y. Lester, Jenny Orsulic, Sandra Sun, Qiang Naresh, Rashi Pihl, Todd Wan, Yunhu Zaren, Howard Sapp, Jennifer Miller, Judy Drwiega, Paul Ojesina, Akinyemi I. Murray, Bradley A. Zhang, Hailei Cherniack, Andrew D. Sougnez, Carrie Pedamallu, Chandra Sekhar Lichtenstein, Lee Meyerson, Matthew Noble, Michael S. Heiman, David I. Voet, Doug Getz, Gad Saksena, Gordon Kim, Jaegil Shih, Juliann Cho, Juok Lawrence, Michael S. Gehlenborg, Nils Lin, Pei Beroukhim, Rameen Frazer, Scott Gabriel, Stacey B. Schumacher, Steven E. Leraas, Kristen M. Lichtenberg, Tara M. Zmuda, Erik Bowen, Jay Frick, Jessica Gastier-Foster, Julie M. Wise, Lisa Gerken, Mark Ramirez, Nilsa C. Danilova, Ludmila Cope, Leslie Baylin, Stephen B. Salvesen, Helga B. Vellano, Christopher P. Ju, Zhenlin Diao, Lixia Zhao, Hao Chong, Zechen Ryan, Michael C. Martinez-Ledesma, Emmanuel Verhaak, Roeland G. Byers, Lauren Averett Yuan, Yuan Chen, Ken Ling, Shiyun Mills, Gordon B. Lu, Yiling Akbani, Rehan Seth, Sahil Liang, Han Wang, Jing Han, Leng Weinstein, John N. Bristow, Christopher A. Zhang, Wei Mahadeshwar, Harshad S. Sun, Huandong Tang, Jiabin Zhang, Jianhua Song, Xingzhi Protopopov, Alexei Shaw, Kenna R. Mills Chin, Lynda Olabode, Oluwole Ojesina, Akinyemi I. DiSaia, Philip Radenbaugh, Amie Haussler, David Zhu, Jingchun Stuart, Josh Chalise, Prabhakar Koestler, Devin Fridley, Brooke L. Godwin, Andrew K. Madan, Rashna Ciriello, Giovanni Martinez, Cathleen Higgins, Kelly Bocklage, Therese Auman, J. Todd Perou, Charles M. Tan, Donghui Parker, Joel S. Hoadley, Katherine A. Wilkerson, Matthew D. Mieczkowski, Piotr A. Skelly, Tara Veluvolu, Umadevi Hayes, D. Neil Rathmell, W. Kimryn Hoyle, Alan P. Simons, Janae V. Wu, Junyuan Mose, Lisle E. Soloway, Matthew G. Balu, Saianand Meng, Shaowu Jefferys, Stuart R. Bodenheimer, Tom Shi, Yan Roach, Jeffrey Thorne, Leigh B. Boice, Lori Huang, Mei Jones, Corbin D. Zuna, Rosemary Walker, Joan Gunderson, Camille Snowbarger, Carie Brown, David Moxley, Katherine Moore, Kathleen Andrade, Kelsi Landrum, Lisa Mannel, Robert McMeekin, Scott Johnson, Starla Nelson, Tina Elishaev, Esther Dhir, Rajiv Edwards, Robert Bhargava, Rohit Tiezzi, Daniel G. Andrade, Jurandyr M. Noushmehr, Houtan Carlotti, Carlos Gilberto, Jr. Tirapelli, Daniela Pretti da Cunha Weisenberger, Daniel J. Van Den Berg, David J. Maglinte, Dennis T. Bootwalla, Moiz S. Lai, Phillip H. Triche, Timothy, Jr. Swisher, Elizabeth M. Agnew, Kathy J. Shelley, Carl Simon Laird, Peter W. Schwarz, Julie Grigsby, Perry Mutch, David CA Canc Genome Atlas Res Network TI Integrated genomic and molecular characterization of cervical cance SO NATURE LA English DT Article ID TO-MESENCHYMAL TRANSITION; RNA-SEQ; TRANSCRIPTION FACTORS; DNA METHYLATION; BREAST-CANCER; 14-3-3-SIGMA; RESISTANCE; EXPRESSION; SIGNATURE; ACCURATE C1 [Burk, Robert D.; Chen, Zigui] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Saller, Charles; Tarvin, Katherine] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [Carvalho, Andre L.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.; Fregnani, Jose H.] Barretos Canc Hosp, Barretos, SP, Brazil. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Yau, Christina; Benz, Christopher] Buck Inst Res Aging, Novato, CA 94945 USA. [Robertson, A. Gordon; Mungall, Karen; Lim, Lynette; Bowlby, Reanne; Sadeghi, Sara; Brooks, Denise; Sipahimalani, Payal; Mar, Richard; Ally, Adrian; Clarke, Amanda; Mungall, Andrew J.; Tam, Angela; Lee, Darlene; Chuah, Eric; Schein, Jacqueline E.; Tse, Kane; Kasaian, Katayoon; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Balasundaram, Miruna; Thiessen, Nina; Dhalla, Noreen; Carlsen, Rebecca; Moore, Richard A.; Holt, Robert A.; Jones, Steven J. M.; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Pantazi, Angeliki; Parfenov, Michael; Kucherlapati, Raju; Hadjipanayis, Angela; Seidman, Jonathan; Kucherlapati, Melanie; Ren, Xiaojia; Xu, Andrew W.; Yang, Lixing; Park, Peter J.; Lee, Semin] Harvard Med Sch, Boston, MA 02115 USA. [Rabeno, Brenda; Huelsenbeck-Dill, Lori; Borowsky, Mark; Cadungog, Mark; Iacocca, Mary; Petrelli, Nicholas; Swanson, Patricia] Christiana Care Hlth Serv Inc, Helen F Graham Canc Ctr, Newark, DE 19713 USA. [Rabeno, Brenda; Huelsenbeck-Dill, Lori; Borowsky, Mark; Cadungog, Mark; Iacocca, Mary; Petrelli, Nicholas; Swanson, Patricia] Christiana Care Hlth Serv Inc, Res Inst, Newark, DE 19713 USA. [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Ojesina, Akinyemi I.; Murray, Bradley A.; Zhang, Hailei; Cherniack, Andrew D.; Sougnez, Carrie; Pedamallu, Chandra Sekhar; Lichtenstein, Lee; Meyerson, Matthew; Noble, Michael S.; Heiman, David I.; Voet, Doug; Getz, Gad; Saksena, Gordon; Kim, Jaegil; Shih, Juliann; Cho, Juok; Lawrence, Michael S.; Gehlenborg, Nils; Lin, Pei; Beroukhim, Rameen; Frazer, Scott; Gabriel, Stacey B.; Schumacher, Steven E.; Protopopov, Alexei] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Ojesina, Akinyemi I.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Le, Xuan] ILSbio LLC, Chestertown, MD 21620 USA. [Sandusky, George] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Adebamowo, Sally N.; Akeredolu, Teniola; Adebamowo, Clement] Inst Human Virol, Abuja, Nigeria. [Reynolds, Sheila M.; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Shelton, Candace; Crain, Daniel; Mallery, David; Curley, Erin; Gardner, Johanna; Penny, Robert; Morris, Scott; Shelton, Troy] Int Genom Consortium, Phoenix, AZ 85004 USA. [Liu, Jia; Lolla, Laxmi; Chudamani, Sudha; Wu, Ye] Leidos Biomed, Rockville, MD 20850 USA. [Birrer, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McLellan, Michael D.; Bailey, Matthew H.; Miller, Christopher A.; Wyczalkowski, Matthew A.; Fulton, Robert S.; Fronick, Catrina C.; Lu, Charles; Mardis, Elaine R.; Appelbaum, Elizabeth L.; Schmidt, Heather K.; Fulton, Lucinda A.; Cordes, Matthew G.; Li, Tiandao; Ding, Li; Wilson, Richard K.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Rader, Janet S.; Behmaram, Behnaz; Uyar, Denise; Bradley, William] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Wrangle, John] Med Univ South Carolina, Charleston, SC 29425 USA. [Pastore, Alessandro; Levine, Douglas A.; Dao, Fanny; Gao, Jianjiong; Schultz, Nikolaus; Sander, Chris; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Einstein, Mark; Teeter, Randall] Montefiore Med Ctr, Bronx, NY 10461 USA. [Benz, Stephen] NantOmics, Santa Cruz, CA 95060 USA. [Wentzensen, Nicolas; Felau, Ina; Zenklusen, Jean C.; Bodelon, Clara; Demchok, John A.; Yang, Liming; Sheth, Margi; Ferguson, Martin L.; Tarnuzzer, Roy; Yang, Hannah; Schiffman, Mark; Zhang, Jiashan; Wang, Zhining; Davidsen, Tanja] NCI, Bethesda, MD 20892 USA. [Olaniyan, Olayinka] Natl Hosp, Abuja, Nigeria. [Hutter, Carolyn M.; Sofia, Heidi J.] NHGRI, Bethesda, MD 20892 USA. [Gordenin, Dmitry A.; Chan, Kin; Roberts, Steven A.; Klimczak, Leszek J.] NIEHS, POB 12233, Durham, NC 27709 USA. [Van Waes, Carter; Chen, Zhong; Saleh, Anthony D.; Cheng, Hui] NIDCD, Bethesda, MD 20892 USA. [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada. [Bartlett, John; Albert, Monique] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Arnaout, Angel; Sekhon, Harman; Gilbert, Sebastien] Ottawa Hosp, Ontario Tumour Bank, Ottawa, ON K1H 8L6, Canada. [Peto, Myron] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Myers, Jerome; Harr, Jodi; Eckman, John; Bergsten, Julie; Tucker, Kelinda; Zach, Leigh Anne] Penrose St Francis Hlth Serv, Colorado Springs, CO 80906 USA. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Sun, Qiang; Naresh, Rashi; Pihl, Todd; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA. [Zaren, Howard; Sapp, Jennifer; Miller, Judy; Drwiega, Paul] St Josephs Candler Hlth Syst, Savannah, GA 31406 USA. [Leraas, Kristen M.; Lichtenberg, Tara M.; Zmuda, Erik; Bowen, Jay; Frick, Jessica; Gastier-Foster, Julie M.; Wise, Lisa; Gerken, Mark; Ramirez, Nilsa C.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Danilova, Ludmila; Cope, Leslie; Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Salvesen, Helga B.] Univ Bergen, Bergen, Norway. [Vellano, Christopher P.; Ju, Zhenlin; Diao, Lixia; Zhao, Hao; Chong, Zechen; Ryan, Michael C.; Martinez-Ledesma, Emmanuel; Verhaak, Roeland G.; Byers, Lauren Averett; Yuan, Yuan; Chen, Ken; Ling, Shiyun; Mills, Gordon B.; Lu, Yiling; Akbani, Rehan; Seth, Sahil; Liang, Han; Wang, Jing; Han, Leng; Weinstein, John N.; Bristow, Christopher A.; Zhang, Wei; Mahadeshwar, Harshad S.; Sun, Huandong; Tang, Jiabin; Zhang, Jianhua; Song, Xingzhi; Protopopov, Alexei; Shaw, Kenna R. Mills; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Olabode, Oluwole] Univ Abuja, Teaching Hosp, Gwagwalada, Abuja, Nigeria. [DiSaia, Philip] Univ Calif Irvine, Orange, CA 92668 USA. [Radenbaugh, Amie; Haussler, David; Zhu, Jingchun; Stuart, Josh] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Chalise, Prabhakar; Koestler, Devin; Fridley, Brooke L.; Godwin, Andrew K.; Madan, Rashna] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Ciriello, Giovanni] Univ Lausanne, Lausanne, Switzerland. [Martinez, Cathleen; Higgins, Kelly; Bocklage, Therese] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Auman, J. Todd; Perou, Charles M.; Tan, Donghui; Parker, Joel S.; Hoadley, Katherine A.; Wilkerson, Matthew D.; Mieczkowski, Piotr A.; Skelly, Tara; Veluvolu, Umadevi; Hayes, D. Neil; Rathmell, W. Kimryn; Hoyle, Alan P.; Simons, Janae V.; Wu, Junyuan; Mose, Lisle E.; Soloway, Matthew G.; Balu, Saianand; Meng, Shaowu; Jefferys, Stuart R.; Bodenheimer, Tom; Shi, Yan; Roach, Jeffrey; Thorne, Leigh B.; Boice, Lori; Huang, Mei; Jones, Corbin D.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Zuna, Rosemary; Walker, Joan; Gunderson, Camille; Snowbarger, Carie; Brown, David; Moxley, Katherine; Moore, Kathleen; Andrade, Kelsi; Landrum, Lisa; Mannel, Robert; McMeekin, Scott; Johnson, Starla; Nelson, Tina] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Elishaev, Esther; Dhir, Rajiv; Edwards, Robert; Bhargava, Rohit] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Tiezzi, Daniel G.; Andrade, Jurandyr M.; Noushmehr, Houtan; Carlotti, Carlos Gilberto, Jr.; Tirapelli, Daniela Pretti da Cunha] Univ Sao Paulo, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP, Brazil. [Weisenberger, Daniel J.; Van Den Berg, David J.; Maglinte, Dennis T.; Bootwalla, Moiz S.; Lai, Phillip H.; Triche, Timothy, Jr.] Univ Southern Calif, Los Angeles, CA 90033 USA. [Swisher, Elizabeth M.; Agnew, Kathy J.] Univ Washington, Seattle, WA 98109 USA. [Shelley, Carl Simon] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Laird, Peter W.] Van Andel Res Inst, Grand Rapids, MI 49503 USA. [Schwarz, Julie; Grigsby, Perry; Mutch, David] Washington Univ, St Louis, MO 63110 USA. RP Ojesina, AI (reprint author), HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.; Ojesina, AI (reprint author), Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA.; Ojesina, AI (reprint author), Univ Alabama Birmingham, Birmingham, AL 35294 USA.; Rader, JS (reprint author), Med Coll Wisconsin, Milwaukee, WI 53226 USA.; Rader, JS (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA. EM ojesina@uab.edu; jrader@mcw.edu; wentzenn@mail.nih.gov; vellcp2@gmail.com NR 67 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 16 PY 2017 VL 543 IS 7645 BP 378 EP + PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9RN UT WOS:000396337400042 ER PT J AU Guerriero, JL Sotayo, A Ponichtera, HE Castrillon, JA Pourzia, AL Schad, S Johnson, SF Carrasco, RD Lazo, S Bronson, RT Davis, SP Lobera, M Nolan, MA Letai, A AF Guerriero, Jennifer L. Sotayo, Alaba Ponichtera, Holly E. Castrillon, Jessica A. Pourzia, Alexandra L. Schad, Sara Johnson, Shawn F. Carrasco, Ruben D. Lazo, Suzan Bronson, Roderick T. Davis, Scott P. Lobera, Mercedes Nolan, Michael A. Letai, Anthony TI Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages SO NATURE LA English DT Article ID CELLS; PROGRESSION; EXPRESSION; THERAPY; CANCER; RESPONSES; EFFICACY; MODULATE; DEFINES; PROTEIN AB Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects(1), but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition)(2,3) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies)(4,5) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro(6). Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy. C1 [Guerriero, Jennifer L.; Sotayo, Alaba; Ponichtera, Holly E.; Castrillon, Jessica A.; Pourzia, Alexandra L.; Schad, Sara; Johnson, Shawn F.; Lazo, Suzan; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Carrasco, Ruben D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Bronson, Roderick T.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Davis, Scott P.; Lobera, Mercedes; Nolan, Michael A.] GlaxoSmithKline, 200 Technol Sq Suite 602, Cambridge, MA 02139 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Nolan, MA (reprint author), GlaxoSmithKline, 200 Technol Sq Suite 602, Cambridge, MA 02139 USA. EM Michael.A.Nolan@gsk.com; Anthony_Letai@dfci.harvard.edu FU NIH NCI [F32CA180733, R01CA205967]; Friends of Dana-Farber, Dancing for a Cure; GlaxoSmithKline FX We thank A. Benowitz and C. Leach for their support and discussions in the preparation of the manuscript. This work was supported by NIH NCI F32CA180733 (J.L.G.), The Friends of Dana-Farber, Dancing for a Cure (J.L.G.), NIH NCI R01CA205967 (A.L.) and a sponsored research agreement from GlaxoSmithKline (A.L., J.L.G.). NR 35 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 16 PY 2017 VL 543 IS 7645 BP 428 EP + DI 10.1038/nature21409 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9RN UT WOS:000396337400052 PM 28273064 ER PT J AU Lindstrom, S Loomis, S Turman, C Huang, HY Huang, JY Aschard, H Chan, AT Choi, H Cornelis, M Curhan, G De Vivo, I Eliassen, AH Fuchs, C Gaziano, M Hankinson, SE Hu, F Jensen, M Kang, JH Kabrhel, C Liang, LM Pasquale, LR Rimm, E Stampfer, MJ Tamimi, RM Tworoger, SS Wiggs, JL Hunter, DJ Kraft, P AF Lindstrom, Sara Loomis, Stephanie Turman, Constance Huang, Hongyan Huang, Jinyan Aschard, Hugues Chan, Andrew T. Choi, Hyon Cornelis, Marilyn Curhan, Gary De Vivo, Immaculata Eliassen, A. Heather Fuchs, Charles Gaziano, Michael Hankinson, Susan E. Hu, Frank Jensen, Majken Kang, Jae H. Kabrhel, Christopher Liang, Liming Pasquale, Louis R. Rimm, Eric Stampfer, Meir J. Tamimi, Rulla M. Tworoger, Shelley S. Wiggs, Janey L. Hunter, David J. Kraft, Peter TI A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; BREAST-CANCER RISK; BODY-MASS INDEX; COMMON VARIANTS; MAMMOGRAPHIC DENSITY; SUSCEPTIBILITY LOCI; METAANALYSIS; HEALTH; WOMEN AB The Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (beta = 0.45, p = 3.48x10(-22)), and using a significance level of p = 0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR = 2.17, 95% CI: 1.79.2.63, p = 2.70x10(-15)), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes. C1 [Lindstrom, Sara; Turman, Constance; Huang, Hongyan; Huang, Jinyan; Aschard, Hugues; De Vivo, Immaculata; Liang, Liming; Hunter, David J.; Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Lindstrom, Sara; Turman, Constance; Huang, Hongyan; Huang, Jinyan; Aschard, Hugues; De Vivo, Immaculata; Eliassen, A. Heather; Hankinson, Susan E.; Hu, Frank; Liang, Liming; Rimm, Eric; Stampfer, Meir J.; Tamimi, Rulla M.; Tworoger, Shelley S.; Hunter, David J.; Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lindstrom, Sara] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Loomis, Stephanie; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Choi, Hyon] Boston Univ, Sch Med, Rheumatol Sect, Boston, MA 02118 USA. [Choi, Hyon] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA 02118 USA. [Cornelis, Marilyn] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Curhan, Gary; De Vivo, Immaculata; Eliassen, A. Heather; Fuchs, Charles; Hankinson, Susan E.; Jensen, Majken; Kang, Jae H.; Kabrhel, Christopher; Pasquale, Louis R.; Rimm, Eric; Stampfer, Meir J.; Tamimi, Rulla M.; Tworoger, Shelley S.; Hunter, David J.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Curhan, Gary; De Vivo, Immaculata; Eliassen, A. Heather; Fuchs, Charles; Hankinson, Susan E.; Jensen, Majken; Kang, Jae H.; Kabrhel, Christopher; Pasquale, Louis R.; Rimm, Eric; Stampfer, Meir J.; Tamimi, Rulla M.; Tworoger, Shelley S.; Hunter, David J.] Harvard Med Sch, Boston, MA USA. [Curhan, Gary] Brigham & Womens Hosp, Dept Med, Div Renal, 75 Francis St, Boston, MA 02115 USA. [Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gaziano, Michael] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Hu, Frank; Jensen, Majken; Rimm, Eric; Stampfer, Meir J.; Hunter, David J.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Kabrhel, Christopher] Harvard Med Sch, Dept Emergency Med, Ctr Vasc Emergencies, Massachusetts Gen Hosp, Boston, MA USA. [Liang, Liming; Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Lindstrom, S (reprint author), Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.; Lindstrom, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Lindstrom, S (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. EM saralind@uw.edu FU National Institute of Health [P01CA87969, P01CA055075, P01DK070756, U01HG004728, UM1CA186107, UM1CA176726, R01CA49449, R01CA50385, R01CA67262, R01CA131332, R01HL034594, R01HL088521, R01HL35464, R01HL116854, R01EY015473, R01EY022305, P30EY014104, R03DC013373, R03CA165131]; Harvard Medical School Distinguished Ophthalmology Scholar award FX This work was supported by National Institute of Health (P01CA87969 (MJS), P01CA055075, P01DK070756 (GC), U01HG004728 (LRP), UM1CA186107 (MJS), UM1CA176726, R01CA49449 (SJH), R01CA50385, R01CA67262 (SJH), R01CA131332 (RMT), R01HL034594, R01HL088521, R01HL35464 (ER), R01HL116854 (CK), R01EY015473 (LRP), R01EY022305 (JLW), P30EY014104 (JLW), R03DC013373 (MC) and R03CA165131 (SL)). Dr. Pasquale is also supported by a Harvard Medical School Distinguished Ophthalmology Scholar award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 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 MAR 16 PY 2017 VL 12 IS 3 AR e0173997 DI 10.1371/journal.pone.0173997 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9KE UT WOS:000396318300108 PM 28301549 ER PT J AU Wakeman, SE AF Wakeman, Sarah E. TI Another Senseless Death - The Case for Supervised Injection Facilities SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID OVERDOSE DEATHS; DRUG C1 [Wakeman, Sarah E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wakeman, Sarah E.] Harvard Med Sch, Boston, MA 02115 USA. RP Wakeman, SE (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Wakeman, SE (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 5 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 MAR 16 PY 2017 VL 376 IS 11 BP 1011 EP 1013 DI 10.1056/NEJMp1613651 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QT UT WOS:000396403700005 PM 28296603 ER PT J AU Bellmunt, J de Wit, R Vaughn, DJ Fradet, Y Lee, JL Fong, L Vogelzang, NJ Climent, MA Petrylak, DP Choueiri, TK Necchi, A Gerritsen, W Gurney, H Quinn, DI Culine, S Sternberg, CN Mai, Y Poehlein, CH Perini, RF Bajorin, DF AF Bellmunt, J. de Wit, R. Vaughn, D. J. Fradet, Y. Lee, J. -L. Fong, L. Vogelzang, N. J. Climent, M. A. Petrylak, D. P. Choueiri, T. K. Necchi, A. Gerritsen, W. Gurney, H. Quinn, D. I. Culine, S. Sternberg, C. N. Mai, Y. Poehlein, C. H. Perini, R. F. Bajorin, D. F. CA KEYNOTE-045 Investigators TI Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; PHASE-III TRIAL; VINFLUNINE PLUS; SUPPORTIVE CARE; CHEMOTHERAPY; NIVOLUMAB; CANCER; FAILURE; TRACT AB BACKGROUND Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG kappa. isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P = 0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P = 0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P = 0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P = 0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma.Funded by Merck; KEYNOTE- 045 ClinicalTrials. gov number, NCT02256436.) C1 [Bellmunt, J.; Choueiri, T. K.] Dana Farber Canc Inst, 450 Brookline Ave,Dana Bldg 1230, Boston, MA 02215 USA. [Bellmunt, J.] Hosp Mar, Med Res Inst, Parc Salut Mar, Barcelona, Spain. [Climent, M. A.] Fdn Inst Valenciano Oncol, Valencia, Spain. [de Wit, R.] Erasmus MC Canc Inst, Rotterdam, Netherlands. [Gerritsen, W.] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Vaughn, D. J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Fradet, Y.] Univ Laval, Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. [Lee, J. -L.] Asan Med Ctr, Seoul, South Korea. [Lee, J. -L.] Univ Ulsan, Coll Med, Seoul, South Korea. [Fong, L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Vogelzang, N. J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Petrylak, D. P.] Yale Univ, Smilow Canc Hosp, New Haven, CT USA. [Necchi, A.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Gurney, H.] Westmead Hosp, Sydney, NSW, Australia. [Gurney, H.] Macquarie Univ, Sydney, NSW, Australia. [Quinn, D. I.] Univ Southern Calif, Norris Comprehens Canc Ctr & Hosp, Los Angeles, CA USA. [Culine, S.] Hop St Louis, Paris, France. [Sternberg, C. N.] San Camillo Hosp, Rome, Italy. [Sternberg, C. N.] Forlanini Hosp, Rome, Italy. [Mai, Y.; Poehlein, C. H.; Perini, R. F.] Merck, Kenilworth, NJ USA. [Bajorin, D. F.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana Bldg 1230, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu FU Merck FX Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436. NR 24 TC 1 Z9 1 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 MAR 16 PY 2017 VL 376 IS 11 BP 1015 EP 1026 DI 10.1056/NEJMoa1613683 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QT UT WOS:000396403700006 PM 28212060 ER PT J AU Boulware, DR Makadzange, AT AF Boulware, David R. Makadzange, A. Tariro TI Case 8-2017: A 39-Year-Old Zimbabwean Man with a Severe Headache SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 9th Annual Workshop on Advanced Clinical Care-AIDS (AWACC) CY NOV 19, 2015 CL Durban, SOUTH AFRICA ID INFECTIOUS-DISEASES SOCIETY; LATERAL FLOW ASSAY; CRYPTOCOCCAL MENINGITIS; ANTIRETROVIRAL THERAPY; OPPORTUNISTIC INFECTIONS; HIV; ADULTS; ADOLESCENTS; GUIDELINES; MORTALITY C1 [Boulware, David R.] Univ Minnesota, Dept Med, Med Ctr, Box 736 UMHC, Minneapolis, MN 55455 USA. [Boulware, David R.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Makadzange, A. Tariro] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Makadzange, A. Tariro] Harvard Med Sch, Boston, MA USA. RP Boulware, DR (reprint author), Univ Minnesota, Dept Med, Med Ctr, Box 736 UMHC, Minneapolis, MN 55455 USA.; Boulware, DR (reprint author), Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. FU NIAID NIH HHS [P30 AI060354] NR 27 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 MAR 16 PY 2017 VL 376 IS 11 BP 1065 EP 1071 DI 10.1056/NEJMcpc1516450 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QT UT WOS:000396403700012 PM 28296602 ER PT J AU Doi, Y Bonomo, RA Hooper, DC Kaye, KS Johnson, JR Clancy, CJ Thaden, JT Stryjewski, ME van Duin, D AF Doi, Yohei Bonomo, Robert A. Hooper, David C. Kaye, Keith S. Johnson, James R. Clancy, Cornelius J. Thaden, Joshua T. Stryjewski, Martin E. van Duin, David CA Gram-Negative Comm ARLG TI Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE gram-negative; antimicrobial resistance; observational studies; interventional studies; clinical trials ID KLEBSIELLA-PNEUMONIAE; CEFTAZIDIME-AVIBACTAM; THERAPY; EPIDEMIOLOGY; SPECTRUM; OUTCOMES; SURVEILLANCE; BACTEREMIA AB Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections. C1 [Doi, Yohei; Bonomo, Robert A.; Clancy, Cornelius J.] Univ Pittsburgh Sch Med, Div Infect Dis, St Petersburg 199034, Russia. [Bonomo, Robert A.] Case Western Reserve Univ, Louis Stokes Cleveland Vet Affairs Med Ctr, Dept Med, Res Serv, Cleveland, OH USA. [Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. [Kaye, Keith S.] Univ Michigan Med Sch, Div Infect Dis, Ann Arbor, MI USA. [Johnson, James R.] Minneapolis Vet Hlth Care Syst, Minneapolis, MN USA. [Thaden, Joshua T.] Duke Univ Sch Med, Div Infect Dis, Durham, NC USA. [Stryjewski, Martin E.] Div Infect Dis, Dept Med, Ctr Educ Med Investigac Clnicas, Norberto Quirno Ciudad Autonoma, Buenos Aires, DF, Argentina. [van Duin, David] Univ North Carolina Sch Med, Div Infect Dis, Chapel Hill, NC USA. [Doi, Yohei] Univ Pittsburgh Sch Med, Div Infect Dis, S829 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. RP Doi, Y (reprint author), Univ Pittsburgh Sch Med, Div Infect Dis, S829 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM yod4@pitt.edu FU National Institute of Allergy and Infectious Diseases of the NIH [UM1AI104681] FX This article was supported by the National Institute of Allergy and Infectious Diseases of the NIH (award number UM1AI104681). NR 25 TC 1 Z9 1 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 MAR 15 PY 2017 VL 64 SU 1 BP S30 EP S35 DI 10.1093/cid/ciw829 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TQ UT WOS:000397305000007 PM 28350901 ER PT J AU Middleton, R Gao, DD Thomas, A Singh, B Au, A Wong, JJL Bomane, A Cosson, B Eyras, E Rasko, JEJ Ritchie, W AF Middleton, Robert Gao, Dadi Thomas, Aubin Singh, Babita Au, Amy Wong, Justin J-L Bomane, Alexandra Cosson, Bertrand Eyras, Eduardo Rasko, John E. J. Ritchie, William TI IRFinder: assessing the impact of intron retention on mammalian gene expression SO GENOME BIOLOGY LA English DT Article DE mRNA splicing; Intron retention; Gene regulation ID STEM-CELLS; RNA; PROGRAM; BINDING; REVEALS; DECAY; DIFFERENTIATION; ACTIVATION AB Intron retention (IR) occurs when an intron is transcribed into pre-mRNA and remains in the final mRNA. We have developed a program and database called IRFinder to accurately detect IR from mRNA sequencing data. Analysis of 2573 samples showed that IR occurs in all tissues analyzed, affects over 80% of all coding genes and is associated with cell differentiation and the cell cycle. Frequently retained introns are enriched for specific RNA binding protein sites and are often retained in clusters in the same gene. IR is associated with lower protein levels and intronretaining transcripts that escape nonsense-mediated decay are not actively translated. C1 [Middleton, Robert; Gao, Dadi; Ritchie, William] Centenary Inst, Bioinformat Lab, Camperdown, NSW 2050, Australia. [Gao, Dadi] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Gao, Dadi] Boston & Harvard Med Sch, Boston, MA USA. [Gao, Dadi; Au, Amy; Wong, Justin J-L; Rasko, John E. J.] Centenary Inst, Gene & Stem Cell Therapy Program, Camperdown, NSW 2050, Australia. [Thomas, Aubin; Ritchie, William] CNRS, UPR 1142, F-34094 Montpellier, France. [Singh, Babita; Eyras, Eduardo] Pompeu Fabra Univ, UPF, Dr Aiguader 88, E-08003 Barcelona, Spain. [Au, Amy; Wong, Justin J-L; Rasko, John E. J.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Wong, Justin J-L] Univ Sydney, Centenary Inst, Gene Regulat Canc Lab, Camperdown, NSW 2050, Australia. [Bomane, Alexandra; Cosson, Bertrand] Univ Paris Diderot, CNRS, Sorbonne Paris Cite, Epigenet & Cell Fate,UMR7216, F-75013 Paris, France. [Eyras, Eduardo] Catalan Inst Res & Adv Studies, ICREA, Passeig Lluis Co 23, E-08010 Barcelona, Spain. [Rasko, John E. J.] Royal Prince Alfred Hosp, Cell & Mol Therapies, Camperdown, NSW 2050, Australia. [Ritchie, William] CNRS, UMR 5203, F-34094 Montpellier, France. RP Ritchie, W (reprint author), Centenary Inst, Bioinformat Lab, Camperdown, NSW 2050, Australia.; Ritchie, W (reprint author), CNRS, UPR 1142, F-34094 Montpellier, France.; Ritchie, W (reprint author), CNRS, UMR 5203, F-34094 Montpellier, France. EM william.ritchie@igh.cnrs.fr FU Agence Nationale de la Recherche [ANR 143683]; National Health and Medical Research Council [1061906, 1080530, 1128175, 1126306]; MINECO (Spanish Government) [BIO2014-52566-R]; FEDER; AGAUR [2014-SGR1121]; Sandra Ibarra Foundation for Cancer [FSI2013] FX This work was supported by the Agence Nationale de la Recherche (ANR 143683); the National Health and Medical Research Council (grant # 1061906, # 1080530, # 1128175, # 1126306). BS and EE were supported by grants BIO2014-52566-R from the MINECO (Spanish Government) and FEDER funds, by AGAUR (2014-SGR1121), and by the Sandra Ibarra Foundation for Cancer (FSI2013). NR 37 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 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAR 15 PY 2017 VL 18 AR 51 DI 10.1186/s13059-017-1184-4 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EP0ZD UT WOS:000397114300001 PM 28298237 ER PT J AU Feldman, S Wuerffel, R Achour, I Wang, LL Carpenter, PB Kenter, AL AF Feldman, Scott Wuerffel, Robert Achour, Ikbel Wang, Lili Carpenter, Phillip B. Kenter, Amy L. TI 53BP1 Contributes to Igh Locus Chromatin Topology during Class Switch Recombination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTIDINE DEAMINASE AID; DOUBLE-STRAND BREAKS; HEAVY-CHAIN LOCUS; ACTIVATED B-CELLS; DNA-DAMAGE; HISTONE H2AX; IN-VIVO; GENOMIC STABILITY; PROTEIN 53BP1; S-REGIONS AB In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in switch (S) regions. Resolution of DNA double-strand breaks proceeds through formation of S-S synaptic complexes. S-S synapsis is mediated by a chromatin loop that spans the C region domain of the Igh locus. S-S junctions are joined via a nonhomologous end joining DNA repair process. CSR occurs via an intrachromosomal looping out and deletion mechanism that is 53BP1 dependent. However, the mechanism by which 53BP1 facilitates deletional CSR and inhibits inversional switching events remains unknown. We report a novel architectural role for 53BP1 in Igh chromatin looping in mouse B cells. Long-range interactions between the Em and 3'E alpha enhancers are significantly diminished in the absence of 53BP1. In contrast, germline transcript promoter: 3'E alpha looping interactions are unaffected by 53BP1 deficiency. Furthermore, 53BP1 chromatin occupancy at sites in the Igh locus is B cell specific, is correlated with histone H4 lysine 20 marks, and is subject to chromatin spreading. Thus, 53BP1 is required for three-dimensional organization of the Igh locus and provides a plausible explanation for the link with 53BP1 enforcement of deletional CSR. C1 [Feldman, Scott; Wuerffel, Robert; Achour, Ikbel; Wang, Lili; Kenter, Amy L.] Univ Illinois, Dept Microbiol & Immunol, Coll Med, 835 South Wolcott Ave MC 790, Chicago, IL 60612 USA. [Carpenter, Phillip B.] Univ Texas Hlth Sci Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Feldman, Scott] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Achour, Ikbel] Univ Arizona, Coll Med, Dept Med, Tucson, AZ USA. [Wang, Lili] Dana Farber Canc Inst, Canc Vaccine Ctr, Dept Med Oncol, Boston, MA 02115 USA. RP Kenter, AL (reprint author), Univ Illinois, Dept Microbiol & Immunol, Coll Med, 835 South Wolcott Ave MC 790, Chicago, IL 60612 USA. EM star1@uic.edu FU National Institutes of Health [R01AI052400, 5R21AI076747-01]; Welch Foundation [AU-1569] FX This work was supported by the National Institutes of Health (Grants R01AI052400 to A.L.K. and 5R21AI076747-01 to P.B.C.) and by the Welch Foundation (Grant AU-1569 to P.B.C.). NR 69 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 MAR 15 PY 2017 VL 198 IS 6 BP 2434 EP 2444 DI 10.4049/j.immunol.1601947 PG 11 WC Immunology SC Immunology GA EN3MD UT WOS:000395911700023 PM 28159901 ER PT J AU Doyle, C Cristofaro, V Sack, BS Lukianov, SN Schafer, M Chung, YG Sullivan, MP Adam, RM AF Doyle, Claire Cristofaro, Vivian Sack, Bryan S. Lukianov, Stefan N. Schaefer, Mattias Chung, Yeun Goo Sullivan, Maryrose P. Adam, Rosalyn M. TI Inosine attenuates spontaneous activity in the rat neurogenic bladder through an A(2B) pathway SO SCIENTIFIC REPORTS LA English DT Article ID SPINAL-CORD-INJURY; PIG URINARY-BLADDER; ADENOSINE-RECEPTORS; DETRUSOR OVERACTIVITY; SMOOTH-MUSCLE; DOWN-REGULATION; PROTEIN-KINASE; AXON OUTGROWTH; K+ CHANNELS; BK CHANNEL AB Neurogenic detrusor overactivity (NDO) is among the most challenging complications of spinal cord injury (SCI). A recent report by us demonstrated an improvement in NDO in SCI rats following chronic systemic treatment with the purine nucleoside inosine. The objective of this study was to investigate the mechanism of action of inosine underlying improvement of NDO. Male Sprague-Dawley rats underwent complete spinal cord transection at T8. Inosine (1 mM) delivered intravesically to SCI rats during conscious cystometry significantly decreased the frequency of spontaneous non-voiding contractions. In isolated tissue assays, inosine (1 mM) significantly decreased the amplitude of spontaneous activity (SA) in SCI bladder muscle strips. This effect was prevented by a pan-adenosine receptor antagonist CGS15943, but not by A(1) or A(3) receptor antagonists. The A(2A) antagonist ZM241385 and A(2B) antagonist PSB603 prevented the effect of inosine. The effect of inosine was mimicked by the adenosine receptor agonist NECA and the A(2B) receptor agonist BAY60-6583. The inhibition of SA by inosine was not observed in the presence of the BK antagonist, iberiotoxin, but persisted in the presence of K-ATP and SK antagonists. These findings demonstrate that inosine acts via an A(2B) receptormediated pathway that impinges on specific potassium channel effectors. C1 [Doyle, Claire; Sack, Bryan S.; Lukianov, Stefan N.; Schaefer, Mattias; Chung, Yeun Goo; Adam, Rosalyn M.] Boston Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA. [Doyle, Claire; Cristofaro, Vivian; Sack, Bryan S.; Schaefer, Mattias; Chung, Yeun Goo; Sullivan, Maryrose P.; Adam, Rosalyn M.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Cristofaro, Vivian; Sullivan, Maryrose P.] VA Boston Healthcare Syst, Div Urol, West Roxbury, MA 02301 USA. [Cristofaro, Vivian; Sullivan, Maryrose P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02467 USA. RP Adam, RM (reprint author), Boston Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA.; Sullivan, MP; Adam, RM (reprint author), Harvard Med Sch, Dept Surg, Boston, MA 02115 USA.; Sullivan, MP (reprint author), VA Boston Healthcare Syst, Div Urol, West Roxbury, MA 02301 USA.; Sullivan, MP (reprint author), Brigham & Womens Hosp, Dept Surg, Boston, MA 02467 USA. EM msullivan@rics.bwh.harvard.edu; rosalyn.adam@childrens.harvard.edu FU Pfizer/Urology Care Foundation; Department of Veterans Affairs Medical Research Service [BX001790]; Children's Urological Foundation; PVA Research Foundation [2909]; National Institutes of Health [P50DK65298, R01DK077195-07] FX The authors would like to thank members of the Urological Diseases Research Center at Boston Children's Hospital for helpful discussions, and Kyle Costa for technical assistance. The authors acknowledge financial support from Pfizer/Urology Care Foundation (C.D); the Department of Veterans Affairs Medical Research Service (BX001790 to M.P.S), the Children's Urological Foundation, the PVA Research Foundation (Grant 2909 to R.M.A.) and the National Institutes of Health (P50DK65298 and R01DK077195-07 to R.M.A). NR 34 TC 0 Z9 0 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 MAR 15 PY 2017 VL 7 AR 44416 DI 10.1038/srep44416 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO4GV UT WOS:000396654300001 PM 28294142 ER PT J AU Emdin, CA Khera, AV Natarajan, P Klarin, D Baber, U Mehran, R Rader, DJ Fuster, V Kathiresan, S AF Emdin, Connor A. Khera, Amit V. Natarajan, Pradeep Klarin, Derek Baber, Usman Mehran, Roxana Rader, Daniel J. Fuster, Valentin Kathiresan, Sekar TI Evaluation of the Pooled Cohort Equations for Prediction of Cardiovascular Risk in a Contemporary Prospective Cohort SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DISEASE; CALIBRATION; PREVENTION; VALIDATION; GUIDELINES; CORONARY; STATINS AB Most guidelines suggest a baseline risk assessment to guide atherosclerotic cardiovascular disease (ASCVD) prevention strategies. The American Heart Association/American College of Cardiology Pooled Cohort Equations (PCEs) is one tool to assess baseline risk; however, the accuracy of this tool has been called into question. We aimed to examine the calibration and discrimination of the PCEs in the Biolmage study, a contemporary multiethnic cohort of asymptomatic adults enrolled from 2008 to 2009 in the Humana Health System in Chicago, Illinois, and Fort Lauderdale, Florida. Our primary end point was hard ASCVD, defined as cardiovascular death, myocardial infarction, and stroke. A total of 3,635 adults who were not on lipid-lowering therapy at baseline were followed for a maximum of 4.6 years. The mean age was 68.6 years; 2000 (55%) participants were women and 935 patients reported being of non-white race (26%). Although 74 ASCVD events were observed over a median follow-up of 2.7 years, 198 events were predicted by the PCEs. The observed event rate was 7.9 per 1,000 participant-years (95% confidence interval [CI] 6.1 to 9.8), whereas the predicted rate by the PCEs was 21 per 1,000 participant-years (95% CI 20.7 to 21.8). This represents an overestimation of 167% (Hosmer Lemeshow chi-square = 173; p <0.001). With regard to discrimination, the C-statistic of the PCEs was 0.65 (CI 0.58 to 0.71). In an analysis restricted to 3,080 participants without diabetes mellitus and with low density lipoprotein cholesterol between 70 and 189 mg/di, the PCEs similarly overestimated risk. by 181% (152 predicted events vs 54 observed events; p <0.001). The PCEs substantially overestimate ASCVD risk in this middle-aged adult insured population. Refinement of existing risk prediction functions may be warranted. (C) 2016 Elsevier Inc. All rights reserved. C1 [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Baber, Usman; Mehran, Roxana; Fuster, Valentin] Icahn Sch Med Mt Sinai, Mt Sinai Med Ctr, Cardiovasc Inst, Dept Med, New York, NY 10029 USA. [Rader, Daniel J.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM skathiresan1@mgh.harvard.edu OI Emdin, Connor/0000-0002-2385-8259 FU BG Medicine Inc. of the HRP Initiative; Abbott; AstraZeneca; Merck; Philips; Takeda FX This study was funded by BG Medicine Inc. on behalf of the HRP Initiative. The HRP Initiative is a precompetitive industry collaboration funded by Abbott, AstraZeneca, Merck, Philips, and Takeda. NR 14 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 15 PY 2017 VL 119 IS 6 BP 881 EP 885 DI 10.1016/j.amjcard.2016.11.042 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP0LR UT WOS:000397079300010 PM 28061997 ER PT J AU Miner, PD Canobbio, MM Pearson, DD Schlater, M Balon, Y Junge, KJ Bhatt, A Barber, D Nickolaus, MJ Kovacs, AH Moons, P Shaw, K Fernandes, SM AF Miner, Pamela D. Canobbio, Mary M. Pearson, Dorothy D. Schlater, Mary Balon, Yvonne Junge, Kathryn J. Bhatt, Ami Barber, Deena Nickolaus, Michelle J. Kovacs, Adrienne H. Moons, Philip Shaw, Kate Fernandes, Susan M. TI Contraceptive Practices of Women With Complex Congenital Heart Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PREGNANCY OUTCOMES; GREAT-ARTERIES; TRANSPOSITION; COLLABORATION; REPAIR; ATRIAL; SWITCH AB Understanding the contraceptive practices of women with complex congenital heart disease (CHD) and providing them individualized contraception counseling may prevent adverse events and unplanned high-risk pregnancies. Given this, we sought to examine the contraceptive practices in women with CHD, describe adverse events associated with contraceptive use, and describe the provision of contraception counseling. Women >18 years were recruited from 2011 to 2014 from 9 adult CHD (ACHD) centers throughout North America. Subjects completed a 48-item questionnaire regarding contraceptive use and perceptions of contraception counseling, and a medical record review was performed. Of 505 subjects, median age was 33 (interquartile range 26 to 44) and 81% had CHD of moderate or great complexity. The majority (86%, 435 of 505) of the cohort had used contraception. The types included barrier methods (87%), oral contraception (OC) 84%, intrauterine device (18%), Depo-Provera (15%), vaginal ring (7%), patch (6%), hormonal implant (2%), Plan B (19%), and sterilization (16%). Overall OC use was not significantly different by CHD complexity. Women with CHD of great complexity were more likely to report a thrombotic event while taking OC than those with less complex CHD (9% vs 1%, p = 0.003). Contraception counseling by the ACHD team was noted by 43% of subjects. Unplanned pregnancy was reported by 25% with no statistical difference by CHD complexity. In conclusion, contraceptive practices of women with complex CHD are highly variable, and the prevalence of blood clots while taking OC is not insignificant while provision of contraception counseling by ACHD providers appears lacking. (C) 2016 Elsevier Inc. All rights reserved. C1 [Miner, Pamela D.; Canobbio, Mary M.] Univ Calif Los Angeles, Med Ctr, Ahmanson UCLA Adult Congenital Heart Dis Ctr, Los Angeles, CA 90024 USA. [Pearson, Dorothy D.] Boston Childrens Hosp, Boston Adult Congenital Heart Program, Boston, MA USA. [Schlater, Mary] Univ Washington, Reg Heart Ctr, Adult Congenital Heart Dis Clin, Seattle, WA 98195 USA. [Balon, Yvonne] Peter Lougheed Hosp, Adult Congenital Heart Clin, Calgary, AB, Canada. [Junge, Kathryn J.] Washington Univ, Barnes Jewish Hosp, Sch Med, Ctr Adults Congenital Heart Dis, St Louis, MO USA. [Bhatt, Ami] Harvard Med Sch, Massachusetts Gen Hosp, Congenital Heart Dis Program, Boston, MA USA. [Barber, Deena] Akron Childrens Hosp, Adult Congenital Heart Serv, Akron, OH USA. [Nickolaus, Michelle J.] Penn State Hershey Program Adult Congenital Heart, Hershey, PA USA. [Kovacs, Adrienne H.] Toronto Gen Hosp, Toronto Congenital Cardiac Ctr Adults, Toronto, ON, Canada. [Moons, Philip] Univ Leuven, Dept Publ Hlth & Primary Care, KU Leuven, Leuven, Belgium. [Shaw, Kate] Stanford Univ, Dept Obstet & Gynecol, Div Family Planning Serv & Res, Palo Alto, CA 94304 USA. [Fernandes, Susan M.] Stanford Univ, Div Pediat Cardiol, Dept Pediat, Palo Alto, CA 94304 USA. [Fernandes, Susan M.] Stanford Univ, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94304 USA. RP Miner, PD (reprint author), Univ Calif Los Angeles, Med Ctr, Ahmanson UCLA Adult Congenital Heart Dis Ctr, Los Angeles, CA 90024 USA. EM pminer@mednet.ucla.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 15 PY 2017 VL 119 IS 6 BP 911 EP 915 DI 10.1016/j.amjcard.2016.11.047 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP0LR UT WOS:000397079300015 PM 28087052 ER PT J AU Singh, JA Dowsey, M Choong, PF AF Singh, Jasvinder A. Dowsey, Michelle Choong, Peter F. TI Patient Endorsement of the Outcome Measures in Rheumatology (OMERACT) Total Joint Replacement (TJR) clinical trial draft core domain set SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID TOTAL KNEE ARTHROPLASTY; TOTAL SHOULDER ARTHROPLASTY; TOTAL ELBOW ARTHROPLASTY; QUALITY-OF-LIFE; PAIN OUTCOMES; INPATIENT SAMPLE; FILTER 2.0; TOTAL HIP; ARTHRITIS; TRENDS AB Background: A patient- and surgeon-Delphi-derived Outcome Measures in Rheumatology (OMERACT) draft core domain set for total joint arthroplasty (TJR) trials was recently developed. Our objective was to obtain further patient stakeholder endorsement of draft core domain set for TJR clinical trials. Methods: We surveyed two patient groups: (1) OMERACT patient partners; and (2) patients who had undergone hip or knee TJR. Patients received an introductory email with explanations about the core domain set and instructions to rate the core domains, i.e., important aspects, of OMERACT TJR clinical trial draft core domain set. Rating was on a nominal scale, where 1-3 indicated a domain of limited importance, 4-6 an important, but not critical domain, and 7-9 a critical domain. We used Mann-Whitney test (a non-parametric test) to compare the distribution of ratings between the two groups. Results: Thirty one survey participants from the OMERACT patient partner group and 118 knee/hip TJR patients responded with response rates of 66 and 80%, respectively. Majority of the survey respondents were female, 87 vs. 53%, and were 55 years or older, 57 vs. 94%. Median (interquartile range [IQR]) scores for six core domains by OMERACT and knee/hip TJR patient groups were, respectively: pain, 8 [8, 9] and 9 [8, 9]; function, 9 [8, 9] and 9 [8, 9]; patient satisfaction, 8 [8, 9] and 8 [7, 9]; revision surgery, 7 [7, 8] and 7 [5, 9]; adverse events, 8 [7, 9] and 8 [6, 9]; and death, 9 [6, 9] and 9 [4, 9]. No statistically significant differences in rating were noted for any of the six core domains between the two groups (p >= 0.31). Among the additional domains, ratings for patient participation did not differ by group (p = 0.98), but ratings for cost were significantly different (p = 0.005). Patients provided qualitative feedback regarding core domains, and did not propose any modifications to the draft core domain set. Conclusions: Two separate patient stakeholder groups endorsed the OMERACT TJR draft core domain set for TJR trials. C1 [Singh, Jasvinder A.] Univ Alabama Birmingham, 510 20th St S,Fac Off Tower 805B, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Birmingham Vet Affairs Med Ctr, 700 19th St S, Birmingham, AL 35233 USA. [Dowsey, Michelle; Choong, Peter F.] Univ Melbourne, St Vincents Hosp, Dept Surg, Melbourne, Vic, Australia. RP Singh, JA (reprint author), Univ Alabama Birmingham, 510 20th St S,Fac Off Tower 805B, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Birmingham Vet Affairs Med Ctr, 700 19th St S, Birmingham, AL 35233 USA. EM Jasvinder.md@gmail.com FU National Health & Medical Research Council Career Development Fellowship [APP1122526] FX A/Prof Dowsey holds a National Health & Medical Research Council Career Development Fellowship (APP1122526). We thank the patients for participating in this study. 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 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD MAR 15 PY 2017 VL 18 AR 111 DI 10.1186/s12891-017-1464-x PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EQ0LE UT WOS:000397761900001 PM 28298194 ER PT J AU Kyle, JE Casey, CP Stratton, KG Zink, EM Kim, YM Zheng, XY Monroe, ME Weitz, KK Bloodsworth, KJ Orton, DJ Ibrahim, YM Moore, RJ Lee, CG Pedersen, C Orwoll, E Smith, RD Burnum-Johnson, KE Baker, ES AF Kyle, Jennifer E. Casey, Cameron P. Stratton, Kelly G. Zink, Erika M. Kim, Young-Mo Zheng, Xueyun Monroe, Matthew E. Weitz, Karl K. Bloodsworth, Kent J. Orton, Daniel J. Ibrahim, Yehia M. Moore, Ronald J. Lee, Christine G. Pedersen, Catherine Orwoll, Eric Smith, Richard D. Burnum-Johnson, Kristin E. Baker, Erin S. TI Comparing identified and statistically significant lipids and polar metabolites in 15-year old serum and dried blood spot samples for longitudinal studies SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID MASS-SPECTROMETRY; FATTY-ACIDS; PROTEOMICS DATA; FILTER-PAPER; TERM STABILITY; ION MOBILITY; DEGREES-C; FRAGMENTATION; LIPOPROTEINS; METABOLOMICS AB RATIONALE: The use of dried blood spots (DBS) has many advantages over traditional plasma and serum samples such as the smaller blood volume required, storage at room temperature, and ability to sample in remote locations. However, understanding the robustness of different analytes in DBS samples is essential, especially in older samples collected for longitudinal studies. METHODS: Here we analyzed the stability of polar metabolites and lipids in DBS samples collected in 2000-2001 and stored at room temperature. The identified and statistically significant molecules were then compared to matched serum samples stored at-80 degrees C to determine if the DBS samples could be effectively used in a longitudinal study following metabolic disease. RESULTS: A total of 400 polar metabolites and lipids were identified in the serum and DBS samples using gas chromatograph/mass spectrometry (GC/MS), liquid chromatography (LC)/MS, and LC/ion mobility spectrometry-MS (LC/IMS-MS). The identified polar metabolites overlapped well between the sample types, though only one statistically significant metabolite was conserved in a case-control study of older diabetic males with low amounts of high-density lipoproteins and high body mass indices, triacylglycerides and glucose levels when compared to non-diabetic patients with normal levels, indicating that degradation in the DBS samples affects polar metabolite quantitation. Differences in the lipid identifications indicated that some oxidation occurs in the DBS samples. However, 36 statistically significant lipids correlated in both sample types. CONCLUSIONS: The difference in the number of statistically significant polar metabolites and lipids indicated that the lipids did not degrade to as great of a degree as the polar metabolites in the DBS samples and lipid quantitation was still possible. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Kyle, Jennifer E.; Casey, Cameron P.; Zink, Erika M.; Kim, Young-Mo; Zheng, Xueyun; Monroe, Matthew E.; Weitz, Karl K.; Bloodsworth, Kent J.; Orton, Daniel J.; Ibrahim, Yehia M.; Moore, Ronald J.; Smith, Richard D.; Burnum-Johnson, Kristin E.; Baker, Erin S.] Pacific Northwest Natl Lab, Earth & Biol Sci Directorate, Richland, WA 99352 USA. [Stratton, Kelly G.] Pacific Northwest Natl Lab, Nat Secur Directorate, Richland, WA 99352 USA. [Lee, Christine G.; Pedersen, Catherine; Orwoll, Eric] Oregon Hlth & Sci Univ, Dept Med, Bone & Mineral Unit, Portland, OR 97201 USA. [Lee, Christine G.] Portland VA Med Ctr, Res Serv, Portland, OR USA. RP Burnum-Johnson, KE; Baker, ES (reprint author), 902 Battelle Blvd,POB 999,MSIN K8-98, Richland, WA 99352 USA. EM kristin.burnum-johnson@pnnl.gov; erin.baker@pnnl.gov RI Kim, Young-Mo/D-3282-2009; OI Kim, Young-Mo/0000-0002-8972-7593; Zheng, Xueyun/0000-0001-9782-4521 FU National Institute of Environmental Health Sciences of the NIH [R01 ES022190]; NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development [R21 HD084788]; National Institute of General Medical Sciences [P41 GM103493]; Laboratory Directed Research and Development Program at Pacific Northwest National Laboratory; U.S. Department of Energy Office of Biological and Environmental Research Genome Sciences Program; National Institute of Allergy and Infectious Diseases [U19 AI106772]; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; DOE [DE-AC05-76RL0 1830] FX The authors would like to thank Nathan Johnson for assistance in preparing the figures. Portions of this research were supported by grants from the National Institute of Environmental Health Sciences of the NIH (R01 ES022190), NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21 HD084788), National Institute of General Medical Sciences (P41 GM103493), and the Laboratory Directed Research and Development Program at Pacific Northwest National Laboratory. This research utilized capabilities developed by the Pan-omics program (funded by the U.S. Department of Energy Office of Biological and Environmental Research Genome Sciences Program) and by the National Institute of Allergy and Infectious Diseases under grant U19 AI106772. The Osteoporotic Fractures in Men (MrOS) Study in the US was supported by the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. This work was performed in the W. R. Wiley Environmental Molecular Sciences Laboratory (EMSL), a DOE national scientific user facility at the Pacific Northwest National Laboratory (PNNL). PNNL is operated by Battelle for the DOE under contract DE-AC05-76RL0 1830. NR 56 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-4198 EI 1097-0231 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD MAR 15 PY 2017 VL 31 IS 5 BP 447 EP 456 DI 10.1002/rcm.7808 PG 10 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA EL3IK UT WOS:000394512600006 PM 27958645 ER PT J AU Kort, NS Ford, JM Roach, BJ Gunduz-Bruce, H Krystal, JH Jaeger, J Reinhart, RMG Mathalon, DH AF Kort, Naomi S. Ford, Judith M. Roach, Brian J. Gunduz-Bruce, Handan Krystal, John H. Jaeger, Judith Reinhart, Robert M. G. Mathalon, Daniel H. TI Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Electroencephalography; Ketamine; N-methyl-D-aspartate glutamate receptor; Predictive coding; Schizophrenia; Speech motor control ID COROLLARY DISCHARGE DYSFUNCTION; AUDITORY SENSORY MEMORY; MISMATCH NEGATIVITY GENERATION; SUBUNIT GENE GRIN2B; HEALTHY-VOLUNTEERS; SPEECH PRODUCTION; SYNAPTIC PLASTICITY; NEUROPHYSIOLOGICAL EVIDENCE; COGNITIVE DEFICITS; PSYCHOTIC SYMPTOMS AB BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback(listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event- related potentials during the talk/ listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case- control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d= 1.14) and schizophrenia(Cohen's d=.85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia. C1 [Kort, Naomi S.; Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA USA. [Ford, Judith M.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Roach, Brian J.] Northern California Inst Res & Educ, San Francisco, CA USA. [Gunduz-Bruce, Handan; Krystal, John H.; Reinhart, Robert M. G.] Yale Univ, Sch Med, New Haven, CT USA. [Gunduz-Bruce, Handan; Krystal, John H.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. [Jaeger, Judith] Clin Dev AstraZeneca Pharmaceut, Wilmington, DE USA. [Jaeger, Judith] Albert Einstein Coll York, Yorktown Hts, NY USA. [Jaeger, Judith] LLC, CognitionMetr, Wilmington, DC USA. [Reinhart, Robert M. G.] Boston Univ, Boston, MA USA. [Mathalon, Daniel H.] Mental Hlth Serv 116D, SFVAMC, 4150 Clement St, San Francisco, CA 94121 USA. RP Mathalon, DH (reprint author), Mental Hlth Serv 116D, SFVAMC, 4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu FU AstraZeneca for an investigator-initiated study (DHM); National Institute of Mental Health [R01 MH-58262, T32 MH089920]; Yale Center for Clinical Investigation [UL1RR024139]; US National Institute on Alcohol Abuse and Alcoholism [P50AA012879] FX This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. NR 109 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 MAR 15 PY 2017 VL 81 IS 6 BP 514 EP 524 DI 10.1016/j.biopsych.2016.06.019 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RS UT WOS:000397300000010 PM 27647218 ER PT J AU Yadav, H Thompson, BT Gajic, O AF Yadav, Hemang Thompson, B. Taylor Gajic, Ognjen TI Is Acute Respiratory Distress Syndrome a Preventable Disease? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE acute lung injury; acute respiratory distress syndrome; prevention; respiratory failure ID ACUTE LUNG INJURY; MECHANICALLY VENTILATED PATIENTS; COMMUNITY-ACQUIRED PNEUMONIA; CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; RANDOMIZED CONTROLLED-TRIAL; CONTROLLED CLINICAL-TRIAL; PLACEBO-CONTROLLED-TRIAL; END-EXPIRATORY PRESSURE; DOUBLE-BLIND AB Despite significant advances in our understanding and management of patients with acute respiratory distress syndrome (ARDS), the morbidity and mortality from ARDS remains high. Given the limited number of effective treatments for established ARDS, the strategic focus of ARDS research has shifted toward identifying patients with or at high risk of ARDS early in the course of the underlying illness, when strategies to reduce the development and progression of ARDS and associated organ failures can be systematically evaluated. In this review, we summarize the rationale, current evidence, and future directions in ARDS prevention. C1 [Yadav, Hemang; Gajic, Ognjen] Mayo Clin, Div Pulm & Crit Care Med, 200 1st St Southwest, Rochester, MN 55905 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. RP Gajic, O (reprint author), Mayo Clin, Div Pulm & Crit Care Med, 200 1st St Southwest, Rochester, MN 55905 USA. EM gajic.ognjen@mayo.edu NR 139 TC 0 Z9 0 U1 4 U2 4 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 MAR 15 PY 2017 VL 195 IS 6 BP 725 EP 736 DI 10.1164/rccm.201609-1767CI PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EO4BX UT WOS:000396640500008 PM 28040987 ER PT J AU Alam, SM Aussedat, B Vohra, Y Meyerhoff, RR Cale, EM Walkowicz, WE Radakovich, NA Anasti, K Armand, L Parks, R Sutherland, L Scearce, R Joyce, MG Pancera, M Druz, A Georgiev, IS Von Holle, T Eaton, A Fox, C Reed, SG Louder, M Bailer, RT Morris, L Abdool-Karim, SS Cohen, M Liao, HX Montefiori, DC Park, PK Fernandez-Tejada, A Wiehe, K Santra, S Kepler, TB Saunders, KO Sodroski, J Kwong, PD Mascola, JR Bonsignori, M Moody, MA Danishefsky, S Haynes, BF AF Alam, S. Munir Aussedat, Baptiste Vohra, Yusuf Meyerhoff, R. Ryan Cale, Evan M. Walkowicz, William E. Radakovich, Nathan A. Anasti, Kara Armand, Lawrence Parks, Robert Sutherland, Laura Scearce, Richard Joyce, M. Gordon Pancera, Marie Druz, Aliaksandr Georgiev, Ivelin S. Von Holle, Tarra Eaton, Amanda Fox, Christopher Reed, Steven G. Louder, Mark Bailer, Robert T. Morris, Lynn Abdool-Karim, Salim S. Cohen, Myron Liao, Hua-Xin Montefiori, David C. Park, Peter K. Fernandez-Tejada, Alberto Wiehe, Kevin Santra, Sampa Kepler, Thomas B. Saunders, Kevin O. Sodroski, Joseph Kwong, Peter D. Mascola, John R. Bonsignori, Mattia Moody, M. Anthony Danishefsky, Samuel Haynes, Barton F. TI Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHEMICAL-SYNTHESIS; CRYSTAL-STRUCTURE; IMMUNE PRESSURE; ENVELOPE TRIMER; RECOGNITION; ANTIGENS; POTENT; ENV; SELECTION; VACCINES AB A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs. C1 [Alam, S. Munir; Meyerhoff, R. Ryan; Anasti, Kara; Armand, Lawrence; Parks, Robert; Sutherland, Laura; Scearce, Richard; Von Holle, Tarra; Eaton, Amanda; Liao, Hua-Xin; Montefiori, David C.; Wiehe, Kevin; Saunders, Kevin O.; Bonsignori, Mattia; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Alam, S. Munir; Liao, Hua-Xin; Montefiori, David C.; Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Alam, S. Munir] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA. [Aussedat, Baptiste; Vohra, Yusuf; Walkowicz, William E.; Park, Peter K.; Fernandez-Tejada, Alberto; Danishefsky, Samuel] Mem Sloan Kettering Canc Ctr, Dept Chem Biol, New York, NY 10065 USA. [Meyerhoff, R. Ryan; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. [Cale, Evan M.; Radakovich, Nathan A.; Joyce, M. Gordon; Pancera, Marie; Druz, Aliaksandr; Georgiev, Ivelin S.; Louder, Mark; Bailer, Robert T.; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Fox, Christopher; Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. [Morris, Lynn; Abdool-Karim, Salim S.] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Morris, Lynn; Abdool-Karim, Salim S.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, ZA-4013 Durban, South Africa. [Cohen, Myron] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA. [Montefiori, David C.; Saunders, Kevin O.] Duke Univ, Sch Med, Dept Surg, Durham, NC 27710 USA. [Santra, Sampa] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kepler, Thomas B.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Sodroski, Joseph] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Moody, M. Anthony] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA. [Liao, Hua-Xin] Jinan Univ, Coll Life Sci & Technol, Guangzhou 510632, Guangdong, Peoples R China. RP Alam, SM; Haynes, BF (reprint author), Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA.; Alam, SM; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA.; Alam, SM (reprint author), Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. EM munir.alam@dm.duke.edu; barton.haynes@dm.duke.edu OI Aussedat, Baptiste/0000-0002-8828-8963; Vohra, Yusuf/0000-0003-0385-2965; Meyerhoff, Ryan/0000-0003-1253-2250 FU NIH, National Institute of Allergy and Infectious Diseases (NIAID) [UM-1 AI100645]; Division of AIDS CHAVI-Immunogen Discovery grant [R01 AI120801-01]; Medical Scientist Training Program training grant [T32GM007171]; Ruth L. Kirschstein National Research Service Award [F30-AI122982-0]; NIAID; Vaccine Research Center, NIAID FX This study was supported by UM-1 AI100645 from NIH, National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS CHAVI-Immunogen Discovery grant, R01 AI120801-01 (K.O.S.), Medical Scientist Training Program training grant T32GM007171 (R.R.M.), Ruth L. Kirschstein National Research Service Award F30-AI122982-0, NIAID (R.R.M.), and the intramural research program of the Vaccine Research Center, NIAID. NR 41 TC 1 Z9 1 U1 5 U2 5 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 MAR 15 PY 2017 VL 9 IS 381 AR eaai7521 DI 10.1126/scitranslmed.aai7521 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EN9GB UT WOS:000396307600005 ER PT J AU Menzaghi, C Marucci, A Antonucci, A De Bonis, C Moreno, LO Salvemini, L Copetti, M Trischitta, V Di Paola, R AF Menzaghi, Claudia Marucci, Antonella Antonucci, Alessandra De Bonis, Concetta Moreno, Lorena Ortega Salvemini, Lucia Copetti, Massimiliano Trischitta, Vincenzo Di Paola, Rosa TI Suggestive evidence of a multicytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals SO SCIENTIFIC REPORTS LA English DT Article ID CIRCULATING CYTOKINE LEVELS; CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; SERUM RESISTIN; ISCHEMIC-STROKE; ADIPOSE-TISSUE; INFLAMMATORY MARKERS; DIABETES-MELLITUS; PERIPHERAL-BLOOD; GENE-EXPRESSION AB In cells and tissues resistin affects IL-1 beta, IL-6, IL-8, IL-12 and TNF-alpha expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA(IR), triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)- prospective design (follow-up 5.4 +/- 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p <0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p <0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p <0.001) and both associated with cardiovascular risk factors (all p <0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI= 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE. C1 [Menzaghi, Claudia; Marucci, Antonella; Antonucci, Alessandra; De Bonis, Concetta; Moreno, Lorena Ortega; Salvemini, Lucia; Trischitta, Vincenzo; Di Paola, Rosa] IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. [Copetti, Massimiliano] IRCCS Casa Sollievo Sofferenza, Unit Biostatist, San Giovanni Rotondo, Italy. [Trischitta, Vincenzo] Sapienza Univ Rome, Dept Expt Med, Rome, Italy. [Moreno, Lorena Ortega] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA USA. RP Trischitta, V; Di Paola, R (reprint author), IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy.; Trischitta, V (reprint author), Sapienza Univ Rome, Dept Expt Med, Rome, Italy. EM vincenzo.trischitta@uniroma1.it; r.dipaola@operapadrepio.it FU Regione Puglia- PST; FESR; EFSD/Pfizer Grant; Societa Italiana di Diabetologia-Fondazione Diabete Ricerca [PONa3_00134 ONEV, PON02_00186_2937475]; Italian Ministry of Health Grant [RF- 2013-02356459] FX We are indebted to the staffs and participants of the GS2 and GHS for their dedication and contributions. This work was supported by: Regione Puglia- PST 2006, FESR 2007-2013, EFSD/Pfizer Grants and Societa Italiana di Diabetologia-Fondazione Diabete Ricerca (CM); PONa3_00134 ONEV, PON02_00186_2937475 Pro. Ali. Fun (VT): Italian Ministry of Health Grants RF- 2013-02356459 (CM), RC2014, RC2015, RC2016 (CM, VT, RDP). NR 48 TC 0 Z9 0 U1 0 U2 0 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 MAR 14 PY 2017 VL 7 AR 44337 DI 10.1038/srep44337 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6KT UT WOS:000396113600001 PM 28290549 ER PT J AU Copeland, LA Graham, LA Richman, JS Rosen, AK Mull, HJ Burns, EA Whittle, J Itani, KMF Hawn, MT AF Copeland, Laurel A. Graham, Laura A. Richman, Joshua S. Rosen, Amy K. Mull, Hillary J. Burns, Edith A. Whittle, Jeff Itani, Kamal M. F. Hawn, Mary T. TI A study to reduce readmissions after surgery in the Veterans Health Administration: design and methodology SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Comorbidity; Methods; Quality of care; Surgical procedures; Operative; Veterans ID SURGICAL CARE; HOSPITAL READMISSIONS; SERVICES RESEARCH; MORTALITY-RATE; QUALITY; AFFAIRS; RISK; IMPROVEMENT; DETERMINANTS; ASSOCIATION AB Background: Hospital readmissions are associated with higher resource utilization and worse patient outcomes. Causes of unplanned readmission to the hospital are multiple with some being better targets for intervention than others. To understand risk factors for surgical readmission and their incremental contribution to current Veterans Health Administration (VA) surgical quality assessment, the study, Improving Surgical Quality: Readmission (ISQ-R), is being conducted to develop a readmission risk prediction tool, explore predisposing and enabling factors, and identify and rank reasons for readmission in terms of salience and mutability. Methods: Harnessing the rich VA enterprise data, predictive readmission models are being developed in data from patients who underwent surgical procedures within the VA 2007-2012. Prospective assessment of psychosocial determinants of readmission including patient self-efficacy, cognitive, affective and caregiver status are being obtained from a cohort having colorectal, thoracic or vascular procedures at four VA hospitals in 2015-2017. Using these two data sources, ISQ-R will develop readmission categories and validate the readmission risk prediction model. A modified Delphi process will convene surgeons, non-surgeon clinicians and quality improvement nurses to rank proposed readmission categories vis-a-vis potential preventability. Discussion: ISQ-R will identify promising avenues for interventions to facilitate improvements in surgical quality, informing specifications for surgical workflow managers seeking to improve care and reduce cost. ISQ-R will work with Veterans Affairs Surgical Quality Improvement Program (VASQIP) to recommend potential new elements VASQIP might collect to monitor surgical complications and readmissions which might be preventable and ultimately improve surgical care.\ C1 [Copeland, Laurel A.] Vet Affairs VA Cent Western Massachusetts Healthc, Leeds, MA 01053 USA. [Copeland, Laurel A.] Texas A&M Hlth Sci Ctr, Coll Med, Temple, TX 76504 USA. [Copeland, Laurel A.] UT Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Graham, Laura A.; Richman, Joshua S.] Birmingham VAMC, Vet Affairs, Birmingham, AL USA. [Rosen, Amy K.; Mull, Hillary J.] VA Boston Healthcare Syst, CHOIR, Vet Affairs, Boston, MA USA. [Rosen, Amy K.; Mull, Hillary J.; Itani, Kamal M. F.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Itani, Kamal M. F.] VA Boston Healthcare Syst, Boston, MA USA. [Burns, Edith A.; Whittle, Jeff] Harvard Sch Med, Cambridge, MA USA. [Burns, Edith A.; Whittle, Jeff] Milwaukee VAMC, Vet Affairs, Milwaukee, WI USA. [Hawn, Mary T.] Palo Alto VAMC, Vet Affairs, Palo Alto, CA USA. [Hawn, Mary T.] Stanford Univ, Sch Med, Dept Surg, Palo Alto, CA 94304 USA. RP Copeland, LA (reprint author), Vet Affairs VA Cent Western Massachusetts Healthc, Leeds, MA 01053 USA.; Copeland, LA (reprint author), Texas A&M Hlth Sci Ctr, Coll Med, Temple, TX 76504 USA. EM LaurelACopeland@gmail.com FU Veterans Health Administration, Health Services Research Development [HX-12-358] FX This research was supported by a research award from the Veterans Health Administration, Health Services Research & Development, award #HX-12-358 (Hawn-PI). NR 44 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 MAR 14 PY 2017 VL 17 AR 198 DI 10.1186/s12913-017-2134-2 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EN5ZY UT WOS:000396085500005 PM 28288681 ER PT J AU Ma, Y Tseng, PH Ahn, A Wu, MS Ho, YL Chen, MF Peng, CK AF Ma, Yan Tseng, Ping-Huei Ahn, Andrew Wu, Ming-Shiang Ho, Yi-Lwun Chen, Ming-Fong Peng, Chung-Kang TI Cardiac Autonomic Alteration and Metabolic Syndrome: An Ambulatory ECG-based Study in A General Population SO SCIENTIFIC REPORTS LA English DT Article ID HEART-RATE-VARIABILITY; TRADITIONAL CHINESE MEDICINE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; SAN-ANTONIO HEART; INSULIN-RESISTANCE; DIABETES-MELLITUS; YOUNG-PATIENTS; PREVALENCE; COMPLEXITY AB Metabolic syndrome (MetS) has been associated with chronic damage to the cardiovascular system. This study aimed to evaluate early stage cardiac autonomic dysfunction with electrocardiography (ECG)-based measures in MetS subjects. During 2012-2013, 175 subjects with MetS and 226 healthy controls underwent ECG recordings of at least 4 hours starting in the morning with ambulatory one-lead ECG monitors. MetS was diagnosed using the criteria defined in the Adult Treatment Panel III, with a modification of waist circumference for Asians. Conventional heart rate variability (HRV) analysis, and complexity index (CI1-20) calculated from 20 scales of entropy (multiscale entropy, MSE), were compared between subjects with MetS and controls. Compared with the healthy controls, subjects with MetS had significantly reduced HRV, including SDNN and pNN20 in time domain, VLF, LF and HF in frequency domain, as well as SD2 in Poincare analysis. MetS subjects have significantly lower complexity index (CI1-20) than healthy subjects (1.69 +/- 0.18 vs. 1.77 +/- 0.12, p < 0.001). MetS severity was inversely associated with the CI1-20 (r = -0.27, p < 0.001). MetS is associated with significant alterations in heart rate dynamics, including HRV and complexity. C1 [Ma, Yan; Peng, Chung-Kang] Harvard Med Sch, Div Interdisciplinary Med & Biotechnol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Tseng, Ping-Huei; Wu, Ming-Shiang; Ho, Yi-Lwun; Chen, Ming-Fong] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Ahn, Andrew] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Wu, MS (reprint author), Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. EM mingshiang@ntu.edu.tw FU National Taiwan University Hospital [NTUH.104-M2854, NTUH.105-003024]; DynaDx Corporation; Delta Environmental & Educational Foundation FX This study was supported by research grants funded by National Taiwan University Hospital (NTUH.104-M2854, NTUH.105-003024) and DynaDx Corporation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Y.M. acknowledges the Fellowship support from Delta Environmental & Educational Foundation. None of the authors has received compensation for the work on this manuscript. The authors thank the staff of the Health Management Center and the Sleep Center at the National Taiwan University Hospital for their assistance. NR 55 TC 0 Z9 0 U1 0 U2 0 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 MAR 14 PY 2017 VL 7 AR 44363 DI 10.1038/srep44363 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6KU UT WOS:000396113700001 PM 28290487 ER PT J AU Tavera-Mendoza, LE Westerling, T Libby, E Marusyk, A Cato, L Cassani, R Cameron, LA Ficarro, SB Marto, JA Klawitter, J Brown, M AF Tavera-Mendoza, Luz E. Westerling, Thomas Libby, Eric Marusyk, Andriy Cato, Laura Cassani, Raymundo Cameron, Lisa A. Ficarro, Scott B. Marto, Jarrod A. Klawitter, Jelena Brown, Myles TI Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vitamin D; vitamin D signaling; autophagy; breast cancer; oncology ID LC3; HYDROXYCHLOROQUINE; INHIBITION; PREVENTION; CALCIUM; DISEASE; MICE AB Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells. C1 [Tavera-Mendoza, Luz E.; Westerling, Thomas; Cato, Laura; Brown, Myles] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, Boston, MA 02215 USA. [Tavera-Mendoza, Luz E.; Westerling, Thomas; Cato, Laura; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Libby, Eric] Santa Fe Inst, Santa Fe, NM 87501 USA. [Marusyk, Andriy] Univ S Florida, Moffitt Canc Ctr, Dept Canc Imaging & Metab, Tampa, FL 33612 USA. [Cassani, Raymundo] Univ Quebec, Inst Natl Rech Sci, Ctr Energie Mat Telecommun, Montreal, PQ H5A 1K6, Canada. [Cameron, Lisa A.] Dana Farber Canc Inst, Confocal & Light Microscopy Core, Boston, MA 02215 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Klawitter, Jelena] Univ Colorado, Dept Anesthesiol, Anschutz Med Campus, Aurora, CO 80045 USA. RP Brown, M (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, Boston, MA 02215 USA.; Brown, M (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. EM myles_brown@dfci.harvard.edu FU National Cancer Institute Grant [P01 CA080111] FX We thank Ana Tavera Mendoza for illustration (Fig. 7) design and drawing; Christine Unitt for help with LC3 immunohistochemistry; Louise M. Trakimas for TEM assistance; Melinda Baker (Thomson Reuters) for invaluable advice in creating the autophagy pathway; the Dana-Farber Animal Facility staff (Michael Terrasi, Antonia Garcia, Daisy Moreno, Carmen Da Silva, Elsy Moreno, and Catherine A. Sypher) for assistance with animal experiments and overall excellence in animal care; and Sonal Jhaveri-Schneider for editing help. This work was supported by National Cancer Institute Grant P01 CA080111 (to M.B.). NR 54 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 MAR 14 PY 2017 VL 114 IS 11 BP E2186 EP E2194 DI 10.1073/pnas.1615015114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6DH UT WOS:000396094200013 PM 28242709 ER PT J AU Bergmark, BA Scirica, BM AF Bergmark, Brian A. Scirica, Benjamin M. TI First, do no (irreparable) harm: infarction, bleeding, and subsequent risk of death. The dangers of false equivalency SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID ACUTE CORONARY SYNDROMES; DUAL ANTIPLATELET THERAPY; MYOCARDIAL-INFARCTION; INTERVENTION; CLOPIDOGREL; VORAPAXAR; DISEASE; IMPACT C1 [Bergmark, Brian A.; Scirica, Benjamin M.] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp,Dept Med, Boston, MA USA. RP Scirica, BM (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. EM bscirica@partners.org FU TIMI Study; Brigham and Women's Hospital from AstraZeneca; Eisai; Poxel; AstraZeneca; Biogen Idec; Boehringer Ingelheim; Covance; Dr Reddy's Laboratory; Elsevier Practice Update Cardiology; GlaxoSmithKline; Lexicon; Merck; NovoNordisk; Sanofi; St. Jude's Medical FX B.M.S. reports research grants via the TIMI Study and Brigham and Women's Hospital from AstraZeneca, Eisai, and Poxel; consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr Reddy's Laboratory, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, NovoNordisk, Sanofi, and St. Jude's Medical; and equity in Health [at] Scale. B.A.B. has nothing to declare. NR 15 TC 1 Z9 1 U1 0 U2 0 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 MAR 14 PY 2017 VL 38 IS 11 BP 811 EP 813 DI 10.1093/eurheartj/ehw639 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO6BS UT WOS:000396777300008 PM 28363223 ER PT J AU Atluru, A AF Atluru, Anupama TI Fashion Overdose How Moschino's Capsule Collection Offended Medicine SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Atluru, Anupama] Harvard Med Sch, Emergency Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Atluru, A (reprint author), Harvard Med Sch, Emergency Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM aatluru@mgh.harvard.edu NR 0 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 MAR 14 PY 2017 VL 317 IS 10 BP 1002 EP 1004 DI 10.1001/jama.2017.1473 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EO5DO UT WOS:000396713400001 PM 28291871 ER PT J AU Reusch, JEB Manson, JE AF Reusch, Jane E. B. Manson, JoAnn E. TI Management of Type 2 Diabetes in 2017 Getting to Goal SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ASSOCIATION; STATEMENT C1 [Reusch, Jane E. B.] Univ Colorado, Anschutz Med Ctr, Ctr Womens Hlth Res, Denver, CO 80202 USA. [Reusch, Jane E. B.] Denver VA Med Ctr, Denver, CO USA. [Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Manson, JoAnn E.] Harvard Med Sch, Boston, MA USA. [Manson, JoAnn E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Manson, JE (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 900 Commonwealth Ave,Third Floor, Boston, MA 02215 USA. EM jmanson@rics.bwh.harvard.edu FU AstraZeneca; Merck FX The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Reusch reported receiving grant funding from AstraZeneca and Merck; and serving on the board of directors for the American Diabetes Association. No other disclosures were reported. NR 7 TC 0 Z9 0 U1 3 U2 3 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 MAR 14 PY 2017 VL 317 IS 10 BP 1015 EP 1016 DI 10.1001/jama.2017.0241 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EO5DO UT WOS:000396713400009 PM 28249081 ER PT J AU Xian, Y O'Brien, EC Liang, L Xu, HL Schwamm, LH Fonarow, GC Bhatt, DL Smith, EE Olson, DM Maisch, L Hannah, D Lindholm, B Lytle, BL Pencina, MJ Hernandez, AF Peterson, ED AF Xian, Ying O'Brien, Emily C. Liang, Li Xu, Haolin Schwamm, Lee H. Fonarow, Gregg C. Bhatt, Deepak L. Smith, Eric E. Olson, DaiWai M. Maisch, Lesley Hannah, Deidre Lindholm, Brianna Lytle, Barbara L. Pencina, Michael J. Hernandez, Adrian F. Peterson, Eric D. TI Association of Preceding Antithrombotic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID EFFECTIVENESS RESEARCH PROSPER; AMERICAN-HEART-ASSOCIATION; HEALTH-CARE PROFESSIONALS; GUIDELINES-STROKE; CENTERED RESEARCH; PATIENTS PREFER; PREDICTING STROKE; ELDERLY-PATIENTS; HIGH-RISK; WARFARIN AB IMPORTANCE Antithrombotic therapies are known to prevent stroke for patients with atrial fibrillation (AF) but are often underused in community practice. OBJECTIVES To examine the prevalence of patients with acute ischemic stroke with known history of AF who were not receiving guideline-recommended antithrombotic treatment before stroke and to determine the association of preceding antithrombotic therapy with stroke severity and in-hospital outcomes. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of 94 474 patients with acute ischemic stroke and known history of AF admitted from October 2012 through March 2015 to 1622 hospitals participating in the Get With the Guidelines-Stroke program. EXPOSURES Antithrombotic therapy before stroke. MAIN OUTCOMES AND MEASURES Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS; range of 0-42, with a higher score indicating greater stroke severity and a score >= 16 indicating moderate or severe stroke), and in-hospital mortality. RESULTS Of 94 474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7176 (7.6%) were receiving therapeuticwarfarin (international normalized ratio [INR] >= 2) and 8290(8.8%) were receiving non-vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79 008patients (83.6%) were not receiving therapeutic anticoagulation; 12 751 (13.5%) had subtherapeuticwarfarin anticoagulation (INR <2) at the time of stroke, 37 674 (39.9%) were receiving antiplatelet therapy only, and 28 583 (30.3%) were not receiving any antithrombotic treatment. Among 91 155 high-risk patients (prestroke CHA(2)DS(2)-VASc score >= 2), 76071 (83.5%) were not receiving therapeuticwarfarin orNOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeuticwarfarin (15.8% [95% CI, 14.8%-16.7%]) andNOACs (17.5%[95% CI, 16.6%-18.4%]) than among those receiving no antithrombotic therapy (27.1%[95% CI, 26.6%-27.7%]), antiplatelet therapy only (24.8%[95% CI, 24.3%-25.3%]), or subtherapeuticwarfarin (25.8% [95% CI, 25.0%-26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeuticwarfarin (6.4%[95% CI, 5.8%-7.0%]) andNOACs (6.3%[95% CI, 5.7%-6.8%]) compared with those receiving no antithrombotic therapy (9.3%[95% CI, 8.9%-9.6%]), antiplatelet therapy only (8.1%[95% CI, 7.8%-8.3%]), or subtherapeuticwarfarin (8.8% [95% CI, 8.3%-9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeuticwarfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51-0.60], 0.65 [0.61-0.71], and 0.88 [0.84-0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67-0.85], 0.79 [0.72-0.88], and 0.83 [0.78-0.88], respectively). CONCLUSIONS AND RELEVANCE Among patients with atrial fibrillation who had experienced an acute ischemic stroke, inadequate therapeutic anticoagulation preceding the stroke was prevalent. Therapeutic anticoagulation was associated with lower odds of moderate or severe stroke and lower odds of in-hospital mortality. C1 [Xian, Ying] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Xian, Ying; O'Brien, Emily C.; Liang, Li; Xu, Haolin; Lytle, Barbara L.; Pencina, Michael J.; Hernandez, Adrian F.; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Cambridge, MA USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, 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. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Olson, DaiWai M.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Xian, Y (reprint author), Duke Clin Res Inst, Dept Neurol, 2400 Pratt St, Durham, NC 27705 USA. EM ying.xian@duke.edu FU Patient-Centered Outcomes Research Institute [CE-1304-7073] FX This work was supported by award CE-1304-7073 from the Patient-Centered Outcomes Research Institute. NR 34 TC 0 Z9 0 U1 3 U2 3 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 MAR 14 PY 2017 VL 317 IS 10 BP 1057 EP 1067 DI 10.1001/jama.2017.1371 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EO5DO UT WOS:000396713400018 PM 28291892 ER PT J AU Khera, AV Kathiresan, S AF Khera, Amit V. Kathiresan, Sekar TI Is Coronary Atherosclerosis One Disease or Many? Setting Realistic Expectations for Precision Medicine SO CIRCULATION LA English DT Article DE atherosclerosis; coronary artery disease; genetics; human C1 [Khera, Amit V.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Genom Med, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. [Khera, Amit V.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Khera, Amit V.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Genom Med, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan1@mgh.harvard.edu FU Harvard Catalyst - National Institutes of Health (NIH) [TR001100]; Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital; National Institutes of Health [HL127564, UM1HG008895] FX Dr Khera's work on this article was supported by a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst funded by the National Institutes of Health (NIH; TR001100). Dr Kathiresan is supported by an Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital and grants from the National Institutes of Health (HL127564 and UM1HG008895). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of Harvard University, the Harvard Catalyst, or the National Institutes of Health. 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 MAR 14 PY 2017 VL 135 IS 11 BP 1005 EP 1007 DI 10.1161/CIRCULATIONAHA.116.026479 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EN7XL UT WOS:000396215400006 PM 28289003 ER PT J AU Xian, Y Federspiel, JJ Hernandez, AF Laskowitz, DT Schwamm, LH Bhatt, DL Smith, EE Fonarow, GC Peterson, ED AF Xian, Ying Federspiel, Jerome J. Hernandez, Adrian F. Laskowitz, Daniel T. Schwamm, Lee H. Bhatt, Deepak L. Smith, Eric E. Fonarow, Gregg C. Peterson, Eric D. TI Use of Intravenous Recombinant Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke Who Take Non-Vitamin K Antagonist Oral Anticoagulants Before Stroke SO CIRCULATION LA English DT Article DE anticoagulant agents; intracranial hemorrhages; stroke, acute; thrombolysis; therapeutic ID HEALTH-CARE PROFESSIONALS; ATRIAL-FIBRILLATION; GUIDELINES-STROKE; INTRACRANIAL HEMORRHAGE; RECEIVING RIVAROXABAN; EARLY MANAGEMENT; RISK SCORE; THROMBOLYSIS; DABIGATRAN; WARFARIN AB BACKGROUND: Intravenous rt-PA (recombinant tissue-type plasminogen activator) is effective in improving outcomes in ischemic stroke; however, there are few data on the use of rt-PA in patients who are receiving a non-vitamin K antagonist oral anticoagulant (NOAC). METHODS: Using data from the American Heart Association Get With The Guidelines-Stroke Registry, we examined the outcomes of use of thrombolytic therapy in patients with ischemic stroke who received anticoagulation with NOACs versus those on warfarin (international normalized ratio < 1.7) or not on anticoagulation from 1289 registry hospitals between October 2012 and March 2015. RESULTS: Of 42 887 patients with ischemic stroke treated with intravenous rt-PA within 4.5 hours, 251 were taking NOACs (dabigatran 87, rivaroxaban 129, and apixaban 35) before their stroke, 1500 were taking warfarin, and 41 136 were on neither. Patients on NOACs or warfarin were older, had more comorbid conditions, and experienced more severe strokes than did those who were not on anticoagulation (median National Institutes of Health Stroke Scale 12, 13, and 9, respectively). Unadjusted rates of symptomatic intracranial hemorrhage in the NOAC, warfarin, and none groups were 4.8%, 4.9%, and 3.9%, respectively (P= 0.11). In comparison with those not on anticoagulation, the adjusted odds ratio for symptomatic intracranial hemorrhage for those on NOACs was 0.92 (95% confidence interval, 0.51-1.65) and for those on warfarin the adjusted odds ratio was 0.85 (95% confidence interval, 0.66-1.10). There were also no significant differences in the risk for life-threatening/serious systemic hemorrhage, any rt-PA complication, in-hospital mortality, and modified Rankin Scale at discharge across 3 groups. Similar results were also found after propensity score matching. CONCLUSIONS: Although experience of using rt-PA in patients with ischemic stroke on a NOAC is limited, these preliminary observations suggest that rt-PA appears to be reasonably well tolerated without prohibitive risks for adverse events among selected NOAC-treated patients. Future studies should evaluate the safety and efficacy of intravenous rt-PA in patients with ischemic stroke who are taking NOACs. C1 [Xian, Ying; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Xian, Ying; Laskowitz, Daniel T.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Federspiel, Jerome J.] Johns Hopkins Sch Med, Dept Gynecol & Obstet, Baltimore, MD USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 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. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. RP Xian, Y (reprint author), Duke Univ, Med Ctr, Dept Neurol, Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27710 USA. EM ying.xian@duke.edu FU American Heart Association [13CRP14410024, 14SDG20460081]; Boeringher-Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical Partnership; AHA Pharmaceutical Roundtable FX This study was supported in part by awards from the American Heart Association (13CRP14410024 and 14SDG20460081). The Get With The Guidelines-Stroke (GWTG-Stroke) program is provided by the American Heart Association/American Stroke Association. The GWTG-Stroke Program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable. NR 47 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 14 PY 2017 VL 135 IS 11 BP 1024 EP 1035 DI 10.1161/CIRCULATIONAHA.116.023940 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EN7XL UT WOS:000396215400010 PM 28119380 ER PT J AU Jia, HB Dai, JN Hou, JB Xing, L Ma, LJ Liu, HM Xu, ME Yao, Y Hu, SN Yamamoto, E Lee, H Zhang, SS Yu, B Jang, IK AF Jia, Haibo Dai, Jiannan Hou, Jingbo Xing, Lei Ma, Lijia Liu, Huimin Xu, Maoen Yao, Yuan Hu, Sining Yamamoto, Erika Lee, Hang Zhang, Shaosong Yu, Bo Jang, Ik-Kyung TI Effective anti-thrombotic therapy without stenting: intravascular optical coherence tomography-based management in plaque erosion (the EROSION study) SO EUROPEAN HEART JOURNAL LA English DT Article DE Plaque erosion; Plaque rupture; Anti thrombotic therapy; Optical coherence tomography; Acute coronary syndrome ID ACUTE CORONARY SYNDROME; ELEVATION MYOCARDIAL-INFARCTION; INTACT FIBROUS CAP; PRIMARY PCI; MANUAL THROMBECTOMY; CALCIFIED NODULE; THROMBUS BURDEN; RUPTURE; THROMBOLYSIS; DEATH AB Aims Plaque erosion, compared with plaque rupture, has distinctly different underlying pathology and therefore may merit tailored therapy. In this study, we aimed to assess whether patients with acute coronary syndrome (ACS) caused by plaque erosion might be stabilized by anti-thrombotic therapy without stent implantation Methods and results This was a single-centre, uncontrolled, prospective, proof-of concept study. Patients with ACS including ST-segment elevation myocardial infarction were prospectively enrolled. If needed, aspiration thrombectomy was performed. Patients diagnosed with plaque erosion by optical coherence tomography (OCT) and residual diameter stenosis <70% on coronary angiogram were treated with anti-thrombotic therapy without stenting. OCT was repeated at 1 month and thrombus volume was measured. The primary endpoint was >50% reduction of thrombus volume at 1 month compared with baseline. The secondary endpoint was a composite of cardiac death, recurrent ischaemia requiring revascularization, stroke, and major bleeding. Among 405 ACS patients with analysable OCT images, plaque erosion was identified in 103 (25.4%) patients. Sixty patients enrolled and 55 patients completed the 1-month followup. Forty-seven patients (47/60, 78.3%; 95% confidence interval: 65.8-87.9%) met the primary endpoint, and 22 patients had no visible thrombus at 1 month. Thrombus volume decreased from 3.7 (1.3, 10.9) mm(3) to 0.2 (0.0, 2.0) mm(3). Minimal flow area increased from 1.7 (1.4, 2.4) mm(2) to 2.1 (1.5, 3.8) mm(2). One patient died of gastrointestinal bleeding, and another patient required repeat percutaneous coronary intervention. The rest of the patients remained asymptomatic Conclusion For patients with ACS caused by plaque erosion, conservative treatment with anti-thrombotic therapy without stenting may be an option. C1 [Jia, Haibo; Hou, Jingbo; Ma, Lijia; Liu, Huimin; Xu, Maoen; Yao, Yuan; Hu, Sining; Zhang, Shaosong; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Key Lab Myocardial Ischemia,Chinese Minist Educ, 246 Xuefu Rd, Harbin 150086, Heilongjiang, Peoples R China. [Dai, Jiannan; Xing, Lei; Yamamoto, Erika; Jang, Ik-Kyung] Massachusetts Gen Hosp, Harvard Med Sch, Div Cardiol, 55 Fruit St,GRB 800, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Biostat, 50 Staniford St,Suite 560, Boston, MA 02114 USA. RP Yu, B (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Key Lab Myocardial Ischemia,Chinese Minist Educ, 246 Xuefu Rd, Harbin 150086, Heilongjiang, Peoples R China.; Jang, IK (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Div Cardiol, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM yubodr@163.com; ijang@mgh.harvard.edu FU AstraZeneca [ISSBRIL0186]; National Natural Science Foundation of China [81330033, 81200076, 81671763]; Harbin Medical University Innovative Scientific Research Grant FX The EROSION study was supported by AstraZeneca (ISSBRIL0186); National Natural Science Foundation of China (grant No. 81330033/B.Y., grant No. 81200076/H.J., grant No. 81671763); Harbin Medical University Innovative Scientific Research Grant (S.H.). NR 26 TC 4 Z9 4 U1 1 U2 1 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 MAR 14 PY 2017 VL 38 IS 11 BP 792 EP 800 DI 10.1093/eurheartj/ehw381 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO2FC UT WOS:000396511000006 PM 27578806 ER PT J AU Grover, FL Vemulapalli, S Carroll, JD Edwards, FH Mack, MJ Thourani, VH Brindis, RG Shahian, DM Ruiz, CE Jacobs, JP Hanzel, G Bavaria, JE Tuzcu, EM Peterson, ED Fitzgerald, S Kourtis, M Michaels, J Christensen, B Seward, WF Hewitt, K Holmes, DR AF Grover, Frederick L. Vemulapalli, Sreekanth Carroll, John D. Edwards, Fred H. Mack, Michael J. Thourani, Vinod H. Brindis, Ralph G. Shahian, David M. Ruiz, Carlos E. Jacobs, Jeffrey P. Hanzel, George Bavaria, Joseph E. Tuzcu, E. Murat Peterson, Eric D. Fitzgerald, Susan Kourtis, Matina Michaels, Joan Christensen, Barbara Seward, William F. Hewitt, Kathleen Holmes, David R., Jr. CA STS-ACC TVT Registry TI 2016 Annual Report of The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic; outcomes; procedural outcomes; procedural risk; transcatheter mitral clip; transcatheter valves; TVT; valve in valve ID UNITED-STATES; REPLACEMENT; OUTCOMES; SURVEILLANCE; EXPERIENCE AB BACKGROUND The Society of Thoracic Surgeons (STS)/ American College of Cardiology Transcatheter Valve Therapy (TVT) Registry captures all procedures with Food and Drug Administration-approved transcatheter valve devices performed in the United States, and is mandated as a condition of reimbursement by the Centers for Medicaid & Medicare Services. OBJECTIVES This annual report focuses on patient characteristics, trends, and outcomes of transcatheter aortic and mitral valve catheter-based valve procedures in the United States. METHODS We reviewed data for all patients receiving commercially approved devices from 2012 through December 31, 2015, that are entered in the TVT Registry. RESULTS The 54,782 patients with transcatheter aortic valve replacement demonstrated decreases in expected risk of 30-day operative mortality (STS Predicted Risk of Mortality [PROM]) of 7% to 6% and transcatheter aortic valve replacement PROM (TVT PROM) of 4% to 3% (both p < 0.0001) from 2012 to 2015. Observed in-hospital mortality decreased from 5.7% to 2.9%, and 1-year mortality decreased from 25.8% to 21.6%. However, 30-day post-procedure pacemaker insertion increased from 8.8% in 2013 to 12.0% in 2015. The 2,556 patients who underwent transcatheter mitral leaflet clip in 2015 were similar to patients from 2013 to 2014, with hospital mortality of 2% and with mitral regurgitation reduced to grade # 2 in 87% of patients (p < 0.0001). The 349 patients who underwent mitral valve-invalve and mitral valve-in-ring procedures were high risk, with an STS PROM for mitral valve replacement of 11%. The observed hospital mortality was 7.2%, and 30-day post-procedure mortality was 8.5%. CONCLUSIONS The TVT Registry is an innovative registry that that monitors quality, patient safety and trends for these rapidly evolving new technologies. (J Am Coll Cardiol 2017; 69: 1215-30) c 2017 by the American College of Cardiology Foundation and The Society of Thoracic Surgeons. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. All rights reserved. C1 [Grover, Frederick L.] Univ Colorado, Sch Med, Dept Surg, Anschutz Med Campus,Acad Off 1,Room 6613, Aurora, CO 80045 USA. [Grover, Frederick L.] Denver Dept Vet Affairs Med Ctr, Denver, CO USA. [Vemulapalli, Sreekanth; Peterson, Eric D.] Duke Univ, Med Ctr, Durham, NC USA. [Carroll, John D.] Univ Colorado, Sch Med, Anschutz Med Campus, Aurora, CO USA. [Edwards, Fred H.] Univ Florida, Jacksonville, FL USA. [Mack, Michael J.] Baylor Scott & White Hlth, Plano, TX USA. [Thourani, Vinod H.] Emory Univ, Atlanta, GA 30322 USA. [Brindis, Ralph G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ruiz, Carlos E.] Hackensack Univ, Med Ctr, Struct & Congenital Heart Ctr, Hackensack, NJ USA. [Ruiz, Carlos E.] Seton Hall Hackensack Univ, Sch Med, Joseph M Sanzari Childrens Hosp, Hackensack, NJ USA. [Jacobs, Jeffrey P.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21205 USA. [Jacobs, Jeffrey P.] All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, St Petersburg, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, St Petersburg, FL USA. [Jacobs, Jeffrey P.] All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Tampa, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, Tampa, FL USA. [Jacobs, Jeffrey P.] All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Orlando, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, Orlando, FL USA. [Hanzel, George] Beaumont Hosp, Royal Oak, MI USA. [Bavaria, Joseph E.] Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Tuzcu, E. Murat] Cleveland Clin, Abu Dhabi, U Arab Emirates. [Fitzgerald, Susan; Michaels, Joan; Christensen, Barbara; Hewitt, Kathleen] Amer Coll Cardiol, Washington, DC USA. [Kourtis, Matina; Seward, William F.] Soc Thorac Surg, Chicago, IL USA. [Holmes, David R., Jr.] Mayo Clin, Rochester, MN USA. [Vemulapalli, Sreekanth] Novella & Premiere Research, Res Triangle Pk, NC USA. [Thourani, Vinod H.] Edwards, Crawley, England. [Hanzel, George] Boston Sci, Watchman Device, Marlborough, MA USA. [Bavaria, Joseph E.] Edwards Lifesci, Irvine, CA USA. [Bavaria, Joseph E.] Medtronic, Minneapolis, MN USA. [Bavaria, Joseph E.] St Jude Med, St Paul, MN USA. [Bavaria, Joseph E.] Boston Sci, Marlborough, MA USA. [Peterson, Eric D.] Amer Coll Cardiol, Soc Thorac Surg, Data Coordinating Ctr, Washington, DC USA. RP Grover, FL (reprint author), Univ Colorado, Sch Med, Dept Surg, Anschutz Med Campus,Acad Off 1,Room 6613, Aurora, CO 80045 USA. EM Frederick.Grover@ucdenver.edu FU Thoracic Surgery Foundation; Edwards; Abbott Vascular; American College of Cardiology; Society of Thoracic Surgeons; Medtronic; Philips; Boston Scientific FX Dr. Grover is the recipient of a Thoracic Surgery Foundation grant for medical mission work in Nepal, funded by Edwards. Dr. Vemulapalli has received research grants from Abbott Vascular, the American College of Cardiology, and The Society of Thoracic Surgeons; and has served as a consultant for Novella and Premiere Research. Dr. Mack has served as the co-principal investigator for the Partner 3 trial and COAPT trial. Dr. Thourani has served as a consultant for Edwards. Dr. Ruiz has received institutional educational grants from Medtronic; and institutional grants from Philips. Dr. Hanzel has served as an unpaid proctor for the Watchman device from Boston Scientific. Dr. Bavaria is a primary investigator for Edwards Lifesciences and Medtronic; and a sub primary investigator for St. Jude Medical and Boston Scientific. Dr. Peterson has served as the co-principal investigator of the Data Coordinating Center for The Society of Thoracic Surgeons-American College of Cardiology Transcatheter Aortic Valve Replacement. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 16 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 14 PY 2017 VL 69 IS 10 BP 1215 EP 1230 DI 10.1016/j.jacc.2016.11.033 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0AG UT WOS:000396360100001 PM 27956264 ER PT J AU Hoy, AR Ly, M Carlsson, CM Okonkwo, OC Zetterberg, H Blennow, K Sager, MA Asthana, S Johnson, SC Alexander, AL Bendlin, BB AF Hoy, Andrew R. Ly, Martina Carlsson, Cynthia M. Okonkwo, Ozioma C. Zetterberg, Henrik Blennow, Kaj Sager, Mark A. Asthana, Sanjay Johnson, Sterling C. Alexander, Andrew L. Bendlin, Barbara B. TI Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; FIBER TRACTOGRAPHY; CORPUS-CALLOSUM; HEALTHY-ADULTS; CSF; BRAIN; DEMENTIA; MRI; SCHIZOPHRENIA; DEGENERATION AB Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While beta-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years) from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE epsilon 4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI. C1 [Hoy, Andrew R.] US Navy, Med Serv Corp, Falls Church, VA 22042 USA. [Hoy, Andrew R.; Alexander, Andrew L.] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, 1530 Med Sci Ctr, Madison, WI 53706 USA. [Hoy, Andrew R.; Alexander, Andrew L.] Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI 53706 USA. [Hoy, Andrew R.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. [Ly, Martina; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Asthana, Sanjay; Johnson, Sterling C.; Bendlin, Barbara B.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Ly, Martina; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Sager, Mark A.; Asthana, Sanjay; Johnson, Sterling C.; Bendlin, Barbara B.] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. [Ly, Martina] Univ Wisconsin, Neurosci Training Program, Madison, WI USA. [Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Sager, Mark A.; Asthana, Sanjay; Johnson, Sterling C.; Bendlin, Barbara B.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI USA. [Zetterberg, Henrik; Blennow, Kaj] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Clin Neurochem Lab,Dept Psychiat & Neurochem, Gothenburg, Sweden. [Zetterberg, Henrik] UCL Inst Neurol, Queen Sq, London WC1N 3BG, England. [Alexander, Andrew L.] Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA. RP Hoy, AR (reprint author), US Navy, Med Serv Corp, Falls Church, VA 22042 USA.; Hoy, AR (reprint author), Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, 1530 Med Sci Ctr, Madison, WI 53706 USA.; Hoy, AR (reprint author), Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI 53706 USA.; Hoy, AR (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. EM Andrew.Hoy@usuhs.edu FU National Institutes of Health [P50AG033514, R01AG027161, P30HD003352, P50MH100031, R01AG037639]; Torsten Soderberg Foundation at the Royal Swedish Academy of Sciences FX Research reported in this publication was supported in part by the National Institutes of Health under Grant Award Numbers P50AG033514, R01AG027161, P30HD003352, P50MH100031, and R01AG037639. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Biomarker analyses in this project was supported by the Torsten Soderberg Foundation at the Royal Swedish Academy of Sciences. NR 88 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 MAR 14 PY 2017 VL 12 IS 3 AR e0173982 DI 10.1371/journal.pone.0173982 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6DM UT WOS:000396094700053 PM 28291839 ER PT J AU Ferreira, D Falahati, F Linden, C Buckley, RF Ellis, KA Savage, G Villemagne, VL Rowe, CC Ames, D Simmons, A Westman, E AF Ferreira, Daniel Falahati, Farshad Linden, Cecilia Buckley, Rachel F. Ellis, Kathryn A. Savage, Greg Villemagne, Victor L. Rowe, Christopher C. Ames, David Simmons, Andrew Westman, Eric TI A 'Disease Severity Index' to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia SO SCIENTIFIC REPORTS LA English DT Article ID PRECLINICAL ALZHEIMERS-DISEASE; HUMAN CEREBRAL-CORTEX; OLDER-ADULTS; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; PROSPECTIVE COHORT; CORTICAL SURFACE; NORMATIVE DATA; MRI DATA AB Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer's disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE epsilon 4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials. C1 [Ferreira, Daniel; Falahati, Farshad; Linden, Cecilia; Simmons, Andrew; Westman, Eric] Karolinska Inst, Ctr Alzheimer Res, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, S-14186 Stockholm, Sweden. [Buckley, Rachel F.] Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic 3010, Australia. [Buckley, Rachel F.; Villemagne, Victor L.; Ames, David] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3084, Australia. [Buckley, Rachel F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. [Ellis, Kathryn A.] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3052, Australia. [Savage, Greg] Macquarie Univ, ARC Ctr Excellence Cognit & Its Disorders, Dept Psychol, Sydney, NSW 2109, Australia. [Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Dept Nucl Med, Heidelberg, Vic 3084, Australia. [Villemagne, Victor L.; Rowe, Christopher C.] Austin Hlth, Ctr PET, Heidelberg, Vic 3084, Australia. [Villemagne, Victor L.; Rowe, Christopher C.] Univ Melbourne, Austin Hlth, Dept Med, Melbourne, Vic 3084, Australia. [Simmons, Andrew] NIHR Biomed Res Ctr Mental Hlth, London SE5 8AF, England. [Simmons, Andrew] NIHR Biomed Res Unit Dementia, London SE5 8AF, England. [Simmons, Andrew; Westman, Eric] Kings Coll London, Ctr Neuroimaging Sci, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London SE5 8AF, England. RP Ferreira, D (reprint author), Karolinska Inst, Ctr Alzheimer Res, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, S-14186 Stockholm, Sweden. EM daniel.ferreira.padilla@ki.se FU Swedish Foundation for Strategic Research (SSF); Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro); Stockholm County Council; Karolinska Institutet; Hjarnfonden; Alzheimerfonden; Stiftelsen for alderssjukdomar vid Karolinska Institutet; Birgitta och Sten Westerberg; Gamla Tjanarinnor and Demensforbundet; CogState Ltd.; Hollywood Private Hospital; Sir Charles Gairdner Hospital; CSIRO; Science and Industry Endowment Fund; NHMRC; Dementia Collaborative Research Centres (DCRC); Alzheimer's Australia (AA); Alzheimer's Association; McCusker Alzheimer's Research Foundation FX This project is financially supported by the Swedish Foundation for Strategic Research (SSF). The authors also thank the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Hjarnfonden, Alzheimerfonden, Stiftelsen for alderssjukdomar vid Karolinska Institutet, Birgitta och Sten Westerberg, Gamla Tjanarinnor and Demensforbundet for additional financial support. The AIBL study (www.AIBL.csiro.au) is a collaboration between CSIRO, Edith Cowan University (ECU), The Florey Institute of Neuroscience and Mental Health (FINMH), National Ageing Research Institute (NARI) and Austin Health. AIBL involves support from CogState Ltd., Hollywood Private Hospital, and Sir Charles Gairdner Hospital. The study received funding support from CSIRO, the Science and Industry Endowment Fund (www.SIEF.org.au), NHMRC and Dementia Collaborative Research Centres (DCRC), Alzheimer's Australia (AA), Alzheimer's Association and the McCusker Alzheimer's Research Foundation. The above-mentioned funding sources had no involvement in the study design, collection, analysis and interpretation of the data, writing of the report and the decision to submit the article for publication. NR 67 TC 0 Z9 0 U1 0 U2 0 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 MAR 13 PY 2017 VL 7 AR 44368 DI 10.1038/srep44368 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8OM UT WOS:000396259700001 PM 28287184 ER PT J AU Morrow, JD Zhou, XB Lao, T Jiang, ZQ Demeo, DL Cho, MH Qiu, WL Cloonan, S Pinto-Plata, V Celli, B Marchetti, N Criner, GJ Bueno, R Washko, GR Glass, K Quackenbush, J Choi, AMK Silverman, EK Hersh, CP AF Morrow, Jarrett D. Zhou, Xiaobo Lao, Taotao Jiang, Zhiqiang Demeo, Dawn L. Cho, Michael H. Qiu, Weiliang Cloonan, Suzanne Pinto-Plata, Victor Celli, Bartholome Marchetti, Nathaniel Criner, Gerard J. Bueno, Raphael Washko, George R. Glass, Kimberly Quackenbush, John Choi, Augustine M. K. Silverman, Edwin K. Hersh, Craig P. TI Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue SO SCIENTIFIC REPORTS LA English DT Article ID GROUP BOX 1; B-CELL; NETWORK ANALYSIS; CIGARETTE-SMOKE; COMPUTED-TOMOGRAPHY; LYMPHOID FOLLICLES; IDENTIFIES GENES; EMPHYSEMA; COPD; PROTEIN AB In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD). We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD. Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci. The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene. Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses. The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies. As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results. C1 [Morrow, Jarrett D.; Zhou, Xiaobo; Lao, Taotao; Jiang, Zhiqiang; Demeo, Dawn L.; Cho, Michael H.; Qiu, Weiliang; Glass, Kimberly; Silverman, Edwin K.; Hersh, Craig P.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02111 USA. [Demeo, Dawn L.; Cho, Michael H.; Celli, Bartholome; Washko, George R.; Silverman, Edwin K.; Hersh, Craig P.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02111 USA. [Cloonan, Suzanne; Choi, Augustine M. K.] NewYork Presbyterian Well Cornell Med Ctr, New York, NY 10001 USA. [Pinto-Plata, Victor] Baystate Med Ctr, Dept Crit Care Med & Pulmonary Disease, Springfield, MA 01107 USA. [Marchetti, Nathaniel; Criner, Gerard J.] Temple Univ, Div Pulm & Crit Care Med, Philadelphia, PA 19111 USA. [Bueno, Raphael] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02111 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02111 USA. RP Hersh, CP (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02111 USA. EM craig.hersh@channing.harvard.edu FU National Institutes of Health [NCT00608764, P01HL105339, R01HL111759, R01HL094635, R01HL130512, R01HL125583, R01HL113264, R01HL127200]; COPD Foundation through AstraZeneca; COPD Foundation through Boehringer Ingelheim; COPD Foundation through Novartis; COPD Foundation through Pfizer; COPD Foundation through Siemens; COPD Foundation through GSK; COPD Foundation through Sunovion; NHLBI [N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119]; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; Cooperative Studies Program/ERIC of the US Department of Veterans Affairs; GlaxoSmithKline [NCT00292552, SCO104960] FX We thank Drs. Amund Gulsvik, Per Bakke, Augusto Litonjua, Pantel Vokonas, Ruth Tal-Singer, and the GenKOLS, NETT/NAS, ECLIPSE, and COPDGene studies for use of their GWAS meta-analysis data. The COPDGene r study (R01 HL089856 and R01 HL089897). (NCT00608764) was funded by the National Institutes of Health and is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, GSK and Sunovion. The National Emphysema Treatment Trial was supported by the NHLBI N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118 and N01HR76119, the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080), and the ECLIPSE study (NCT00292552; GSK code SCO104960) were funded by GlaxoSmithKline. This work was supported by National Institutes of Health [P01HL105339 to EKS, R01HL111759 to JQ, R01HL094635 to CPH, R01HL130512 to CPH, R01HL125583 to CPH, R01HL113264 to MHC, R01HL127200 to XZ]. NR 80 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 MAR 13 PY 2017 VL 7 AR 44232 DI 10.1038/srep44232 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8NI UT WOS:000396256700001 PM 28287180 ER PT J AU Angin, M Fathi, A King, M Ledoux, MB Piechocka-Trocha, A Altfeld, M Addo, MM AF Angin, Mathieu Fathi, Anahita King, Melanie Ledoux, Mary B. Piechocka-Trocha, Alicja Altfeld, Marcus Addo, Marylyn M. TI Acute HIV-1 infection is associated with increased plasma levels of heme oxygenase-1 and presence of heme oxygenase-1-specific regulatory T cells SO AIDS LA English DT Article DE CD8positive; cytotoxic T lymphocytes; heme oxygenase-1; HIV-1; regulatory T cells; suppressor T cells; T lymphocytes ID IMMUNODEFICIENCY-VIRUS-INFECTION; HEAVY-CHAIN FERRITIN; TGF-BETA; IN-VITRO; INDUCTION; ACTIVATION; INDIVIDUALS; DISEASE; LIPOPOLYSACCHARIDE; LYMPHOCYTES AB Objective: Heme oxygenase-1 (HO-1) is an inducible stress response protein with potent anti-inflammatory activity and recent data suggest a potentially beneficial role in HIV pathogenesis. We investigated the impact of HO-1 and a novel subset of HO-1-specific CD8(+) regulatory T-cells on virus-specific T-cell immunity in HIV-1-infected individuals. Methods: HO-1 protein levels were quantified in plasma from individuals at different stages of HIV-1 disease and longitudinally following primary HIV infection. HO-1-specific CD8(+) T-cells were investigated by flow cytometry using human leukocyte antigen (HLA) class I pentamers. Flow-sorted HO-1-specific CD8(+) T-cells were cultured and tested for suppressive activity on HIV-1-specific cytotoxic T-cell clones clones. HO-1 gene expression was determined in sorted peripheral blood mononuclear cell (PBMC) subsets from individuals with acute HIV-1 infection. Results: HO-1 plasma levels were significantly increased in HIV-1 infection, with the highest levels in individuals with acute HIV-1 infection, and gradually declined over time. The frequency of CD8(+) T-cells specific for HO-1 was elevated in study participants with primary HIV-1 infection and flow-sorted HO-1-specific CD8(+) T-cells were capable of suppressing HIV-1-specific lysis of cytotoxic T-cell clones clones. HO-1 gene expression was upregulated in multiple immune cell subsets during acute HIV-1 infection and HO-1 overexpression modulated anti-HIV immunity in vitro. Conclusion: Our data suggest that HO-1 is induced during acute HIV-1 infection, likely mediating anti-inflammatory effects and driving expansion of HO-1-specific CD8(+) regulatory T-cells capable of suppressing HIV-1-specific immune responses in vitro. The investigation of HO-1 and the novel CD8(+) regulatory cell type described here provide further insight into immune regulation in HIV-1 infection and may hold potential for future immunotherapeutic intervention. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Angin, Mathieu; Fathi, Anahita; King, Melanie; Ledoux, Mary B.; Piechocka-Trocha, Alicja; Altfeld, Marcus; Addo, Marylyn M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Fathi, Anahita] Univ Munster, Munster, North Rhine Wes, Germany. [Altfeld, Marcus; Addo, Marylyn M.] Leibniz Inst Expt Virol, Dept Viral Immunol, Hamburg, Germany. [Addo, Marylyn M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Addo, Marylyn M.] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany. [Altfeld, Marcus; Addo, Marylyn M.] German Ctr Infect Res DZIF, Standort Hamburg Luebeck Borstel, Hamburg, Germany. RP Addo, MM (reprint author), Univ Klinikum Hamburg Eppendorf, Emerging Infect, Med Klin & Poliklin 1, Martinistr 52, D-20246 Hamburg, Germany. EM m.addo@uke.de NR 49 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 13 PY 2017 VL 31 IS 5 BP 635 EP 641 DI 10.1097/QAD.0000000000001390 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4TT UT WOS:000396000500004 PM 28060008 ER PT J AU Tsai, AC Pierce, CM AF Tsai, Alexander C. Pierce, Chester M. TI Limitations of using the Lorenz curve framework to understand the distribution of population viral load SO AIDS LA English DT Letter ID GINI COEFFICIENT; INEQUALITY C1 [Tsai, Alexander C.; Pierce, Chester M.] Massachusetts Gen Hosp, Div Global Psychiat, Boston, MA 02114 USA. RP Tsai, AC (reprint author), MGH Global Hlth, 125 Nashua St,7th Floor, Boston, MA 02114 USA. EM actsai@partners.org 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 13 PY 2017 VL 31 IS 5 BP 742 EP 742 DI 10.1097/QAD.0000000000001388 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4TT UT WOS:000396000500018 PM 28225454 ER PT J AU Torres, MJ Romano, A Celik, G Demoly, P Khan, DA Macy, E Park, M Blumenthal, K Aberer, W Castells, M Barbaud, A Mayorga, C Bonadonna, P AF Torres, M. J. Romano, A. Celik, G. Demoly, P. Khan, D. A. Macy, E. Park, M. Blumenthal, K. Aberer, W. Castells, M. Barbaud, A. Mayorga, C. Bonadonna, P. TI Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America SO CLINICAL AND TRANSLATIONAL ALLERGY LA English DT Review DE Drug; Hypersensitivity; Allergy; Diagnosis; Skin test; In vitro test; IgE; T-cells; Drug provocation test; Sensitization; United States; Europe ID STEVENS-JOHNSON-SYNDROME; IMMEDIATE ALLERGIC REACTIONS; BASOPHIL ACTIVATION TEST; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BETA-LACTAM ANTIBIOTICS; LYMPHOCYTE-TRANSFORMATION TEST; NEUROMUSCULAR BLOCKING-AGENTS; CETUXIMAB-INDUCED ANAPHYLAXIS; TOXIC EPIDERMAL NECROLYSIS; PARAMETER-UPDATE 2015 AB Drug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. perspectives. While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated. C1 [Torres, M. J.] IBIMA Reg Univ Hosp Malaga UMA, Natl Network ARADyAL, Allergy Unit, Pavil C,Plaza Hosp Civil, Malaga 29009, Spain. [Torres, M. J.] BIONAND Andalusian Ctr Nanomed & Biotechnol, Malaga, Spain. [Romano, A.] Presidio Columbus, Allergy Unit, Rome, Italy. [Romano, A.] IRCCS Oasi Maria SS, Troina, Italy. [Celik, G.] Ankara Univ, Sch Med, Dept Chest Dis, Div Immunol & Allergy, Ankara, Turkey. [Demoly, P.] Univ Hosp Montpellier, Hop Arnaud de Villeneuve, Montpellier, France. [Demoly, P.] UPMC Paris 06, Sorbonne Univ, UMRS 1136, IPLESP,Equipe EPAR, F-75013 Paris, France. [Khan, D. A.] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Allergy & Immunol, Dallas, TX USA. [Macy, E.] Kaiser Permanente Hlth Care Program, San Diego, CA USA. [Park, M.] Mayo Clin, Coll Med, Div Allerg Dis, Rochester, MN 55905 USA. [Blumenthal, K.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Blumenthal, K.] Harvard Med Sch, Boston, MA USA. [Aberer, W.] Med Univ Graz, Dept Dermatol, Graz, Austria. [Castells, M.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Barbaud, A.] UPMC Univ Paris 06, Sorbonne Univ, Dermatol & Allergol Dept, Tenon Hosp,AP HP, 4 Rue Chine, F-75020 Paris, France. [Mayorga, C.] IBIMA Reg Univ Hosp Malaga UMA, Allergy Unit, Pavil C,Plaza Hosp Civil, Malaga 29009, Spain. [Bonadonna, P.] Azienda Osped Univ Intergrata Verona, Allergy Unit, Verona, Italy. RP Torres, MJ (reprint author), IBIMA Reg Univ Hosp Malaga UMA, Natl Network ARADyAL, Allergy Unit, Pavil C,Plaza Hosp Civil, Malaga 29009, Spain. EM mjtorresj@ibima.eu NR 81 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 2045-7022 J9 CLIN TRANSL ALLERGY JI Clin. Transl. Allergy PD MAR 13 PY 2017 VL 7 AR 7 DI 10.1186/s13601-017-0144-0 PG 13 WC Allergy SC Allergy GA EN5VN UT WOS:000396073900001 PM 28293415 ER PT J AU Goncalves, OF Soares, JM Carvalho, S Leite, J Ganho-Avila, A Fernandes-Goncalves, A Pocinho, F Carracedo, A Sampaio, A AF Goncalves, Oscar F. Soares, Jose Miguel Carvalho, Sandra Leite, Jorge Ganho-Avila, Ana Fernandes-Goncalves, Ana Pocinho, Fernando Carracedo, Angel Sampaio, Adriana TI Patterns of Default Mode Network Deactivation in Obsessive Compulsive Disorder SO SCIENTIFIC REPORTS LA English DT Article ID FUNCTIONAL CONNECTIVITY; RESTING-STATE; BRAIN; TASK AB The objective of the present study was to research the patterns of Default Mode Network (DMN) deactivation in Obsessive Compulsive Disorder (OCD) in the transition between a resting and a non-rest emotional condition. Twenty-seven participants, 15 diagnosed with OCD and 12 healthy controls (HC), underwent a functional neuroimaging paradigm in which DMN brain activation in a resting condition was contrasted with activity during a non-rest condition consisting in the presentation of emotionally pleasant and unpleasant images. Results showed that HC, when compared with OCD, had a significant deactivation in two anterior nodes of the DMN (medial frontal and superior frontal) in the non-rest pleasant stimuli condition. Additional analysis for the whole brain, contrasting the resting condition with all the non-rest conditions grouped together, showed that, compared with OCD, HC had a significantly deactivation of a widespread brain network (superior frontal, insula, middle and superior temporal, putamen, lingual, cuneus, and cerebellum). Concluding, the present study found that OCD patients had difficulties with the deactivation of DMN even when the non-rest condition includes the presentation of emotional provoking stimuli, particularly evident for images with pleasant content. C1 [Goncalves, Oscar F.; Carvalho, Sandra; Leite, Jorge; Ganho-Avila, Ana; Sampaio, Adriana] Univ Minho, Sch Psychol, CIPsi, Neuropsychophysiol Lab, Braga, Portugal. [Goncalves, Oscar F.; Carvalho, Sandra; Leite, Jorge] Spaulding Rehabil Hosp, Spaulding Neuromodulat Ctr, Dept Phys Med & Rehabil, Boston, MA USA. [Goncalves, Oscar F.; Carvalho, Sandra; Leite, Jorge] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA 02114 USA. [Goncalves, Oscar F.] Northeastern Univ, Dept Appl Psychol, Boston, MA 02115 USA. [Soares, Jose Miguel] Univ Minho, Life & Hlth Sci Res Inst, Braga, Portugal. [Soares, Jose Miguel] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Fernandes-Goncalves, Ana] CUF Porto Hosp, Dept Psychiat, Oporto, Portugal. [Pocinho, Fernando] Univ Coimbra Hosp, Dept Psychiat, Coimbra, Portugal. [Carracedo, Angel] Univ Santiago de Compostela, Fac Med, Inst Legal Med, Forens Genet Unit, Galicia, Spain. RP Goncalves, OF (reprint author), Univ Minho, Sch Psychol, CIPsi, Neuropsychophysiol Lab, Braga, Portugal.; Goncalves, OF (reprint author), Spaulding Rehabil Hosp, Spaulding Neuromodulat Ctr, Dept Phys Med & Rehabil, Boston, MA USA.; Goncalves, OF (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA 02114 USA.; Goncalves, OF (reprint author), Northeastern Univ, Dept Appl Psychol, Boston, MA 02115 USA. EM goncalves@psi.uminho.pt FU Brazilian National Counsel for Scientific and Technological Development (CNPq) [401143/20147]; Portuguese Foundation for Science and Technology; Portuguese Ministry of Science, Technology and Higher Education through national funds; FEDER through COMPETE2020 under the PT2020 Partnership Agreement [POCI-01-0145FEDER-007653] FX The first author was funded by the Brazilian National Counsel for Scientific and Technological Development (CNPq) as a Special Visiting Researcher of the Science Without Borders program (grant number: 401143/20147). This study was partially conducted at the Neuropsychophysiology Lab from the 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 Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145FEDER-007653). NR 38 TC 0 Z9 0 U1 0 U2 0 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 MAR 13 PY 2017 VL 7 AR 44468 DI 10.1038/srep44468 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN7SK UT WOS:000396202300001 PM 28287615 ER PT J AU Zheng, J Cheng, R Lin, JH Yu, DH Ma, LL Jia, LA Zhang, L Wang, L Xiao, JC Liang, SH AF Zheng, Jian Cheng, Ran Lin, Jin-Hong Yu, Dong-Hai Ma, Longle Jia, Lina Zhang, Lan Wang, Lu Xiao, Ji-Chang Liang, Steven H. TI An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of F-18-Labeled alpha-SCF3 Carbonyl Compounds SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE F-18-labeling; difluorocarbene; fluorine; sulfuration; trifluoromethylthiolation ID NUCLEOPHILIC TRIFLUOROMETHYLTHIOLATION; DIFLUOROMETHYLENE PHOSPHABETAINE; TERMINAL ALKYNES; ORGANIC HALIDES; ARYL HALIDES; SULFUR; COMPLEX; REAGENT; PHOSPHOBETAINE; DERIVATIVES AB Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long-standing trifluoromethyl anion-based theory. Mechanistic elucidation reveals an unprecedented chemical process for the formation of thiocarbonyl fluoride and also enables transition-metal-mediated trifluoromethylthiolation and [F-18]trifluoromethylthiolation of alpha-bromo carbonyl compounds with broad substrate scope and compatibility. C1 [Zheng, Jian; Lin, Jin-Hong; Yu, Dong-Hai; Xiao, Ji-Chang] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Organ Chem, Key Lab Organofluorine Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China. [Cheng, Ran] Tianjin Univ, Sch Pharmaceut Sci & Technol, 92 Weijin Rd, Tianjin 300072, Peoples R China. [Cheng, Ran; Ma, Longle; Wang, Lu; Liang, Steven H.] Harvard Med Sch, Div Nucl Med & Mol Imaging, 55 Fruit St,White 427, Boston, MA 02115 USA. [Cheng, Ran; Ma, Longle; Wang, Lu; Liang, Steven H.] Harvard Med Sch, Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St,White 427, Boston, MA 02115 USA. [Cheng, Ran; Ma, Longle; Wang, Lu; Liang, Steven H.] Harvard Med Sch, Dept Radiol, 55 Fruit St,White 427, Boston, MA 02115 USA. [Jia, Lina; Zhang, Lan] Chinese Acad Sci, Shanghai Inst Appl Phys, 2019 Jialuo Rd, Shanghai 201800, Peoples R China. RP Xiao, JC (reprint author), Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Organ Chem, Key Lab Organofluorine Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China.; Liang, SH (reprint author), Harvard Med Sch, Div Nucl Med & Mol Imaging, 55 Fruit St,White 427, Boston, MA 02115 USA.; Liang, SH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Gordon Ctr Med Imaging, 55 Fruit St,White 427, Boston, MA 02115 USA.; Liang, SH (reprint author), Harvard Med Sch, Dept Radiol, 55 Fruit St,White 427, Boston, MA 02115 USA. EM jchxiao@sioc.ac.cn; liang.steven@mgh.harvard.edu FU National Basic Research Program of China [2015CB931900, 2012CBA01200]; National Natural Science Foundation [21421002, 21472222, 21502214, 21672242]; Chinese Academy of Sciences [XDA02020105, XDA02020106]; Science and Technology Commission of Shanghai Municipality [15DZ1200102, 14ZR1448800]; China Scholarship Council [201506250036]; NIH career development award [DA038000] FX We would like to thank Dr. Shubin Liu (University of North Carolina) for helpful discussion. This work was financially supported by the National Basic Research Program of China (2015CB931900, 2012CBA01200), the National Natural Science Foundation (21421002, 21472222, 21502214, 21672242), the Chinese Academy of Sciences (XDA02020105, XDA02020106), and the Science and Technology Commission of Shanghai Municipality (15DZ1200102, 14ZR1448800). R.C. is supported by China Scholarship Council (201506250036). S.H.L. is a recipient of an NIH career development award (DA038000). NR 62 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD MAR 13 PY 2017 VL 56 IS 12 BP 3196 EP 3200 DI 10.1002/anie.201611761 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EP4CX UT WOS:000397329300010 PM 28194833 ER PT J AU Fan, QW Aksoy, O Wong, RA Ilkhanizadeh, S Novotny, CJ Gustafson, WC Truong, AYQ Cayanan, G Simonds, EF Haas-Kogan, D Phillips, JJ Nicolaides, T Okaniwa, M Shokat, KM Weiss, WA AF Fan, Qiwen Aksoy, Ozlem Wong, Robyn A. Ilkhanizadeh, Shirin Novotny, Chris J. Gustafson, William C. Truong, Albert Yi-Que Cayanan, Geraldine Simonds, Erin F. Haas-Kogan, Daphne Phillips, Joanna J. Nicolaides, Theodore Okaniwa, Masanori Shokat, Kevan M. Weiss, William A. TI A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma SO CANCER CELL LA English DT Article ID GROWTH-FACTOR RECEPTOR; RAPAMYCIN COMPLEX; MAMMALIAN TARGET; MOLECULAR-BASIS; CANCER; ACTIVATION; RESISTANCE; LANDSCAPE; EFFICACY; GLIOMA AB Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1. C1 [Fan, Qiwen; Aksoy, Ozlem; Wong, Robyn A.; Ilkhanizadeh, Shirin; Cayanan, Geraldine; Simonds, Erin F.; Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Novotny, Chris J.; Okaniwa, Masanori; Shokat, Kevan M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Fan, Qiwen; Aksoy, Ozlem; Wong, Robyn A.; Ilkhanizadeh, Shirin; Gustafson, William C.; Cayanan, Geraldine; Simonds, Erin F.; Phillips, Joanna J.; Weiss, William A.] Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Gustafson, William C.; Truong, Albert Yi-Que; Nicolaides, Theodore; Weiss, William A.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Truong, Albert Yi-Que; Phillips, Joanna J.; Nicolaides, Theodore; Weiss, William A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA. [Haas-Kogan, Daphne] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. RP Weiss, WA (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA.; Weiss, WA (reprint author), Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.; Weiss, WA (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA.; Weiss, WA (reprint author), Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA. EM waweiss@gmail.com OI Simonds, Erin/0000-0002-3497-4861; Weiss, William/0000-0003-2230-9132 FU NIH [R01NS091620, R01NS089868, R01CA148699, U01CA176287, P30CA82103, U54CA163155, P50AA017072]; Kura Oncology; Children's Tumor Foundation; CureSearch Foundation; Ross K. MacNeill Foundation; Samuel Waxman Cancer Research Foundation FX We thank Francis Burrows, Arman Jahangiri, and Yi Liu for critical review, Pingda Ren and Liansheng Li for small-molecule inhibitors, and David James for GBM5, GBM12, and GBM43. K.M.S. is an inventor on patents related to MLN0128 held by the University of California, San Francisco, and sublicensed to Takeda Pharmaceuticals. M.O. is an employee of, and K.M.S. is a consultant to Takeda Pharmaceutical Company, Limited, which is conducting MLN0128 clinical trials. Supported by NIH grants R01NS091620, R01NS089868, R01CA148699, R01NS089868, U01CA176287, P30CA82103, U54CA163155, P50AA017072, and Kura Oncology; as well as Children's Tumor, CureSearch, Ross K. MacNeill, and the Samuel Waxman Cancer Research Foundations. NR 28 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAR 13 PY 2017 VL 31 IS 3 BP 424 EP 435 DI 10.1016/j.ccell.2017.01.014 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN8VA UT WOS:000396276700014 PM 28292440 ER PT J AU Davids, MS Roberts, AW Seymour, JF Pagel, JM Kahl, BS Wierda, WG Puvvada, S Kipps, TJ Anderson, MA Salem, AH Dunbar, M Zhu, M Peale, F Ross, JA Gressick, L Desai, M Kim, SY Verdugo, M Humerickhouse, RA Gordon, GB Gerecitano, JF AF Davids, Matthew S. Roberts, Andrew W. Seymour, John F. Pagel, John M. Kahl, Brad S. Wierda, William G. Puvvada, Soham Kipps, Thomas J. Anderson, Mary Ann Salem, Ahmed Hamed Dunbar, Martin Zhu, Ming Peale, Franklin Ross, Jeremy A. Gressick, Lori Desai, Monali Kim, Su Young Verdugo, Maria Humerickhouse, Rod A. Gordon, Gary B. Gerecitano, John F. TI Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR LYSIS SYNDROME; ANTITUMOR-ACTIVITY; CHROMOSOME-TRANSLOCATION; SELECTIVE INHIBITOR; DOSE-ESCALATION; GENE-EXPRESSION; BCL2; PHARMACOKINETICS AB Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrom macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. (C) 2017 by American Society of Clinical Oncology C1 [Davids, Matthew S.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Roberts, Andrew W.; Seymour, John F.; Anderson, Mary Ann] Univ Melbourne, Melbourne, Vic, Australia. [Roberts, Andrew W.; Anderson, Mary Ann] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Roberts, Andrew W.; Anderson, Mary Ann] Eliza Hall Inst Med Res, Melbourne, Vic, Australia. [Seymour, John F.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Pagel, John M.] Swedish Canc Inst, Seattle, WA USA. [Kahl, Brad S.] Washington Univ, Sch Med, St Louis, MO USA. [Wierda, William G.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Puvvada, Soham] Univ Arizona, Tucson, AZ USA. [Kipps, Thomas J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Ross, Jeremy A.; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A.; Gordon, Gary B.] AbbVie, Chicago, IL USA. [Salem, Ahmed Hamed] Ain Shams Univ, Fac Pharm, Cairo, Egypt. [Peale, Franklin] Genentech Inc, San Francisco, CA 94080 USA. [Gerecitano, John F.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Gerecitano, John F.] Weill Cornell Med Ctr, New York, NY USA. RP Davids, MS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Matthew_Davids@dfci.harvard.edu FU AbbVie; Genentech; National Institutes of Health/National Cancer Institute Cancer Center Support Grant [P30 CA008748]; Career Development Award from the American Society of Clinical Oncology FX Supported by AbbVie (which also funded editorial support) and Genentech; in part by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant No. P30 CA008748 (J.F.G.); and in part by a Career Development Award from the American Society of Clinical Oncology (M.S.D.). NR 23 TC 1 Z9 1 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 MAR 10 PY 2017 VL 35 IS 8 BP 826 EP U37 DI 10.1200/JCO.2016.70.4320 PG 12 WC Oncology SC Oncology GA EO0DF UT WOS:000396367800005 PM 28095146 ER PT J AU Temel, JS Greer, JA El-Jawahri, A Pirl, WF Park, ER Jackson, VA Back, AL Kamdar, M Jacobsen, J Chittenden, EH Rinaldi, SP Gallagher, ER Eusebio, JR Li, ZG Muzikansky, A Ryan, DP AF Temel, Jennifer S. Greer, Joseph A. El-Jawahri, Areej Pirl, William F. Park, Elyse R. Jackson, Vicki A. Back, Anthony L. Kamdar, Mihir Jacobsen, Juliet Chittenden, Eva H. Rinaldi, Simone P. Gallagher, Emily R. Eusebio, Justin R. Li, Zhigang Muzikansky, Alona Ryan, David P. TI Effects of Early Integrated Palliative Care in Patients With Lung and GI Cancer: A Randomized Clinical Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; ONCOLOGY CARE; ASSOCIATIONS; OUTCOMES; PROJECT; HEALTH AB Purpose We evaluated the impact of early integrated palliative care (PC) in patients with newly diagnosed lung and GI cancer. Patients and Methods We randomly assigned patients with newly diagnosed incurable lung or noncolorectal GI cancer to receive either early integrated PC and oncology care (n = 175) or usual care (n 5 175) between May 2011 and July 2015. Patients who were assigned to the intervention met with a PC clinician at least once per month until death, whereas those who received usual care consulted a PC clinician upon request. The primary end point was change in quality of life (QOL) from baseline to week 12, per scoring by the Functional Assessment of Cancer Therapy-General scale. Secondary end points included change in QOL from baseline to week 24, change in depression per the Patient Health Questionnaire-9, and differences in end-of-life communication. Results Intervention patients (v usual care) reported greater improvement inQOLfrom baseline to week 24 (1.59 v -3.40; P = .010) but not week 12 (0.39 v -1.13; P = .339). Intervention patients also reported lower depression at week 24, controlling for baseline scores (adjusted mean difference, -1.17; 95% CI, -2.33 to -0.01; P = .048). Intervention effects varied by cancer type, such that intervention patients with lung cancer reported improvements in QOL and depression at 12 and 24 weeks, whereas usual care patients with lung cancer reported deterioration. Patients with GI cancers in both study groups reported improvements in QOL and mood by week 12. Intervention patients versus usual care patients were more likely to discuss their wishes with their oncologist if they were dying (30.2% v 14.5%; P = .004). Conclusion For patients with newly diagnosed incurable cancers, early integrated PC improved QOL and other salient outcomes, with differential effects by cancer type. Early integrated PC may be most effective if targeted to the specific needs of each patient population. C1 [Temel, Jennifer S.; Greer, Joseph A.; El-Jawahri, Areej; Pirl, William F.; Park, Elyse R.; Jackson, Vicki A.; Kamdar, Mihir; Jacobsen, Juliet; Chittenden, Eva H.; Rinaldi, Simone P.; Gallagher, Emily R.; Eusebio, Justin R.; Muzikansky, Alona; Ryan, David P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Temel, Jennifer S.; Greer, Joseph A.; El-Jawahri, Areej; Pirl, William F.; Park, Elyse R.; Jackson, Vicki A.; Kamdar, Mihir; Jacobsen, Juliet; Chittenden, Eva H.; Muzikansky, Alona; Ryan, David P.] Harvard Med Sch, Boston, MA USA. [Back, Anthony L.] Univ Washington, Seattle, WA 98195 USA. [Li, Zhigang] Geisel Sch Med Dartmouth, Lebanon, NH USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Ctr Canc, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM jtemel@partners.org FU National Institutes of Health [NCT01401907]; National Institute of Nursing Research Grant [R01-NR012735] FX Supported by the National Institutes of Health Grant No. NCT01401907 and National Institute of Nursing Research Grant No. R01-NR012735. NR 24 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 MAR 10 PY 2017 VL 35 IS 8 BP 834 EP U48 DI 10.1200/JCO.2016.70.5046 PG 11 WC Oncology SC Oncology GA EO0DF UT WOS:000396367800006 ER PT J AU Seisen, T Krasnow, RE Bellmunt, J Roupret, M Leow, JJ Lipsitz, SR Vetterlein, MW Preston, MA Hanna, N Kibel, AS Sun, MX Choueiri, TK Trinh, QD Chang, SL AF Seisen, Thomas Krasnow, Ross E. Bellmunt, Joaquim Roupret, Morgan Leow, Jeffrey J. Lipsitz, Stuart R. Vetterlein, Malte W. Preston, Mark A. Hanna, Nawar Kibel, Adam S. Sun, Maxine Choueiri, Toni K. Trinh, Quoc-Dien Chang, Steven L. TI Effectiveness of Adjuvant Chemotherapy After Radical Nephroureterectomy for Locally Advanced and/or Positive Regional Lymph Node Upper Tract Urothelial Carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UPPER URINARY-TRACT; TRANSITIONAL-CELL CARCINOMA; PROPENSITY SCORE METHODS; NEOADJUVANT CHEMOTHERAPY; CANCER; OUTCOMES; BLADDER; CISPLATIN; SURVIVAL; TIME AB Purpose There is limited evidence to support the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we hypothesized that such treatment is associated with overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease. Patients and Methods Within the National Cancer Database (2004 to 2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW) -adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the two treatment groups. In addition, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathologic stage (pT3/T4N0, pT3/T4Nx and pTanyN+), and surgical margin status. Results Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation, respectively, after RNU. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation (47.41 [interquartile range, 19.88 to 112.39] v 35.78 [interquartile range, 14.09 to 99.22] months; P < .001). The 5-year IPTW-adjusted rates of OS for AC versus observation were 43.90% and 35.85%, respectively. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit (hazard ratio, 0.77 [95% CI, 0.68 to 0.88]; P < .001). This benefit was consistent across all subgroups examined (all P < .05), and no significant heterogeneity of treatment effect was observed (all P-interaction > .05). Conclusion We report an OS benefit in patients who received AC versus observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence. (C) 2017 by American Society of Clinical Oncology C1 [Seisen, Thomas; Krasnow, Ross E.; Leow, Jeffrey J.; Lipsitz, Stuart R.; Vetterlein, Malte W.; Preston, Mark A.; Hanna, Nawar; Kibel, Adam S.; Sun, Maxine; Trinh, Quoc-Dien; Chang, Steven L.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Bellmunt, Joaquim; Choueiri, Toni K.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Roupret, Morgan] Pierre & Marie Curie Univ, Pitie Salpetriere Hosp, AP HP, Paris, France. RP Chang, SL (reprint author), Brigham & Womens Hosp, Div Urol Surg, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM slchang@bwh.harvard.edu FU Vattikuti Urology Institute; Conquer Cancer Foundation of the American Society of Clinical Oncology; Prostate Cancer Foundation FX Supported by an unrestricted educational grant from the Vattikuti Urology Institute, a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology, and a Young Investigator Award from the Prostate Cancer Foundation (all to Q.-D.T.). NR 35 TC 1 Z9 1 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 MAR 10 PY 2017 VL 35 IS 8 BP 852 EP U78 DI 10.1200/JCO.2016.69.4141 PG 15 WC Oncology SC Oncology GA EO0DF UT WOS:000396367800008 PM 28045620 ER PT J AU Agarwala, SS Lee, SJ Yip, W Rao, UN Tarhini, AA Cohen, GI Reintgen, DS Evans, TL Brell, JM Albertini, MR Atkins, MB Dakhil, SR Conry, RM Sosman, JA Flaherty, LE Sondak, VK Carson, WE Smylie, MG Pappo, AS Kefford, RF Kirkwood, JM AF Agarwala, Sanjiv S. Lee, Sandra J. Yip, Waiki Rao, Uma N. Tarhini, Ahmad A. Cohen, Gary I. Reintgen, Douglas S. Evans, Terry L. Brell, Joanna M. Albertini, Mark R. Atkins, Michael B. Dakhil, Shaker R. Conry, Robert M. Sosman, Jeffrey A. Flaherty, Lawrence E. Sondak, Vernon K. Carson, William E. Smylie, Michael G. Pappo, Alberto S. Kefford, Richard F. Kirkwood, John M. TI Phase III Randomized Study of 4 Weeks of High-Dose Interferon-alpha-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-RISK; CUTANEOUS MELANOMA; ADJUVANT THERAPY; MAINTENANCE TREATMENT; CONFIDENCE-INTERVALS; NODE METASTASES; DOUBLE-BLIND; RECURRENCE; ALPHA-2A; IPILIMUMAB AB Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN alpha-2b at 20 MU/m(2)/d IV for 5 days (Monday to Friday) every week for 4 weeks (IFN) or OBS. Stratification factors were pathologic lymph node status, lymph node staging procedure, Breslow depth, ulceration of the primary lesion, and disease stage. The primary end point was relapse-free survival. Secondary end points included overall survival, toxicity, and quality of life. Results A total of 1,150 patients were randomly assigned. At a median follow-up of 7 years, the 5-year relapse-free survival rate was 0.70 (95% CI, 0.66 to 0.74) for OBS and 0.70, (95% CI, 0.66 to 0.74) for IFN (P = .964). The 5-year overall survival rate was 0.83 (95% CI, 0.79 to 0.86) for OBS and 0.83 (95% CI, 0.80 to 0.86) for IFN (P = .558). Treatment-related grade 3 and higher toxicity was 4.6% versus 57.9% for OBS and IFN, respectively (P < .001). Quality of life was worse for the treated group. Conclusion Four weeks of IV induction as part of the Eastern Cooperative Oncology Group high-dose IFN regimen is not better than OBS alone for patients with intermediate-risk melanoma as defined in this trial. (C) 2017 by American Society of Clinical Oncology C1 [Agarwala, Sanjiv S.] St Lukes Univ Hosp, Easton, PA USA. [Rao, Uma N.; Tarhini, Ahmad A.; Evans, Terry L.; Kirkwood, John M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Lee, Sandra J.; Yip, Waiki] Dana Farber Canc Inst, ECOG ACRIN Biostat Ctr, Boston, MA 02115 USA. [Cohen, Gary I.] Greater Baltimore Med Ctr, Baltimore, MD USA. [Reintgen, Douglas S.] Lakeland Reg Canc Ctr, Lakeland, FL USA. [Sondak, Vernon K.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Brell, Joanna M.] MetroHlth Med Ctr, Cleveland, OH USA. [Carson, William E.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Albertini, Mark R.] Univ Wisconsin Hosp, Madison, WI USA. [Atkins, Michael B.] Georgetown Med Ctr, Washington, DC USA. [Dakhil, Shaker R.] Canc Ctr Kansas, Wichita, KS USA. [Conry, Robert M.] Univ Alabama Birmingham, Birmingham, AL USA. [Sosman, Jeffrey A.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Pappo, Alberto S.] St Jude Childrens Res Hosp Oncol, Memphis, TN USA. [Flaherty, Lawrence E.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Smylie, Michael G.] Cross Canc Inst, Edmonton, AB, Canada. [Kefford, Richard F.] Sydney West Area Hlth Serv, Westmead, NSW, Australia. RP Agarwala, SS (reprint author), St Lukes Canc Ctr, 1600 Riverside Circle, Easton, PA 18045 USA. EM ssagarwala0501@gmail.com FU National Cancer Institute of the National Institutes of Health [CA180820, CA21115, CA180794, CA23318, CA66636, CA180844, CA39229, CA180802]; Canadian Cancer Society Research Institute Grant [021039]; NCI of the NIH [CA16116, CA17145, CA180853, CA14548, CA180799, CA21076, CA80775, CA189808, CA35431, CA180855, CA180847, CA49957, CA180888, CA32102, CA180835, CA14028, CA73950, CA077658, CA077202, CA180886, CA180899, CA098543, CA098413] FX Supported by the National Cancer Institute of the National Institutes of Health under award Nos. CA180820, CA21115, CA180794, CA23318, CA66636, CA180844, CA39229, CA180802, CA16116, CA17145, CA180853, CA14548, CA180799, CA21076, CA80775, CA189808, CA35431, CA180855, CA180847, CA49957, CA180888, CA32102, CA180835, CA14028, CA73950, CA077658, CA077202, CA180886, CA180899, CA098543, and CA098413, and Canadian Cancer Society Research Institute Grant No.021039. 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 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 MAR 10 PY 2017 VL 35 IS 8 BP 885 EP U123 DI 10.1200/JCO.2016.70.2951 PG 11 WC Oncology SC Oncology GA EO0DF UT WOS:000396367800012 PM 28135150 ER PT J AU Armenian, SH Lacchetti, C Barac, A Carver, J Constine, LS Denduluri, N Dent, S Douglas, PS Durand, JB Ewer, M Fabian, C Hudson, M Jessup, M Jones, LW Ky, B Mayer, EL Moslehi, J Oeffinger, K Ray, K Ruddy, K Lenihan, D AF Armenian, Saro H. Lacchetti, Christina Barac, Ana Carver, Joseph Constine, Louis S. Denduluri, Neelima Dent, Susan Douglas, Pamela S. Durand, Jean-Bernard Ewer, Michael Fabian, Carol Hudson, Melissa Jessup, Mariell Jones, Lee W. Ky, Bonnie Mayer, Erica L. Moslehi, Javid Oeffinger, Kevin Ray, Katharine Ruddy, Kathryn Lenihan, Daniel TI Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC BREAST-CANCER; CONGESTIVE-HEART-FAILURE; HIGH-DOSE CHEMOTHERAPY; TRASTUZUMAB-INDUCED CARDIOTOXICITY; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; HEMATOPOIETIC-CELL TRANSPLANTATION; VENTRICULAR EJECTION FRACTION; MEDIASTINAL HODGKIN LYMPHOMA; INVOLVED-NODE RADIOTHERAPY; RANDOMIZED PHASE-III AB Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction. (C) 2016 by American Society of Clinical Oncology C1 [Lacchetti, Christina] Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. [Armenian, Saro H.] City Hope Natl Med Ctr, Duarte, CA USA. [Denduluri, Neelima] Virginia Canc Specialists, Arlington, VA USA. [Barac, Ana] Medstar Washington Hosp Ctr, Medstar Heart Inst, Washington, DC USA. [Carver, Joseph; Jessup, Mariell] Univ Penn, Philadelphia, PA 19104 USA. [Ky, Bonnie] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Constine, Louis S.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Jones, Lee W.; Oeffinger, Kevin] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Dent, Susan] Ottawa Hosp, Ctr Canc, Ottawa, ON, Canada. [Douglas, Pamela S.] Duke Univ, Durham, NC USA. [Durand, Jean-Bernard; Ewer, Michael] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Fabian, Carol] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Hudson, Melissa] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Moslehi, Javid; Lenihan, Daniel] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Ray, Katharine] Patient Representat, Nashville, TN USA. [Mayer, Erica L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ruddy, Kathryn] Mayo Clin, Rochester, MN USA. RP Armenian, SH (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org FU Genentech (Inst); Amgen (Inst); Novartis (Inst); Hoffman-La Roche (Inst); Bristol-Myers Squibb (Inst); Gilead Sciences (Inst); Edwards Lifesciences (Inst); HeartFlow (Inst); Roche (Inst); Merck (Inst); Singulex (Inst); Ibis Biosciences (Inst); GE Healthcare (Inst); DSM (Inst); National Cancer Institute; AKTIVAgainst Cancer; Memorial Sloan Kettering Cancer Center Support Grant/Core Grant [P30 CA008748]; Myriad Genetics; Pfizer; Acorda Therapeutics; Millennium Pharmaceuticals FX Amgen (Inst), Novartis (Inst), Genentech (Inst); Hoffman-La Roche (Inst); Bristol-Myers Squibb (Inst), Gilead Sciences (Inst), Edwards Lifesciences (Inst), HeartFlow (Inst), Roche (Inst), Novartis (Inst), Merck (Inst), Singulex (Inst), Ibis Biosciences (Inst), GE Healthcare (Inst); DSM (Inst); National Cancer Institute, AKTIVAgainst Cancer, and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748); Myriad Genetics, Pfizer; Acorda Therapeutics, Millennium Pharmaceuticals NR 161 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 MAR 10 PY 2017 VL 35 IS 8 BP 893 EP U144 DI 10.1200/JCO.2016.70.5400 PG 21 WC Oncology SC Oncology GA EO0DF UT WOS:000396367800013 PM 27918725 ER PT J AU Lau, MS Schwartz, MG Kundu, S Savol, AJ Wang, PI Marr, SK Grau, DJ Schorderet, P Sadreyev, RI Tabin, CJ Kingston, RE AF Lau, Mei Sheng Schwartz, Matthew G. Kundu, Sharmistha Savol, Andrej J. Wang, Peggy I. Marr, Sharon K. Grau, Daniel J. Schorderet, Patrick Sadreyev, Ruslan I. Tabin, Clifford J. Kingston, Robert E. TI Mutation of a nucleosome compaction region disrupts Polycomb-mediated axial patterning SO SCIENCE LA English DT Article ID GROUP PROTEINS; CHROMATIN; COMPLEX; PRC1; MICE; REPRESSOR AB Nucleosomes play important structural and regulatory roles by tightly wrapping the DNA that constitutes the metazoan genome. The Polycomb group (PcG) proteins modulate nucleosomes to maintain repression of key developmental genes, including Hox genes whose temporal and spatial expression is tightly regulated to guide patterning of the anterior-posterior body axis. CBX2, a component of the mammalian Polycomb repressive complex 1 (PRC1), contains a compaction region that has the biochemically defined activity of bridging adjacent nucleosomes. Here, we demonstrate that a functional compaction region is necessary for proper body patterning, because mutating this region leads to homeotic transformations similar to those observed with PcG loss-of-function mutations. We propose that CBX2-driven nucleosome compaction is a key mechanism by which PcG proteins maintain gene silencing during mouse development. C1 [Lau, Mei Sheng; Kundu, Sharmistha; Savol, Andrej J.; Wang, Peggy I.; Marr, Sharon K.; Grau, Daniel J.; Schorderet, Patrick; Sadreyev, Ruslan I.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lau, Mei Sheng; Schwartz, Matthew G.; Savol, Andrej J.; Wang, Peggy I.; Tabin, Clifford J.; Kingston, Robert E.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Sadreyev, Ruslan I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Med Sch, Boston, MA 02114 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Kingston, RE (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM kingston@molbio.mgh.harvard.edu FU Agency of Science, Research and Technology, Singapore; NIH [GM043901, HD032443, P30DK040561] FX We thank W. Press and S. Miller for guidance on mouse work; R. Mostoslavsky, J. Lee, and the R.E.K. laboratory for discussions; G. Zhou and L. Wu for advice on generating mutant mice; and J. Cochrane, S. Miller, and I. Tchasovnikarova for critical reading of the manuscript. This work was supported by the Agency of Science, Research and Technology, Singapore (M.S.L.), NIH (GM043901 to R.E.K., HD032443 to C.J.T., and P30DK040561 to R. I. S.). ChIP-seq and RNA-seq data sets are available under Gene Expression Omnibus (GEO) accession numbers GSE86085 and GSE89929. M.S.L. and R.E.K. designed the project. M.G.S. performed skeletal analyses; S. K. performed ChIP for qPCR and ChIP-seq from wild-type mESCs; S.K.M. performed mouse genotyping; D.J.G. performed chromatin remodeling assays; and M.S.L. conducted all other experiments. P.S. advised on mouse work. A. J. S., P. I. W., and R. I. S. performed bioinformatics analyses. M.S.L., M. G. S., P. S., C.J.T., and R.E.K. wrote the manuscript. NR 17 TC 0 Z9 0 U1 1 U2 1 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 MAR 10 PY 2017 VL 355 IS 6329 SI SI DI 10.1126/science.aah5403 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9VY UT WOS:000396348900046 ER PT J AU Chen, J Fan, F Wang, JY Long, Y Gao, CL Stanton, RC Xu, Y AF Chen, Jiao Fan, Fang Wang, J. Y. Long, Yang Gao, C. L. Stanton, R. C. Xu, Yong TI The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis SO SCIENTIFIC REPORTS LA English DT Article ID COTRANSPORTER 2 INHIBITION; MELLITUS; GLUCOSE; CANAGLIFLOZIN; INSULIN; EMPAGLIFLOZIN; KETOACIDOSIS; GLUCAGON; THERAPY; METFORMIN AB To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials. C1 [Chen, Jiao; Fan, Fang; Wang, J. Y.; Long, Yang; Gao, C. L.; Xu, Yong] Affiliated Hosp Southwest Med Coll, Dept Endocrinol, Luzhou 646000, Sichuan, Peoples R China. [Stanton, R. C.] Joslin Diabet Ctr, Boston, MA USA. [Stanton, R. C.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Stanton, R. C.] Harvard Med Sch, Boston, MA USA. RP Xu, Y (reprint author), Affiliated Hosp Southwest Med Coll, Dept Endocrinol, Luzhou 646000, Sichuan, Peoples R China. EM xywyll@aliyun.com NR 46 TC 0 Z9 0 U1 0 U2 0 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 MAR 9 PY 2017 VL 7 AR 44128 DI 10.1038/srep44128 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6UT UT WOS:000396139600001 PM 28276512 ER PT J AU Ferradal, SL Yuki, K Vyas, R Ha, CG Yi, F Stopp, C Wypij, D Cheng, HH Newburger, JW Kaza, AK Franceschini, MA Kussman, BD Grant, PE AF Ferradal, Silvina L. Yuki, Koichi Vyas, Rutvi Ha, Christopher G. Yi, Francesca Stopp, Christian Wypij, David Cheng, Henry H. Newburger, Jane W. Kaza, Aditya K. Franceschini, Maria A. Kussman, Barry D. Grant, P. Ellen TI Non-invasive Assessment of Cerebral Blood Flow and Oxygen Metabolism in Neonates during Hypothermic Cardiopulmonary Bypass: Feasibility and Clinical Implications SO SCIENTIFIC REPORTS LA English DT Article ID DIFFUSE CORRELATION SPECTROSCOPY; AORTIC-ARCH RECONSTRUCTION; CONGENITAL HEART-DEFECTS; INFANT CARDIAC-SURGERY; NEURODEVELOPMENTAL OUTCOMES; CIRCULATORY ARREST; BRAIN-INJURY; PERFUSION; HEMODYNAMICS; ARTERIAL AB The neonatal brain is extremely vulnerable to injury during periods of hypoxia and/or ischemia. Risk of brain injury is increased during neonatal cardiac surgery, where pre-existing hemodynamic instability and metabolic abnormalities are combined with long periods of low cerebral blood flow and/or circulatory arrest. Our understanding of events associated with cerebral hypoxia-ischemia during cardiopulmonary bypass (CPB) remains limited, largely due to inadequate tools to quantify cerebral oxygen delivery and consumption non-invasively and in real-time. This pilot study aims to evaluate cerebral blood flow (CBF) and oxygen metabolism (CMRO2) intraoperatively in neonates by combining two novel non-invasive optical techniques: frequency-domain near-infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS). CBF and CMRO2 were quantified before, during and after deep hypothermic cardiopulmonary bypass (CPB) in nine neonates. Our results show significantly decreased CBF and CMRO2 during hypothermic CPB. More interestingly, a change of coupling between both variables is observed during deep hypothermic CPB in all subjects. Our results are consistent with previous studies using invasive techniques, supporting the concept of FD-NIRS/DCS as a promising technology to monitor cerebral physiology in neonates providing the potential for individual optimization of surgical management. C1 [Ferradal, Silvina L.; Vyas, Rutvi; Ha, Christopher G.; Yi, Francesca; Grant, P. Ellen] Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Harvard Med Sch, Boston, MA 02115 USA. [Yuki, Koichi] Childrens Hosp, Harvard Med Sch, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Stopp, Christian; Wypij, David; Cheng, Henry H.; Newburger, Jane W.] Boston Childrens Hosp, Harvard Med Sch, Dept Cardiol, Boston, MA USA. [Kaza, Aditya K.] Boston Childrens Hosp, Harvard Med Sch, Dept Cardiovasc Surg, Boston, MA USA. [Franceschini, Maria A.] Massachusetts Gen Hosp, Harvard Med Sch, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Ferradal, SL (reprint author), Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Harvard Med Sch, Boston, MA 02115 USA. EM silvina.ferradal@gmail.com; ellen.grant@childrens.harvard.edu FU NIH/NICHD [R21-HD072505, R01-HD076258] FX We are grateful to the patients and families for their participation. We thank Daniel Wigmore and Erica McDavitt for assisting with recruitment. We would also like to thank Dr. Juliette Selb for her comments on the manuscript and Dr. Erin Buckley for help with analysis. This work was supported by NIH/NICHD grants R21-HD072505 (PEG) and R01-HD076258 (PEG). NR 39 TC 0 Z9 0 U1 0 U2 0 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 MAR 9 PY 2017 VL 7 AR 44117 DI 10.1038/srep44117 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6UO UT WOS:000396139100001 PM 28276534 ER PT J AU Venkatraman, A Edlow, BL Immordino-Yang, MH AF Venkatraman, Anand Edlow, Brian L. Immordino-Yang, Mary Helen TI The Brainstem in Emotion: A Review SO FRONTIERS IN NEUROANATOMY LA English DT Article DE brainstem; emotion; networks; interoception; feeling; midbrain; pons; medulla ID CORTICOTROPIN-RELEASING-FACTOR; RETICULAR ACTIVATING SYSTEM; DORSAL RAPHE NUCLEUS; PERIAQUEDUCTAL GRAY; LOCUS-COERULEUS; NORADRENERGIC MODULATION; TEGMENTAL NUCLEUS; PATHWAYS; MIDBRAIN; BEHAVIOR AB Emotions depend upon the integrated activity of neural networks that modulate arousal, autonomic function, motor control, and somatosensation. Brainstem nodes play critical roles in each of these networks, but prior studies of the neuroanatomic basis of emotion, particularly in the human neuropsychological literature, have mostly focused on the contributions of cortical rather than subcortical structures. Given the size and complexity of brainstem circuits, elucidating their structural and functional properties involves technical challenges. However, recent advances in neuroimaging have begun to accelerate research into the brainstem's role in emotion. In this review, we provide a conceptual framework for neuroscience, psychology and behavioral science researchers to study brainstem involvement in human emotions. The "emotional brainstem" is comprised of three major networks - Ascending, Descending and Modulatory. The Ascending network is composed chiefly of the spinothalamic tracts and their projections to brainstem nuclei, which transmit sensory information from the body to rostral structures. The Descending motor network is subdivided into medial projections from the reticular formation that modulate the gain of inputs impacting emotional salience, and lateral projections from the periaqueductal gray, hypothalamus and amygdala that activate characteristic emotional behaviors. Finally, the brainstem is home to a group of modulatory neurotransmitter pathways, such as those arising from the raphe nuclei (serotonergic), ventral tegmental area (dopaminergic) and locus coeruleus (noradrenergic), which form a Modulatory network that coordinates interactions between the Ascending and Descending networks. Integration of signaling within these three networks occurs at all levels of the brainstem, with progressively more complex forms of integration occurring in the hypothalamus and thalamus. These intermediary structures, in turn, provide input for the most complex integrations, which occur in the frontal, insular, cingulate and other regions of the cerebral cortex. Phylogenetically older brainstem networks inform the functioning of evolutionarily newer rostral regions, which in turn regulate and modulate the older structures. Via these bidirectional interactions, the human brainstem contributes to the evaluation of sensory information and triggers fixed-action pattern responses that together constitute the finely differentiated spectrum of possible emotions. C1 [Venkatraman, Anand] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Edlow, Brian L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Edlow, Brian L.] Harvard Med Sch, Boston, MA 02115 USA. [Immordino-Yang, Mary Helen] Univ Southern Calif, Brain & Creat Inst, Los Angeles, CA 90007 USA. [Immordino-Yang, Mary Helen] Univ Southern Calif, Rossier Sch Educ, Los Angeles, CA 90007 USA. [Immordino-Yang, Mary Helen] Univ Southern Calif, Neurosci Grad Program, Los Angeles, CA 90007 USA. RP Immordino-Yang, MH (reprint author), Univ Southern Calif, Brain & Creat Inst, Los Angeles, CA 90007 USA.; Immordino-Yang, MH (reprint author), Univ Southern Calif, Rossier Sch Educ, Los Angeles, CA 90007 USA.; Immordino-Yang, MH (reprint author), Univ Southern Calif, Neurosci Grad Program, Los Angeles, CA 90007 USA. EM immordin@usc.edu OI Venkatraman, Anand/0000-0003-4429-2271 FU NINDS [K23NS094538]; American Academy of Neurology/American Brain Foundation; James S. McDonnell Foundation FX This work was supported by the NINDS (K23NS094538), American Academy of Neurology/American Brain Foundation, and the James S. McDonnell Foundation. NR 104 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD MAR 9 PY 2017 VL 11 AR 15 DI 10.3389/fnana.2017.00015 PG 12 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA EN1SC UT WOS:000395789300001 PM 28337130 ER PT J AU Bowers, JS Nelson, MH Majchrzak, K Bailey, SR Rohrer, B Kaiser, ADM Atkinson, C Gattinoni, L Paulos, CM AF Bowers, Jacob S. Nelson, Michelle H. Majchrzak, Kinga Bailey, Stefanie R. Rohrer, Baerbel Kaiser, Andrew D. M. Atkinson, Carl Gattinoni, Luca Paulos, Chrystal M. TI Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion SO JCI INSIGHT LA English DT Article ID CD8(+) T-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; ESTABLISHED MELANOMA; CANCER-IMMUNOTHERAPY; TRANSFER THERAPY; TELOMERE LENGTH; HUMAN EFFECTOR; MEMORY CELLS AB Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8(+) T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4(+) T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR(+)) Th17 cells also retained their ability to regress human mesothelioma, while CAR(+) Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence. C1 [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Atkinson, Carl; Paulos, Chrystal M.] Med Univ South Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Paulos, Chrystal M.] Med Univ South Carolina, Dept Dermatol, Charleston, SC 29425 USA. [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Paulos, Chrystal M.] Med Univ South Carolina, Dept Surg, Charleston, SC 29425 USA. [Majchrzak, Kinga] Warsaw Univ Life Sci, Dept Physiol Sci, Fac Vet Med, Warsaw, Poland. [Rohrer, Baerbel] Med Univ South Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. [Rohrer, Baerbel] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Kaiser, Andrew D. M.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kaiser, Andrew D. M.] Miltenyi Biotec, Bergisch Gladbach, Germany. RP Bowers, JS; Paulos, CM (reprint author), Med Univ South Carolina, Hollings Canc Ctr, 86 Jonathan Lucas St,Room 606B MSC509, Charleston, SC 29425 USA. EM bowersjs@musc.edu; paulos@musc.edu FU Hollings Cell Evaluation Therapy; Hollings Cell Evaluation & Therapy, and Hollings Biostatistics Shared Resources, Hollings Cancer Center, MUSC [P30 CA138313]; NIH [F30 CA200272, T32 GM008716, F31 CA192787]; Jeane B. Kempner Foundation; ACS [122704-PF-13-084-01-LIB]; NCI [R01 CA175061, R01 CA208514]; KL2 South Carolina Clinical & Translational Research grant [UL1 TR000062]; ACS-IRG grant [016623-004]; MUSC start-up funds FX We thank Logan Huff and Hannah Knochelmann for experimental support and Kent Armeson for help in statistical analysis of this work. This research was supported in part by the Hollings Cell Evaluation & Therapy, and Hollings Biostatistics Shared Resources, Hollings Cancer Center, MUSC (P30 CA138313).; This work was supported by NIH fellowship grant F30 CA200272 and NIH training grant T32 GM008716 to J.S. Bowers, a Jeane B. Kempner Foundation grant and ACS Postdoctoral fellowship (122704-PF-13-084-01-LIB) grant to M.H. Nelson, an NIH fellowship grant F31 CA192787 to S.R. Bailey, and NCI grants R01 CA175061 and R01 CA208514, KL2 South Carolina Clinical & Translational Research grant UL1 TR000062, ACS-IRG grant 016623-004, and MUSC start-up funds to C.M. Paulos. NR 57 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 9 PY 2017 VL 2 IS 5 AR e90772 DI 10.1172/jci.insight.90772 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5FA UT WOS:000396029800010 PM 28289713 ER PT J AU Guillermier, C Fazeli, PK Kim, S Lun, M Zuflacht, JP Milian, J Lee, H Francois-Saint-Cyr, H Horreard, F Larson, D Rosen, ED Lee, RT Lechene, CP Steinhauser, ML AF Guillermier, Christelle Fazeli, Pouneh K. Kim, Soomin Lun, Mingyue Zuflacht, Jonah P. Milian, Jessica Lee, Hang Francois-Saint-Cyr, Hugues Horreard, Francois Larson, David Rosen, Evan D. Lee, Richard T. Lechene, Claude P. Steinhauser, Matthew L. TI Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity SO JCI INSIGHT LA English DT Article ID GROWTH-FACTOR-I; IMPROVES GLYCEMIC CONTROL; INSULIN SENSITIVITY; ADIPOCYTE DIFFERENTIATION; VIVO MEASUREMENT; TURNOVER; TISSUE; DYNAMICS; HOMEOSTASIS; CELLS AB Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-isotope imaging mass spectrometry. In a first-in-human study, we utilize stable isotope tracers of DNA synthesis and de novo lipogenesis to prospectively measure cell birth and adipocyte lipid turnover. In a study of healthy adults, we elucidate an age-dependent decline in new adipocyte generation and adipocyte lipid turnover. A linear regression model suggests that the aging effect could be mediated by a decline in insulin-like growth factor-1 (IGF-1). This study therefore establishes a method for measurement of cell turnover and metabolism in humans with subcellular resolution while implicating the growth hormone/IGF-1 axis in adipose tissue aging. C1 [Guillermier, Christelle; Kim, Soomin; Lun, Mingyue; Lechene, Claude P.; Steinhauser, Matthew L.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Guillermier, Christelle; Lechene, Claude P.; Steinhauser, Matthew L.] Brigham & Womens Hosp, Ctr NanoImaging, Cambridge, MA USA. [Guillermier, Christelle; Fazeli, Pouneh K.; Lee, Hang; Rosen, Evan D.; Lee, Richard T.; Lechene, Claude P.; Steinhauser, Matthew L.] Harvard Med Sch, Boston, MA USA. [Fazeli, Pouneh K.; Lee, Richard T.] Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. [Zuflacht, Jonah P.; Milian, Jessica; Steinhauser, Matthew L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Francois-Saint-Cyr, Hugues; Larson, David] CAMECA, Madison, WI USA. [Horreard, Francois] Cameca SA, Gennevilliers, France. [Rosen, Evan D.] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, Boston, MA 02215 USA. [Rosen, Evan D.; Lee, Richard T.; Steinhauser, Matthew L.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Lee, Richard T.; Steinhauser, Matthew L.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Lee, Richard T.] Harvard Univ, Dept Stem Cell & Regenerat Med, Cambridge, MA 02138 USA. RP Steinhauser, ML (reprint author), 77 Ave Louis Pasteur,New Res Bldg,Room 458, Boston, MA 02115 USA. EM msteinhauser@partners.org FU Harvard Catalyst [NCATS/NIH UL1 TR001102]; Harvard Stem Cell Institute; Brigham and Women's Hospital Funds FX We thank CAMECA and F. Hillion for providing usage of a NanoSIMS instrument, which was used for the development of analytical strategies utilized in this study. We thank T. Perlstein for assistance with the human protocols. This work was funded by resources from the clinical research center and by a pilot grant (to EDR, RTL, CPL, and MLS) both from the Harvard Catalyst (NCATS/NIH UL1 TR001102 to EDR, RTL, CPL, and MLS), the Harvard Stem Cell Institute (to MLS), and Brigham and Women's Hospital Funds (to MLS). NR 41 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 9 PY 2017 VL 2 IS 5 AR e90349 DI 10.1172/jci.insight.90349 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5FA UT WOS:000396029800006 PM 28289709 ER PT J AU Solomon, GM Francis, R Chu, KK Birket, SE Gabriel, G Trombley, JE Lemke, KL Klena, N Turner, B Tearney, GJ Lo, CW Rowe, SM AF Solomon, George M. Francis, Richard Chu, Kengyeh K. Birket, Susan E. Gabriel, George Trombley, John E. Lemke, Kristi L. Klena, Nikolai Turner, Brett Tearney, Guillermo J. Lo, Cecilia W. Rowe, Steven M. TI Assessment of ciliary phenotype in primary ciliary dyskinesia by micro-optical coherence tomography SO JCI INSIGHT LA English DT Article ID CONGENITAL HEART-DISEASE; INNER DYNEIN ARMS; BEAT PATTERN; AIRWAY; MOTILITY; ORIENTATION; DYSFUNCTION; CLEARANCE; MUTATIONS; CHILDREN AB Ciliary motion defects cause defective mucociliary transport (MCT) in primary ciliary dyskinesia (PCD). Current diagnostic tests do not assess how MCT is affected by perturbation of ciliary motion. In this study, we sought to use micro-optical coherence tomography (mu OCT) to delineate the mechanistic basis of cilia motion defects of PCD genes by functional categorization of cilia motion. Tracheae from three PCD mouse models were analyzed using mu OCT to characterize ciliary motion and measure MCT. We developed multiple measures of ciliary activity, integrated these measures, and quantified dyskinesia by the angular range of the cilia effective stroke (ARC). Ccdc39(-/-) mice, with a known severe PCD mutation of ciliary axonemal organization, had absent motile ciliary regions, resulting in abrogated MCT. In contrast, Dnah5(-)/(-) mice, with a missense mutation of the outer dynein arms, had reduced ciliary beat frequency (CBF) but preserved motile area and ciliary stroke, maintaining some MCT. Wdr69(-/-) PCD mice exhibited normal motile area and CBF and partially delayed MCT due to abnormalities of ciliary ARC. Visualization of ciliary motion using mu OCT provides quantitative assessment of ciliary motion and MCT. Comprehensive ciliary motion investigation in situ classifies ciliary motion defects and quantifies their contribution to delayed mucociliary clearance. C1 [Solomon, George M.; Birket, Susan E.; Trombley, John E.; Turner, Brett; Rowe, Steven M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Solomon, George M.; Birket, Susan E.; Trombley, John E.; Turner, Brett; Rowe, Steven M.] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA. [Francis, Richard; Gabriel, George; Lemke, Kristi L.; Klena, Nikolai; Lo, Cecilia W.] Univ Pittsburgh, Pittsburgh, PA USA. [Chu, Kengyeh K.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chu, Kengyeh K.; Tearney, Guillermo J.] Wellman Ctr Photomed, Boston, MA 02114 USA. RP Rowe, SM (reprint author), MCLM 706 1918 Univ Blvd, Birmingham, AL 35294 USA. EM smrowe@uab.edu FU NIH [P30 DK072482, HL1116213, HL098180, GM104412]; Cystic Fibrosis Foundation [CLANCY09Y0, SORSCH15RO]; Mucociliary Clearance Consortium - Cystic Fibrosis Foundation Therapeutics FX This work is supported by grants from the NIH (P30 DK072482 to SMR, HL1116213 to SMR and GJT, and HL098180 and GM104412 to CWL), the Cystic Fibrosis Foundation (CLANCY09Y0 to GMS and SORSCH15RO to GMS), and the Mucociliary Clearance Consortium (to SMR and GJT) funded by Cystic Fibrosis Foundation Therapeutics. NR 44 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 9 PY 2017 VL 2 IS 5 AR e91702 DI 10.1172/jci.insight.91702 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5FA UT WOS:000396029800016 PM 28289722 ER PT J AU Saez, B Walter, MJ Graubert, TA AF Saez, Borja Walter, Matthew J. Graubert, Timothy A. TI Splicing factor gene mutations in hematologic malignancies SO BLOOD LA English DT Review ID PRE-MESSENGER-RNA; CHRONIC LYMPHOCYTIC-LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; RING SIDEROBLASTS; SF3B1 MUTATIONS; SRSF2 MUTATIONS; SOMATIC MUTATIONS; U2AF1 MUTATIONS AB Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. C1 [Saez, Borja; Graubert, Timothy A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Saez, Borja] Univ Navarra, Ctr Appl Med Res, Navarra, Spain. [Walter, Matthew J.] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. RP Graubert, TA (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA.; Walter, MJ (reprint author), Washington Univ, Sch Med, 660 S Euclid Ave,Campus Box 8007, St Louis, MO 63110 USA. EM mjwalter@wustl.edu; tgraubert@partners.org FU National Institutes of Health/National Cancer Institute SPORE in Leukemia [P50CA171963]; Edward P. Evans Foundation; Lottie Caroline Hardy Trust; Leukemia and Lymphoma Society Scholar Award FX This work was support by a National Institutes of Health/National Cancer Institute SPORE in Leukemia (P50CA171963) (T.A.G. and M.J.W.), the Edward P. Evans Foundation (M.J.W. and T.A.G.), the Lottie Caroline Hardy Trust (T.A.G. and M.J.W.), and a Leukemia and Lymphoma Society Scholar Award (M.J.W.). NR 115 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 MAR 9 PY 2017 VL 129 IS 10 BP 1260 EP 1269 DI 10.1182/blood-2016-10-692400 PG 10 WC Hematology SC Hematology GA EP3OW UT WOS:000397292600010 PM 27940478 ER PT J AU Hideshima, T Cottini, F Nozawa, Y Seo, HS Ohguchi, H Samur, MK Cirstea, D Mimura, N Iwasawa, Y Richardson, PG Munshi, NC Chauhan, D Massefski, W Utsugi, T Dhe-Paganon, S Anderson, KC AF Hideshima, Teru Cottini, Francesca Nozawa, Yoshihisa Seo, Hyuk-Soo Ohguchi, Hiroto Samur, Mehmet K. Cirstea, Diana Mimura, Naoya Iwasawa, Yoshikazu Richardson, Paul G. Munshi, Nikhil C. Chauhan, Dharminder Massefski, Walter Utsugi, Teruhiro Dhe-Paganon, Sirano Anderson, Kenneth C. TI p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma SO BLOOD LA English DT Article ID LENALIDOMIDE PLUS DEXAMETHASONE; DNA-DAMAGE; THALIDOMIDE ANALOGS; DOSE DEXAMETHASONE; T-CELLS; P53; PHOSPHORYLATION; POMALIDOMIDE; APOPTOSIS; CEREBLON AB p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase that phosphorylates (serine residue Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in multiple myeloma (MM) patients, and, conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers MM cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of proapoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient and p53-mutant MM cell lines and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin-dependent kinase inhibitor 2C. Our previous studies showed that immunomodulatory drugs (IMiDs) downregulate p21 and trigger apoptosis in wild-typep53 MM. 1S cells, Importantly, we demonstrate by pull-down, nuclear magnetic resonance spectroscopy, differential scanning fluorimetry, and isothermal titration calorimetry that IMiDs bind and inhibit TP53RK, with biologic sequelae similar to TP53RK knockdown. Our studies therefore demonstrate that either genetic or pharmacological inhibition of TP53RK triggers MM cell apoptosis via both p53-Myc axisdependent and axis-independent pathways, validating TP53RK as a novel therapeutic target in patients with poor-prognosis MM. (Blood. 2017;129(10):1308-1319) C1 [Hideshima, Teru; Cottini, Francesca; Ohguchi, Hiroto; Cirstea, Diana; Mimura, Naoya; Richardson, Paul G.; Munshi, Nikhil C.; Chauhan, Dharminder; Anderson, Kenneth C.] Harvard Med Sch, Jerome Lipper Multiple Myeloma Ctr, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 2 USA. [Nozawa, Yoshihisa; Iwasawa, Yoshikazu; Utsugi, Teruhiro] Taisho Pharmaceut Co Ltd, Discovery & Preclin Res Div, Tsukuba, Ibaraki, Japan. [Seo, Hyuk-Soo; Massefski, Walter; Dhe-Paganon, Sirano] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. [Seo, Hyuk-Soo; Dhe-Paganon, Sirano] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Samur, Mehmet K.] Dana Farber Canc Inst, Dept Biostatist & Computat Biol, Boston, MA USA. [Samur, Mehmet K.] Harvard Sch Publ Hlth, Boston, MA USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM anderson@dfci.harvard.edu FU National Institutes of Health, Specialized Programs of Research Excellence [P50100707]; National Institutes of Health, National Cancer Institute [P01-CA078378, R01-CA050947, R01CA178264]; American Cancer Society Clinical Research Professor FX This study was supported by grants from the National Institutes of Health, Specialized Programs of Research Excellence-P50100707 (K.C.A.) and the National Institutes of Health, National Cancer Institute (P01-CA078378 and R01-CA050947) (K.C.A.) (R01CA178264) (T.H.and K.C.A.).K.C.A.is an American Cancer Society Clinical Research Professor. NR 50 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 MAR 9 PY 2017 VL 129 IS 10 BP 1308 EP 1319 DI 10.1182/blood-2016-09-738500 PG 12 WC Hematology SC Hematology GA EP3OW UT WOS:000397292600015 PM 28082445 ER PT J AU Merryman, RW Kim, HT Zinzani, PL Carlo-Stella, C Ansell, SM Perales, MA Avigdor, A Halwani, AS Houot, R Marchand, T Dhedin, N Lescaut, W Thiebaut-Bertrand, A Francois, S Stamatoullas-Bastard, A Rohrlich, PS Wallet, HL Castagna, L Santoro, A Bachanova, V Bresler, SC Srivastava, A Kim, H Pesek, E Chammas, M Reynolds, C Ho, VT Antin, JH Ritz, J Soiffer, RJ Armand, P AF Merryman, Reid W. Kim, Haesook T. Zinzani, Pier Luigi Carlo-Stella, Carmelo Ansell, Stephen M. Perales, Miguel-Angel Avigdor, Abraham Halwani, Ahmad S. Houot, Roch Marchand, Tony Dhedin, Nathalie Lescaut, Willy Thiebaut-Bertrand, Anne Francois, Sylvie Stamatoullas-Bastard, Aspasia Rohrlich, Pierre-Simon Wallet, Helene Labussiere Castagna, Luca Santoro, Armando Bachanova, Veronika Bresler, Scott C. Srivastava, Amitabh Kim, Harim Pesek, Emily Chammas, Marie Reynolds, Carol Ho, Vincent T. Antin, Joseph H. Ritz, Jerome Soiffer, Robert J. Armand, Philippe TI Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; REFRACTORY HODGKINS LYMPHOMA; T-CELLS; MARROW TRANSPLANTATION; PROGRAMMED DEATH-1; UNRELATED DONORS; EUROPEAN GROUP; WORKING PARTY; BLOOD; LETHALITY AB Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1(+) T cells and decreased ratios of T-regulatory cells to conventionalCD4 andCD8 T cells. In conclusion, HSCTafter PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade. C1 [Merryman, Reid W.; Pesek, Emily; Chammas, Marie; Reynolds, Carol; Ho, Vincent T.; Antin, Joseph H.; Ritz, Jerome; Soiffer, Robert J.; Armand, Philippe] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. [Merryman, Reid W.; Pesek, Emily; Chammas, Marie; Reynolds, Carol; Ho, Vincent T.; Antin, Joseph H.; Ritz, Jerome; Soiffer, Robert J.; Armand, Philippe] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Zinzani, Pier Luigi] Univ Bologna, Inst Hematol LeA Seragnoli, Bologna, Italy. [Carlo-Stella, Carmelo; Castagna, Luca; Santoro, Armando] Humanitas Clin & Res Ctr, Milan, Italy. [Carlo-Stella, Carmelo; Castagna, Luca; Santoro, Armando] Univ Milan, Dept Hematol & Oncol, Milan, Italy. [Ansell, Stephen M.] Mayo Clin, Rochester, MN USA. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Adult Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Avigdor, Abraham] Chaim Sheba Med Ctr, Div Hematol & Bone Marrow Transplantat, Tel Hashomer, Israel. [Halwani, Ahmad S.] Huntsman Canc Inst, Salt Lake City, UT USA. [Houot, Roch; Marchand, Tony] Ctr Hosp Univ CHU Rennes, Serv Hematol Clin, Rennes, France. [Houot, Roch] INSERM, Rennes, France. [Dhedin, Nathalie] Hop St Louis, AP HP, Serv Hematol Adolescents & Jeunes Adultes, Paris, France. [Lescaut, Willy] Ctr Hosp Princesse Grace, Serv Med Interne & Oncohematol, Monaco, Monaco. [Thiebaut-Bertrand, Anne] CHU Grenoble, Clin Univ Hematol, Grenoble, France. [Francois, Sylvie] CHU Angers, Serv Malad Sang, Angers, France. [Thiebaut-Bertrand, Anne] Ctr Henri Becquerel, Serv Hematol Clin, Rouen, France. [Rohrlich, Pierre-Simon] CHU Nice, Serv Hematol & Oncohematol Pediat, Nice, France. [Wallet, Helene Labussiere] Hosp Civils Lyon, Serv Hematol Clin, Lyon, France. [Bachanova, Veronika] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Bresler, Scott C.; Srivastava, Amitabh] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Kim, Harim] Seoul Natl Univ, Univ Coll Med, Seoul, South Korea. RP Armand, P (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org FU Harold and Virginia Lash/David Lash Fund for Lymphoma Research; Italian Association for Cancer Research [15835]; Ted and Eileen Pasquarello Fund; Leukemia Research Fund in Leukemia and Transplantation; National Institutes of Health, National Cancer Institute [R01CA183559, R01CA183560] FX This study was supported in part by research funding from the Harold and Virginia Lash/ David Lash Fund for Lymphoma Research (P.A.), by the Italian Association for Cancer Research (grant 15835) (C.C.- S.), by the Ted and Eileen Pasquarello Fund: Leukemia Research Fund in Leukemia and Transplantation (R.J.S.), and by the National Institutes of Health, National Cancer Institute grants (R01CA183559 and R01CA183560) (R.J.S.and J.R.). NR 37 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 MAR 9 PY 2017 VL 129 IS 10 BP 1380 EP 1388 DI 10.1182/blood-2016-09-738385 PG 9 WC Hematology SC Hematology GA EP3OW UT WOS:000397292600021 PM 28073785 ER PT J AU Gansner, JM Leung, AD Superdock, M Blair, MC Ammerman, MB Durand, EM Barut, B Handin, RI Stachura, DL Lu, CF Springer, TA Zon, LI AF Gansner, John M. Leung, Alexander D. Superdock, Michael Blair, Megan C. Ammerman, Michelle B. Durand, Ellen M. Barut, Bruce Handin, Robert I. Stachura, David L. Lu, Chafen Springer, Timothy A. Zon, Leonard I. TI Sorting zebrafish thrombocyte lineage cells with a Cd41 monoclonal antibody enriches hematopoietic stem cell activity SO BLOOD LA English DT Letter ID GLANZMANN THROMBASTHENIA; ENGRAFTMENT C1 [Gansner, John M.; Handin, Robert I.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA USA. [Leung, Alexander D.] Univ Wisconsin, Sch Med & Publ Hlth, Div Vasc Surg, Madison, WI USA. [Superdock, Michael; Blair, Megan C.; Ammerman, Michelle B.; Durand, Ellen M.; Barut, Bruce] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Barut, Bruce] Howard Hughes Med Inst, Boston, MA 02115 USA. [Stachura, David L.] Calif State Univ Chico, Dept Biol Sci, Chico, CA 95929 USA. [Lu, Chafen; Springer, Timothy A.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Lu, Chafen; Springer, Timothy A.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Zon, Leonard I.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Zon, Leonard I.] Harvard Med Sch, Howard Hughes Med Inst, Stem Cell Program, Boston, MA USA. [Zon, Leonard I.] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. RP Zon, LI (reprint author), Boston Childrens Hosp, Karp Res Bldg,7th Floor,300 Longwood Ave, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI) [R01HL048801, P01HL32262-32, U01HL100001-05, T32HL116324-03]; NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [P30DK49216, R24DK092760, K01DK087814-01A1]; T32 training grants from the NIH; National Cancer Institute [T32CA009172-39]; NIH, NIDDK [K01DK087814-01A1] FX This work was supported in part by funding from the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI; grants R01HL048801, P01HL32262-32, and U01HL100001-05) and NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grants P30DK49216 and R24DK092760) (L.I.Z.); T32 training grants from the NIH, National Cancer Institute (grant T32CA009172-39) and the NIH, NHLBI (grant T32HL116324-03) (J.M.G.); and the NIH, NIDDK (grant K01DK087814-01A1) (D.L.S.). NR 12 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 MAR 9 PY 2017 VL 129 IS 10 BP 1394 EP 1397 DI 10.1182/blood-2016-12-759993 PG 4 WC Hematology SC Hematology GA EP3OW UT WOS:000397292600023 PM 28126924 ER PT J AU Lu, WQ Yao, X Ouyang, P Dong, NN Wu, D Jiang, XW Wu, ZR Zhang, C Xu, ZY Tang, Y Zou, SE Liu, MY Li, J Zeng, MH Lin, P Cheng, FX Huang, J AF Lu, Weiqiang Yao, Xue Ouyang, Ping Dong, Ningnin Wu, Dang Jiang, Xingwu Wu, Zengrui Zhang, Chen Xu, Zhongyu Tang, Yun Zou, Shien Liu, Mingyao Li, Jian Zeng, Minghua Lin, Ping Cheng, Feixiong Huang, Jin TI Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURES; A(4) HYDROLASE; RECRUITMENT; POTENT; 5-LIPOXYGENASE; CHEMOTAXIS; VORINOSTAT; ACTIVATION; NINTEDANIB; EFFICACY AB Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both Land 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with wellknown clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis. C1 [Lu, Weiqiang; Yao, Xue; Ouyang, Ping; Dong, Ningnin; Wu, Dang; Wu, Zengrui; Zhang, Chen; Xu, Zhongyu; Tang, Yun; Li, Jian; Huang, Jin] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China. [Lu, Weiqiang; Jiang, Xingwu; Liu, Mingyao] East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. [Lu, Weiqiang; Jiang, Xingwu; Liu, Mingyao] East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Zou, Shien] Fudan Univ, Obstet & Gynecol Hosp, Dept Gynecol, Shanghai 200011, Peoples R China. [Zeng, Minghua] Guangxi Normal Univ, Sch Chem & Chem Engn, Minist Educ, Key Lab Chem & Mol Engn Med Resources, Guilin 541004, Peoples R China. [Lin, Ping; Cheng, Feixiong] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China. [Lin, Ping; Cheng, Feixiong] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China. [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Cheng, Feixiong] Harvard Med Sch, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Cheng, Feixiong] Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Huang, J (reprint author), East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China.; Cheng, FX (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China.; Cheng, FX (reprint author), Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China.; Cheng, FX (reprint author), Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA.; Cheng, FX (reprint author), Harvard Med Sch, Ctr Canc Syst Biol, Boston, MA 02215 USA.; Cheng, FX (reprint author), Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02215 USA. EM fxcheng1985@gmail.com; huangjin@ecust.edu.cn FU National Natural Science Foundation of China [81402482, 21222211, 91313303, 81573020]; Shanghai Committee of Science and Technology [14ZR1411100, 15431902000]; China Postdoctoral Science Foundation [2014M551361, 2015T80415]; BAGUI scholar program [2014A001]; Guangxi Committee of Science and Technology [2014GXNSFFA118003]; Project of Talents Highland of Guangxi Province FX We thank Michaela S. Fooksa and Prof. Donald H. Rubin at Vanderbilt University School of Medicine for improving the English of the manuscript. We thank the staff at SSRF beamline BL17U for assistance with data collection. We thank Prof. Colin D. Funk (Department of Biochemistry, Queen's University, Canada) for pCDNA3-5-LOX, pCDNA3-p-12LOX, and pCDNA3-15-LOX-1 and Prof. Marcia E. Newcomer (Department of Biological Sciences, Louisiana State University) for stable 5 -LOX. Supported by grants from the National Natural Science Foundation of China (grants 81402482, 21222211, 91313303, 81573020), the Shanghai Committee of Science and Technology (grants 14ZR1411100, 15431902000), China Postdoctoral Science Foundation grant (2014M551361, 2015T80415), BAGUI scholar program (2014A001), Guangxi Committee of Science and Technology (2014GXNSFFA118003), and the Project of Talents Highland of Guangxi Province. NR 44 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAR 9 PY 2017 VL 60 IS 5 BP 1817 EP 1828 DI 10.1021/acs.jrnedchem.6b01507 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EN9BQ UT WOS:000396296100014 PM 28218840 ER PT J AU Kim, AR Ulirsch, JC Wilmes, S Unal, E Moraga, I Karakukcu, M Yuan, D Kazerounian, S Abdulhay, NJ King, DS Gupta, N Gabriel, SB Lander, ES Patiroglu, T Ozcan, A Ozdemir, MA Garcia, KC Piehler, J Gazda, HT Klein, DE Sankaran, VG AF Kim, Ah Ram Ulirsch, Jacob C. Wilmes, Stephan Unal, Ekrem Moraga, Ignacio Karakukcu, Musa Yuan, Daniel Kazerounian, Shideh Abdulhay, Nour J. King, David S. Gupta, Namrata Gabriel, Stacey B. Lander, Eric S. Patiroglu, Turkan Ozcan, Alper Ozdemir, Mehmet Akif Garcia, K. Christopher Piehler, Jacob Gazda, Hanna T. Klein, Daryl E. Sankaran, Vijay G. TI Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation SO CELL LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; MYELOPROLIFERATIVE NEOPLASMS; GENETIC-VARIATION; ERYTHROPOIETIN RECEPTOR; BIASED AGONISM; TYROSINE; IDENTIFICATION; PHOSPHATASE; INHIBITOR; PROTEINS AB Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies. C1 [Kim, Ah Ram; Ulirsch, Jacob C.; Abdulhay, Nour J.; Sankaran, Vijay G.] Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Boston, MA 02115 USA. [Kim, Ah Ram; Ulirsch, Jacob C.; Abdulhay, Nour J.; Sankaran, Vijay G.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kim, Ah Ram; Ulirsch, Jacob C.; Abdulhay, Nour J.; Gupta, Namrata; Gabriel, Stacey B.; Lander, Eric S.; Gazda, Hanna T.; Sankaran, Vijay G.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Wilmes, Stephan; Piehler, Jacob] Univ Osnabruck, Dept Biol, Div Biophys, D-49076 Osnabruck, Germany. [Unal, Ekrem; Karakukcu, Musa; Patiroglu, Turkan; Ozcan, Alper; Ozdemir, Mehmet Akif] Erciyes Univ, Fac Med, Div Pediat Hematol & Oncol, Dept Pediat, TR-38039 Kayseri, Turkey. [Moraga, Ignacio; Garcia, K. Christopher] Stanford Univ, Howard Hughes Med Inst, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Yuan, Daniel; Kazerounian, Shideh; Gazda, Hanna T.] Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA. [King, David S.] Univ Calif Berkeley, Howard Hughes Med Inst, Mass Spectrometry Lab, Berkeley, CA 94720 USA. [Klein, Daryl E.] Yale Univ, Sch Med, Dept Pharmacol, Canc Biol Inst, West Haven, CT 06516 USA. RP Sankaran, VG (reprint author), Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Klein, DE (reprint author), Yale Univ, Sch Med, Dept Pharmacol, Canc Biol Inst, West Haven, CT 06516 USA. EM daryl.klein@yale.edu; sankaran@broadinstitute.org FU NIH [R01DK103794, R33HL120791, R01HL107558, K02HL111156, U54HG003067] FX We are grateful to the family described in this paper for their willingness to participate in this study. We thank M. Lemmon, S. Harrison, H. Lodish, F. Bunn, J. Casanova, D. Nathan, S. Orkin, D. Ginsburg, and members of the Sankaran laboratory for valuable comments and advice on this work. We thank S. Ozcan for assistance with aspirate imaging. This work was funded by NIH grants R01DK103794 and R33HL120791 (V.G.S.), R01HL107558 and K02HL111156 (H.T.G), and U54HG003067 (S.B.G. and E.S.L.). NR 62 TC 0 Z9 0 U1 3 U2 3 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 MAR 9 PY 2017 VL 168 IS 6 BP 1053 EP + DI 10.1016/j.cell.2017.02.026 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8ZF UT WOS:000396287900013 PM 28283061 ER PT J AU Drane, P Brault, ME Cui, GF Meghani, K Chaubey, S Detappe, A Parnandi, N He, YZ Zheng, XF Botuyan, MV Kalousi, A Yewdell, WT Munch, C Harper, JW Chaudhuri, J Soutoglou, E Mer, G Chowdhury, D AF Drane, Pascal Brault, Marie-Eve Cui, Gaofeng Meghani, Khyati Chaubey, Shweta Detappe, Alexandre Parnandi, Nishita He, Yizhou Zheng, Xiao-Feng Botuyan, Maria Victoria Kalousi, Alkmini Yewdell, William T. Muench, Christian Harper, J. Wade Chaudhuri, Jayanta Soutoglou, Evi Mer, Georges Chowdhury, Dipanjan TI TIRR regulates 53BP1 by masking its histone methyl-lysine binding function SO NATURE LA English DT Article ID CLASS-SWITCH RECOMBINATION; DNA-DAMAGE-RESPONSE; STRAND BREAK REPAIR; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; CYTOPLASMIC DOMAIN; END RESECTION; PROTEIN; SITES; RECRUITMENT AB P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1. C1 [Drane, Pascal; Brault, Marie-Eve; Meghani, Khyati; Chaubey, Shweta; Detappe, Alexandre; Parnandi, Nishita; He, Yizhou; Zheng, Xiao-Feng; Chowdhury, Dipanjan] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Cui, Gaofeng; Botuyan, Maria Victoria; Mer, Georges] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Kalousi, Alkmini; Soutoglou, Evi] IGBMC, F-67404 Illkirch Graffenstaden, France. [Yewdell, William T.; Chaudhuri, Jayanta] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Grad Sch, Immunol Program, New York, NY 10065 USA. [Muench, Christian; Harper, J. Wade] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Chaudhuri, Jayanta] Weill Cornell Med Sch, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA. [Chowdhury, Dipanjan] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Chowdhury, Dipanjan] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Muench, Christian] Goethe Univ, Sch Med, Inst Biochem 2, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. RP Chowdhury, D (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA.; Chowdhury, D (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Chowdhury, D (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM dipanjan_chowdhury@dfci.harvard.edu FU National Institute of Allergy and Infectious Diseases [R01 AI101897-01]; National Cancer Institute [R01CA142698-07, 4T32CA009149-40]; Leukemia and Lymphoma Society Scholar Grant; Claudia Adams Barr Program for Innovative Cancer Research; Department of Defense Ovarian Cancer Award; Breast SPORE Pilot Award; Robert and Deborah First Fund Award; National Institutes of Health [R01 CA132878, R01 GM116829]; Mayo Clinic Brain Cancer SPORE Program Pilot Award [P50 CA108961]; National Institutes of Health/National Institute of Allergy and Infectious Disease grants [1RO1AI072194, 1RO1AI124186]; National Cancer Institute Cancer Center Support grant [P30CA008748]; [AG011085] FX We are grateful to L. Xu for RIF1 antibody and S. Boulton for RIF1-/- MEFs. D.C. is supported by R01 AI101897-01 (National Institute of Allergy and Infectious Diseases) and R01CA142698-07 (National Cancer Institute), a Leukemia and Lymphoma Society Scholar Grant, the Claudia Adams Barr Program for Innovative Cancer Research, a Department of Defense Ovarian Cancer Award, a Breast SPORE Pilot Award, and a Robert and Deborah First Fund Award. G.M. is supported by National Institutes of Health grants R01 CA132878 and R01 GM116829, and a Mayo Clinic Brain Cancer SPORE Program Pilot Award (P50 CA108961). J.W.H. is supported by AG011085. J.C. is supported by National Institutes of Health/National Institute of Allergy and Infectious Disease grants (1RO1AI072194 and 1RO1AI124186) and a National Cancer Institute Cancer Center Support grant (P30CA008748). W.T.Y. is supported by a training grant from the National Cancer Institute (4T32CA009149-40). NR 51 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 211 EP + DI 10.1038/nature21358 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700032 PM 28241136 ER PT J AU Pan, YD Tian, T Park, CO Lofftus, SY Mei, SL Liu, X Luo, C O'Malley, JT Gehad, A Teague, JE Divito, SJ Fuhlbrigge, R Puigserver, P Krueger, JG Hotamisligil, GS Clark, RA Kupper, TS AF Pan, Youdong Tian, Tian Park, Chang Ook Lofftus, Serena Y. Mei, Shenglin Liu, Xing Luo, Chi O'Malley, John T. Gehad, Ahmed Teague, Jessica E. Divito, Sherrie J. Fuhlbrigge, Robert Puigserver, Pere Krueger, James G. Hotamisligil, Goekhan S. Clark, Rachael A. Kupper, Thomas S. TI Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism SO NATURE LA English DT Article ID FATTY-ACID OXIDATION; SKIN; IMMUNITY; INFECTION; IMMUNIZATION; RESPONSES; TRIGGER; VIRUS; IL-15 AB Tissue-resident memory T (T-RM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens(1-4). However, the biological pathways that enable the long-term survival of T-RM cells are obscure(4,5). Here we show that mouse CD8(+) T-RM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8(+) T-RM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T-CM) cells in lymph nodes. In vitro, CD8(+) T-RM cells, but not CD8(+) T-CM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8(+) T-RM cells. The persistence of CD8(+) T-RM cells in the skin was strongly diminished by inhibition of mitochondrial FFA beta-oxidation in vivo. Moreover, skin CD8(+) T-RM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8(+) T-RM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8(+) T-RM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8(+) T-RM cells, and suggest that CD8(+) T-RM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity. C1 [Pan, Youdong; Tian, Tian; Park, Chang Ook; Lofftus, Serena Y.; O'Malley, John T.; Gehad, Ahmed; Teague, Jessica E.; Divito, Sherrie J.; Fuhlbrigge, Robert; Clark, Rachael A.; Kupper, Thomas S.] Harvard Med Sch Boston, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Pan, Youdong; Tian, Tian; Park, Chang Ook; Lofftus, Serena Y.; Mei, Shenglin; O'Malley, John T.; Gehad, Ahmed; Teague, Jessica E.; Divito, Sherrie J.; Fuhlbrigge, Robert; Clark, Rachael A.; Kupper, Thomas S.] Harvard Med Sch, Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Boston, MA 02115 USA. [Mei, Shenglin] Dana Farber Canc Inst, Ctr Funct Epigenet, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Xing] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Program Cellular & Mol Med, Boston, MA USA. [Luo, Chi; Puigserver, Pere] Harvard Med Sch, Dana Farber Canc Inst, Dept Cell Biol, Dept Canc Biol, Boston, MA USA. [Krueger, James G.] Rockefeller Univ, Dept Dermatol, New York, NY USA. [Hotamisligil, Goekhan S.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Clark, Rachael A.; Kupper, Thomas S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. RP Kupper, TS (reprint author), Harvard Med Sch Boston, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA.; Kupper, TS (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Boston, MA 02115 USA.; Kupper, TS (reprint author), Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. EM tkupper@bwh.harvard.edu FU NIH [R01AI041707, R01AI127654, TR01AI097128, R01AR063962]; Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI14C1799] FX We thank B. Moss (US National Institute of Health (NIH)) for providing rVACV expressing the OT-I T cell epitope OVA257-264, as well as WR-VACV. This work was supported by NIH grants R01AI041707 (T.S.K.), R01AI127654 (T.S.K.), TR01AI097128 (T.S.K. and R.A.C.) and R01AR063962 (R.A.C.). C.O.P. was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1799). NR 30 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 252 EP + DI 10.1038/nature21379 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700041 PM 28219080 ER PT J AU Wan, LL Wen, H Li, YY Lyu, J Xi, YX Hoshii, T Joseph, JK Wang, XL Loh, YHE Erb, MA Souza, AL Bradner, JE Shen, L Li, W Li, HT Allis, CD Armstrong, SA Shi, XB AF Wan, Liling Wen, Hong Li, Yuanyuan Lyu, Jie Xi, Yuanxin Hoshii, Takayuki Joseph, Julia K. Wang, Xiaolu Loh, Yong-Hwee E. Erb, Michael A. Souza, Amanda L. Bradner, James E. Shen, Li Li, Wei Li, Haitao Allis, C. David Armstrong, Scott A. Shi, Xiaobing TI ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia SO NATURE LA English DT Article ID RNA-POLYMERASE-II; MLL-REARRANGED LEUKEMIA; ELONGATION COMPLEX; TRANSCRIPTION ELONGATION; H3K79 METHYLATION; STEM-CELLS; P-TEFB; CHROMATIN; INHIBITION; BROMODOMAINS AB Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs(1). Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors(2,3). We recently identified the YEATS domain as an acetyl-lysine-binding module(4), but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia. C1 [Wan, Liling; Joseph, Julia K.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA. [Wan, Liling; Hoshii, Takayuki; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. [Wan, Liling; Hoshii, Takayuki; Armstrong, Scott A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Wen, Hong; Wang, Xiaolu; Shi, Xiaobing] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA. [Wen, Hong; Shi, Xiaobing] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA. [Li, Yuanyuan; Li, Haitao] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Med, Dept Basic Med Sci,MOE Key Lab Prot Sci, Beijing 100084, Peoples R China. [Li, Yuanyuan; Li, Haitao] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China. [Lyu, Jie; Xi, Yuanxin; Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Loh, Yong-Hwee E.; Shen, Li] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Loh, Yong-Hwee E.; Shen, Li] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Erb, Michael A.; Souza, Amanda L.; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Shi, Xiaobing] Univ Texas Houston, Grad Sch Biomed Sci, Genes & Dev & Epigenet & Mol Carcinogenesis Grad, Houston, TX 77030 USA. [Souza, Amanda L.; Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP Allis, CD (reprint author), Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA.; Armstrong, SA (reprint author), Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA.; Armstrong, SA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Shi, XB (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA.; Shi, XB (reprint author), Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA.; Shi, XB (reprint author), Univ Texas Houston, Grad Sch Biomed Sci, Genes & Dev & Epigenet & Mol Carcinogenesis Grad, Houston, TX 77030 USA. EM alliscd@rockefeller.edu; scott_armstrong@dfci.harvard.edu; xbshi@mdanderson.org FU NIH [1R01CA204639-01, CA66996, CA140575, R01HG007538, R01CA193466]; Leukaemia and Lymphoma Society [LLS-SCOR 7006-13]; Rockefeller University; NIH/NCI [1R01CA204020-01]; Cancer Prevention and Research Institute of Texas [RP160237, RP170285]; Welch Foundation [G1719]; Major State Basic Research Development Program in China [2016YFA0500700, 2015CB910503]; Tsinghua University Initiative Scientific Research Program FX We thank H. Li, M. Armstrong, C.-W. Chen, M. Yu, H. Chu, K. Tanaka, D. Peng and T. Scott for discussions and technical supports. We are grateful to The Rockefeller University Genomic Resource Center, Flow Cytometry Resource Center, The MD Anderson Science Park Next-Generation Sequencing Facility (CPRIT RP120348), The Sequencing and Microarray Facility and The Flow Cytometry and Cellular Imaging Core Facility (NIH/NCI P30CA016672), The Shanghai Synchrotron Radiation Facility BL17U beamline, and The China National Center for Protein Sciences Beijing for facility supports. The research was supported by funds from NIH (1R01CA204639-01), the Leukaemia and Lymphoma Society (LLS-SCOR 7006-13), and The Rockefeller University to C.D.A.; NIH grants (CA66996 and CA140575) and the Leukaemia and Lymphoma Society to S.A.A.; grants from NIH/NCI (1R01CA204020-01), Cancer Prevention and Research Institute of Texas (RP160237 and RP170285) and Welch Foundation (G1719) to X.S.; grants from the Major State Basic Research Development Program in China (2016YFA0500700 and 2015CB910503), and the Tsinghua University Initiative Scientific Research Program to H.L.; and grants from NIH (R01HG007538 and R01CA193466) to W.L. X.S. is a recipient of a Leukaemia & Lymphoma Society Career Development Award and an R. Lee Clark Fellow and Faculty Scholar of MD Anderson Cancer Center. L.W. is a fellow of the Jane Coffin Childs Memorial Fund. Y.L. is a Tsinghua Advanced Innovation fellow. NR 27 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 265 EP + DI 10.1038/nature21687 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700044 PM 28241141 ER PT J AU Erb, MA Scott, TG Li, BE Xie, HF Paulk, J Seo, HS Souza, A Roberts, JM Dastjerdi, S Buckley, DL Sanjana, NE Shalem, O Nabet, B Zeid, R Offei-Addo, NK Dhe-Paganon, S Zhang, F Orkin, SH Winter, GE Bradner, JE AF Erb, Michael A. Scott, Thomas G. Li, Bin E. Xie, Huafeng Paulk, Joshiawa Seo, Hyuk-Soo Souza, Amanda Roberts, Justin M. Dastjerdi, Shiva Buckley, Dennis L. Sanjana, Neville E. Shalem, Ophir Nabet, Behnam Zeid, Rhamy Offei-Addo, Nana K. Dhe-Paganon, Sirano Zhang, Feng Orkin, Stuart H. Winter, Georg E. Bradner, James E. TI Transcription control by the ENL YEATS domain in acute leukaemia SO NATURE LA English DT Article ID BET BROMODOMAIN INHIBITION; MIXED-LINEAGE LEUKEMIA; H3K79 METHYLATION; HISTONE CROTONYLATION; ESSENTIAL GENES; IN-VIVO; C-MYC; CHROMATIN; CELLS; PROTEIN AB Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome(1). The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control(2). Despite recent progress made in targeting chromatin regulators in cancer(3), available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease. C1 [Erb, Michael A.; Scott, Thomas G.; Paulk, Joshiawa; Souza, Amanda; Roberts, Justin M.; Dastjerdi, Shiva; Buckley, Dennis L.; Nabet, Behnam; Zeid, Rhamy; Winter, Georg E.; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Bin E.; Xie, Huafeng; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Li, Bin E.; Xie, Huafeng; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Li, Bin E.; Xie, Huafeng; Orkin, Stuart H.] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Seo, Hyuk-Soo; Offei-Addo, Nana K.; Dhe-Paganon, Sirano] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Sanjana, Neville E.; Shalem, Ophir; Zhang, Feng] Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Sanjana, Neville E.; Shalem, Ophir] MIT, McGovern Inst Brain Res, Dept Biol Engn, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Orkin, Stuart H.] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Bradner, James E.] Harvard Med Sch, Dept Med, Boston, MA USA. [Winter, Georg E.] Austrian Acad Sci, Res Ctr Mol Med, A-1090 Vienna, Austria. [Bradner, James E.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bradner, JE (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. EM james.bradner@novartis.com FU NIH [R01-CA176745, P01-CA109901]; EMBO long-term fellowship; Pathway to Independence Award from the NHGRI [R00-HG008171] FX The authors thank S. A. Armstrong, C. D. Allis, and X. Shi for transparent and supportive dialogue. We also thank J. A. Perry for editing the manuscript and N. S. Gray and C. J. Ott for suggestions. Quantitative proteomics studies were performed by R. Kunz. This research was supported by philanthropic gifts from K. Lubin and E. Woods, as well as NIH grants (R01-CA176745 and P01-CA109901 to J.E.B.). G.E.W. was supported by an EMBO long-term fellowship. D.L.B. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). N. E. S. is supported by a Pathway to Independence Award (R00-HG008171) from the NHGRI. NR 31 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 270 EP + DI 10.1038/nature21688 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700045 PM 28241139 ER PT J AU Andropoulos, DB Greene, MF AF Andropoulos, Dean B. Greene, Michael F. TI Anesthesia and Developing Brains - Implications of the FDA Warning SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID GENERAL-ANESTHESIA; EXPOSURE; AGE C1 [Andropoulos, Dean B.] Texas Childrens Hosp, Dept Anesthesiol, Houston, TX 77030 USA. [Andropoulos, Dean B.] Baylor Coll Med, Houston, TX 77030 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Andropoulos, DB (reprint author), Texas Childrens Hosp, Dept Anesthesiol, Houston, TX 77030 USA.; Andropoulos, DB (reprint author), Baylor Coll Med, Houston, TX 77030 USA. NR 5 TC 0 Z9 0 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 MAR 9 PY 2017 VL 376 IS 10 BP 905 EP 907 DI 10.1056/NEJMp1700196 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JA UT WOS:000395626500001 PM 28177852 ER PT J AU Woolley, AE Montgomery, MW Savage, WJ Achebe, MO Dunford, K Villeda, S Maguire, JH Marty, FM AF Woolley, Ann E. Montgomery, Mary W. Savage, William J. Achebe, Maureen O. Dunford, Kathleen Villeda, Sarah Maguire, James H. Marty, Francisco M. TI Post-Babesiosis Warm Autoimmune Hemolytic Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MALARIA AB BACKGROUND Babesiosis, a tickborne zoonotic disease caused by intraerythrocytic protozoa of the genus babesia, is characterized by nonimmune hemolytic anemia that resolves with antimicrobial treatment and clearance of parasitemia. The development of warm-antibody autoimmune hemolytic anemia (also known as warm autoimmune hemolytic anemia [WAHA]) in patients with babesiosis has not previously been well described. METHODS After the observation of sporadic cases of WAHA that occurred after treatment of patients for babesiosis, we conducted a retrospective cohort study of all the patients with babesiosis who were cared for at our center from January 2009 through June 2016. Data on covariates of interest were extracted from the medical records, including any hematologic complications that occurred within 3 months after the diagnosis and treatment of babesiosis. RESULTS A total of 86 patients received a diagnosis of babesiosis during the 7.5-year study period; 18 of these patients were asplenic. WAHA developed in 6 patients 2 to 4 weeks after the diagnosis of babesiosis, by which time all the patients had had clinical and laboratory responses to antimicrobial treatment of babesiosis, including clearance of Babesia microti parasitemia. All 6 patients were asplenic (P < 0.001) and had positive direct antiglobulin tests for IgG and complement component 3; warm autoantibodies were identified in all these patients. No alternative explanation for clinical hemolysis was found. WAHA required immunosuppressive treatment in 4 of the 6 patients. CONCLUSIONS We documented post-babesiosis WAHA in patients who did not have a history of autoimmunity; asplenic patients appeared to be particularly at risk. C1 [Woolley, Ann E.; Montgomery, Mary W.; Dunford, Kathleen; Villeda, Sarah; Maguire, James H.; Marty, Francisco M.] Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Boston, MA USA. [Savage, William J.] Harvard Med Sch, Brigham & Womens Hosp, Div Transfus Med, Boston, MA USA. [Achebe, Maureen O.] Harvard Med Sch, Brigham & Womens Hosp, Div Hematol, Boston, MA USA. [Woolley, Ann E.; Montgomery, Mary W.; Savage, William J.; Achebe, Maureen O.; Maguire, James H.; Marty, Francisco M.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Woolley, Ann E.; Achebe, Maureen O.; Marty, Francisco M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Woolley, AE (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM awoolley@bwh.harvard.edu NR 23 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 MAR 9 PY 2017 VL 376 IS 10 BP 939 EP 946 DI 10.1056/NEJMoa1612165 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JA UT WOS:000395626500010 PM 28273010 ER PT J AU Fogerty, RL Greenwald, JL McDermott, S Lin, AE Stone, JR AF Fogerty, Robert L. Greenwald, Jeffrey L. McDermott, Shaunagh Lin, Angela E. Stone, James R. TI Case 7-2017: A 73-Year-Old Man with Confusion and Recurrent Epistaxis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; WEBER-RENDU-SYNDROME; VASCULAR MALFORMATIONS; LIVER-DISEASE; DIAGNOSIS C1 [Fogerty, Robert L.] Yale Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Greenwald, Jeffrey L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [McDermott, Shaunagh] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Greenwald, Jeffrey L.] Harvard Med Sch, Dept Med, Boston, MA USA. [McDermott, Shaunagh] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Lin, Angela E.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Stone, James R.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Fogerty, RL (reprint author), Yale Sch Med, Dept Internal Med, New Haven, CT 06510 USA. FU GlaxoSmithKline; Alnylam Pharmaceuticals; USP Labs FX Dr. Stone reports receiving consulting fees from GlaxoSmithKline, lecture fees from Alnylam Pharmaceuticals, and fees from USP Labs for expert testimony in a case regarding dimethylamylamine toxicity. No other potential conflict of interest relevant to this article was reported. NR 21 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 MAR 9 PY 2017 VL 376 IS 10 BP 973 EP 981 DI 10.1056/NEJMcpc1613462 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JA UT WOS:000395626500015 ER PT J AU Sousa, GR Gomes, JAS Damasio, MPS Nunes, MCP Costa, HS Medeiros, NI Fares, RCG Chaves, AT Correa-Oliveira, R Rocha, MOC AF Sousa, Giovane R. Gomes, Juliana A. S. Damasio, Marcos Paulo S. Nunes, Maria Carmo P. Costa, Henrique S. Medeiros, Nayara I. Fares, Rafaelle C. G. Chaves, Ana Thereza Correa-Oliveira, Rodrigo Rocha, Manoel Otavio C. TI The role of interleukin 17-mediated immune response in Chagas disease: High level is correlated with better left ventricular function SO PLOS ONE LA English DT Article ID HEART-DISEASE; T-CELLS; B-CELLS; CARDIOMYOPATHY; IL-17; ECHOCARDIOGRAPHY; ASSOCIATION; MANAGEMENT; CAPACITY; FAMILY AB Interleukin 17A (IL-17A) has been associated with protective rather than pathogenic response in Chagas disease (ChD). However, it is not established whether or not IL-17Amediated immune response is correlated with patient's left ventricular (LV) function in ChD. To address this question we have gathered cardiac functional parameters from ChD patients and analysed the possible relationship between their plasma IL-17A levels and LV function. Plasma IL-17A levels were measured by BD Cytometric Bead Array (CBA) in 240 patients with positive specific serology for Trypanosoma cruzi (T. cruzi) grouped as indeterminate (IND) and Chagas cardiomyopathy (CARD) forms. The levels of IL-17A in ChD patients were compared with 32 healthy individuals, mean age of 39 years, 50% male, that were also included as a control group (non-infected [NI]). The overall mean age of ChD patients was 46 years and 52% were male. The IND group included 95 asymptomatic patients, with ages ranging from 27 to 69 years (mean of 43 years), and 42.1% of them were male. The CARD group included 145 patients, which 58.6% were male, with ages ranging from 23 to 67 years (mean of 49). The IND group presented substantially higher levels of IL17A, median of 26.16 (3.66-48.33) as compared to both the CARD group, median of 13.89 (3.87-34.54) (P < 0.0001), and the NI group, median of 10.78 (6.23-22.26) (P < 0.0001). The data analysis demonstrated that the IND group comprises a significantly greater proportion (P < 0.001) of high IL-17A producers (52.6%, 50 of 95 subjects) than do the other groups. A significant direct correlation was verified between IL-17A levels and cardiac function expressed by LV ejection fraction (LVEF), LV diastolic diameter (LVDd), and body surface area (BSA)-indexed LVDd as well as ratio of the early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') in both groups. We demonstrated that plasma IL17A levels has an accurate sensitivity and specificity to predict heart failure in serology-positive patients and might be a useful parameter to distinguish patients with or without cardiac impairment. This study indicates a consistent relationship between high expression of IL17A and better LV in human chronic ChD. Our data raise the possibility that IL-17A plays an important immunomodulatory role in the chronic phase of ChD and might be involved in protection against myocardial damage. C1 [Sousa, Giovane R.; Gomes, Juliana A. S.; Nunes, Maria Carmo P.; Costa, Henrique S.; Chaves, Ana Thereza; Rocha, Manoel Otavio C.] Univ Fed Minas Gerais, Sch Med, Postgrad Course Infect Dis & Trop Med, Belo Horizonte, MG, Brazil. [Gomes, Juliana A. S.; Damasio, Marcos Paulo S.] Univ Fed Minas Gerais, Inst Biol Sci, Dept Morphol, Lab Cell Cell Interact, Belo Horizonte, MG, Brazil. [Medeiros, Nayara I.; Fares, Rafaelle C. G.; Correa-Oliveira, Rodrigo] Fiocruz MS, Ctr Pesquisas Rene Rachou, Lab Cellular & Mol Immunol, Belo Horizonte, MG, Brazil. [Correa-Oliveira, Rodrigo] Natl Inst Sci & Technol Trop Dis INCT DT, Belo Horizonte, MG, Brazil. [Sousa, Giovane R.] Harvard Med Sch, Joslin Diabet Ctr, Immunobiol Sect, Boston, MA 02115 USA. [Damasio, Marcos Paulo S.] Univ Dundee, Sch Life Sci, Div Cell Signalling & Immunol, Dundee, Scotland. [Fares, Rafaelle C. G.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Sousa, GR (reprint author), Univ Fed Minas Gerais, Sch Med, Postgrad Course Infect Dis & Trop Med, Belo Horizonte, MG, Brazil.; Sousa, GR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Immunobiol Sect, Boston, MA 02115 USA. EM giovane.sousa@gmail.com FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [407692/2012-6, 478846/2009-6, 404151/2012-4, 475497/2007-4, 403592/2008-9, 308219/2012-0]; Fundacao de Amparo a Pesquisa do Estado de Minas Gerais [APQ-02601-10, APQ-04129-10, PPM-00501-13]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Amparo Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil FX This work was funded by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, http//www.cripq.br, [407692/2012-6, 478846/2009-6, 404151/2012-4 (RCO), 475497/2007-4, 403592/2008-9, 308219/2012-0 (JASG)] and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais, http://www.fapermg.br, [APQ-02601-10, APQ-04129-10, PPM-00501-13 (JASG)]. JASG, MCPN, RCO and MOCR are CNPq Research Fellows. GRS was supported by a Ph.D. Studentship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank the colleagues of the Division of Echocardiography and of the Referral Outpatient Center for Chagas Disease at the Clinical Hospital, UFMG as well as of the Laboratory of Cellular and Molecular Immunology and of the Flow Cytometry facility at the Centro de Pesquisas Rene Rachou, FIOCRUZ for their technical assistance. The authors also thank the Program for Technological Development in Tools for Health PDTIS FIOCRUZ for the use of its facilities. We acknowledge Professor Paul Crocker at the Division of Cell Signalling and Immunology, University of Dundee, UK for helpful discussions. We are very grateful to all patients and control volunteers who participated in this study. This work was supported by the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil. JASG, MCPN, RCO and MOCR are CNPq Research Fellows. GRS was supported by a Ph.D. Studentship from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). NR 38 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 MAR 9 PY 2017 VL 12 IS 3 AR e0172833 DI 10.1371/journal.pone.0172833 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6AW UT WOS:000396087900130 PM 28278264 ER PT J AU Lin, M Gao, Y Diefenbach, TJ Shen, JK Hornicek, FJ Park, YI Xu, F Lu, TJ Amiji, M Duan, ZF AF Lin, Min Gao, Yan Diefenbach, Thomas J. Shen, Jacson K. Hornicek, Francis J. Park, Yong Il Xu, Feng Lu, Tian Jian Amiji, Mansoor Duan, Zhenfeng TI Facial Layer-by-Layer Engineering of Upconversion Nanoparticles for Gene Delivery: Near-Infrared-Initiated Fluorescence Resonance Energy Transfer Tracking and Overcoming Drug Resistance in Ovarian Cancer SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE upconversion nanoparticles; gene delivery; FRET; gene knockdown; drug sensitivity ID ENHANCED SIRNA DELIVERY; PACLITAXEL RESISTANCE; GOLD NANOPARTICLES; IN-VIVO; BIOMEDICAL APPLICATIONS; CELLS; FRET; RNA; NANOPHOSPHORS; STATISTICS AB Development of multidrug resistance (MDR) contributes to the majority of treatment failures in clinical chemotherapy. We report facial layer-by-layer engineered upconversion nanoparticles (UCNPs) for near-infrared (NIR)-initiated tracking and delivery of small interfering RNA (siRNA) to enhance chemotherapy efficacy by silencing the MDR1 gene and resensitizing resistant ovarian cancer cells to drug. Layer-by-layer engineered UCNPs were loaded with MDR1 gene-silencing siRNA (MDR1-siRNA) by electrostatic interaction. The delivery vehicle enhances MDR1-siRNA cellular uptake, protects MDR1-siRNA from nuclease degradation, and promotes endosomal escape for silencing the MDR gene. The intrinsic photon upconversion of UCNPs provides an unprecedented opportunity for monitoring intracellular attachment and release of MDR1-siRNA by NIR-initiated fluorescence resonance energy transfer occurs between donor UCNPs and acceptor fluorescence dye-labeled MDR1-siRNA. Enhanced chemotherapeutic efficacy in vitro was demonstrated by cell viability assay. The developed delivery vehicle holds great potential in delivery and imaging-guided tracking of therapeutic gene targets for effective treatment of drug-resistant cancers. C1 [Lin, Min; Gao, Yan; Shen, Jacson K.; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Park, Yong Il] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Lin, Min; Xu, Feng; Lu, Tian Jian] Xi An Jiao Tong Univ, Key Lab Biomed Informat Engn, Minist Educ, Sch Life Sci & Technol, Xian 710049, Peoples R China. [Lin, Min; Xu, Feng; Lu, Tian Jian] Xi An Jiao Tong Univ, BEBC, Xian 710049, Peoples R China. [Diefenbach, Thomas J.] Ragon Inst MGH Massachusetts Inst Technol MIT & H, Cambridge, MA 02139 USA. [Park, Yong Il] Chonnam Natl Univ, Sch Chem Engn, Gwangju 61186, South Korea. [Amiji, Mansoor] Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. RP Lin, M; Duan, ZF (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA.; Lin, M (reprint author), Xi An Jiao Tong Univ, Key Lab Biomed Informat Engn, Minist Educ, Sch Life Sci & Technol, Xian 710049, Peoples R China.; Lin, M (reprint author), Xi An Jiao Tong Univ, BEBC, Xian 710049, Peoples R China. EM minlin@xjtu.edu.cn; ZDUAN@mgh.harvard.edu FU Gategno fund; Wechsler fund; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1 [CA 151452]; National Natural Science Foundation of China [11402192]; Fundamental Research Funds for the Central Universities [2016qngz03] FX This study is supported in part by grants from the Gategno and Wechsler funds. Dr. Duan is supported, in part, through a grant from Sarcoma Foundation of America (SFA), a grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452, By the National Natural Science Foundation of China (11402192), and the Fundamental Research Funds for the Central Universities (2016qngz03). We thank Dr. Ralph Weissleder for his insights and support on this work. NR 52 TC 0 Z9 0 U1 14 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD MAR 8 PY 2017 VL 9 IS 9 BP 7941 EP 7949 DI 10.1021/acsami.6b15321 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA EN7MD UT WOS:000396186000009 PM 28177223 ER PT J AU Riad, FS Razak, E Saba, S Shalaby, A Nemec, J AF Riad, Fady S. Razak, Eathar Saba, Samir Shalaby, Alaa Nemec, Jan TI Recent heart rate history affects QT interval duration in atrial fibrillation SO PLOS ONE LA English DT Article ID ACTION-POTENTIAL DURATION; TORSADE-DE-POINTES; RATE DEPENDENCE; MORTALITY; PROLONGATION; DYNAMICS; FORMULAS AB QT interval prolongation is associated with a risk of polymorphic ventricular tachycardia. QT interval shortens with increasing heart rate and correction for this effect is necessary for meaningful QT interval assessment. We aim to improve current methods of correcting the QT interval during atrial fibrillation (AF). Digitized Holter recordings were analyzed from patients with AF. Models of QT interval dependence on RR intervals were tested by sorting the beats into 20 bins based on corrected RR interval and assessing ST-T variability within the bins. Signal-averaging within bins was performed to determine QT/RR dependence. Data from 30 patients (29 men, 69.3 7.3 years) were evaluated. QT behavior in AF is well described by a linear function (slope-0.19) of steady-state corrected RR interval. Corrected RR is calculated as a combination of an exponential weight function with time-constant of 2 minutes and a smaller "immediate response" component (weight- 0.18). This model performs significantly (p<0.0001) better than models based on instantaneous RR interval only including Bazett and Fridericia. It also outperforms models based on shorter time-constants and other previously proposed models. This model may improve detection of repolarization delay in AF. QT response to heart rate changes in AF is similar to previously published QT dynamics during atrial pacing and in sinus rhythm. C1 [Riad, Fady S.] Univ Pittsburgh, Med Ctr, Dept Internal Med, Pittsburgh, PA USA. [Razak, Eathar; Shalaby, Alaa] VA Pittsburgh Healthcare Syst, Dept Cardiol, Pittsburgh, PA USA. [Saba, Samir; Nemec, Jan] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA 15260 USA. [Razak, Eathar] CHI Franciscan Hlth, Franciscan Heart & Vasc Associates St Joseph, Tacoma, WA USA. RP Nemec, J (reprint author), Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA 15260 USA. EM limidus@hotmail.com NR 29 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 MAR 8 PY 2017 VL 12 IS 3 AR e0172962 DI 10.1371/journal.pone.0172962 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5VL UT WOS:000396073700033 PM 28273109 ER PT J AU Sheehan, DF Criss, SD Gazelle, GS Pandharipande, PV Kong, CY AF Sheehan, Deirdre F. Criss, Steven D. Gazelle, G. Scott Pandharipande, Pari V. Kong, Chung Yin TI Evaluating lung cancer screening in China: Implications for eligibility criteria design from a microsimulation modeling approach SO PLOS ONE LA English DT Article ID SPIRAL COMPUTED-TOMOGRAPHY; COST-EFFECTIVENESS; TOBACCO CONTROL; AIR-POLLUTION; UNITED-STATES; RISK; POPULATION; MORTALITY; SMOKING; BENEFITS AB More than half of males in China are current smokers and evidence from western countries tells us that an unprecedented number of smoking-attributable deaths will occur as the Chinese population ages. We used the China Lung Cancer Policy Model (LCPM) to simulate effects of computed tomography (CT)-based lung cancer screening in China, comparing the impact of a screening guideline published in 2015 by a Chinese expert group to a version developed for the United States by the U.S. Centers for Medicare & Medicaid Services (CMS). The China LCPM, built using an existing lung cancer microsimulation model, can project population outcomes associated with interventions for smoking-related diseases. After calibrating the model to published Chinese smoking prevalence and lung cancer mortality rates, we simulated screening from 2016 to 2050 based on eligibility criteria from the CMS and Chinese guidelines, which differ by age to begin and end screening, pack-years smoked, and years since quitting. Outcomes included number of screens, mortality reduction, and life-years saved for each strategy. We projected that in the absence of screening, 14.98 million lung cancer deaths would occur between 2016 and 2050. Screening with the CMS guideline would prevent 0.72 million deaths and 5.8 million life-years lost, resulting in 6.58% and 1.97% mortality reduction in males and females, respectively. Screening with the Chinese guideline would prevent 0.74 million deaths and 6.6 million life-years lost, resulting in 6.30% and 2.79% mortality reduction in males and females, respectively. Through 2050, 1.43 billion screens would be required using the Chinese screening strategy, compared to 988 million screens using the CMS guideline. In conclusion, CT-based lung cancer screening implemented in 2016 and based on the Chinese screening guideline would prevent about 20,000 (2.9%) more lung cancer deaths through 2050, but would require about 445 million (44.7%) more screens than the CMS guideline. C1 [Sheehan, Deirdre F.; Criss, Steven D.; Gazelle, G. Scott; Pandharipande, Pari V.; Kong, Chung Yin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Gazelle, G. Scott; Pandharipande, Pari V.; Kong, Chung Yin] Harvard Med Sch, Boston, MA 02115 USA. [Gazelle, G. Scott] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Kong, CY (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA.; Kong, CY (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM joey@mgh-ita.org FU National Institutes of Health [U01CA199284] FX This work was supported by National Institutes of Health, Grant number: U01CA199284, https://www.nih.gov/. NR 39 TC 0 Z9 0 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 MAR 8 PY 2017 VL 12 IS 3 AR e0173119 DI 10.1371/journal.pone.0173119 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5VL UT WOS:000396073700040 PM 28273181 ER PT J AU Gevers, D Kugathasan, S Knights, D Kostic, AD Knight, R Xavier, RJ AF Gevers, Dirk Kugathasan, Subra Knights, Dan Kostic, Aleksandar D. Knight, Rob Xavier, Ramnik J. TI A Microbiome Foundation for the Study of Crohn's Disease SO CELL HOST & MICROBE LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; ORAL MICROBIOTA; DYSBIOSIS AB Our 2014 study published in Cell Host & Microbe, "The Treatment-Naive Microbiome in New-Onset Crohn's Disease,'' was designed to improve our understanding of the microbiome's role in Crohn's disease by studying a unique, well-suited cohort and sample set. This commentary provides a hindsight perspective of this original study as well as future outlook. C1 [Gevers, Dirk] Janssen Res & Dev LLC, Janssen Human Microbiome Inst, Cambridge, MA 02142 USA. [Kugathasan, Subra] Emory Univ, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Atlanta, GA 30322 USA. [Knights, Dan] Univ Minnesota, Dept Comp Sci & Engn, St Paul, MN 55108 USA. [Knights, Dan] Univ Minnesota, Inst Biotechnol, St Paul, MN 55108 USA. [Kostic, Aleksandar D.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Kostic, Aleksandar D.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Knight, Rob] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Knight, Rob] Univ Colorado, Dept Chem & Biochem, Campus Box 215, Boulder, CO 80309 USA. [Knight, Rob] Howard Hughes Med Inst, Boulder, CO 80309 USA. [Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 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. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Med Sch, Boston, MA 02114 USA. RP Gevers, D (reprint author), Janssen Res & Dev LLC, Janssen Human Microbiome Inst, Cambridge, MA 02142 USA. EM dgevers3@its.jnj.com NR 13 TC 0 Z9 0 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 8 PY 2017 VL 21 IS 3 BP 301 EP 304 DI 10.1016/j.chom.2017.02.012 PG 4 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EO0GF UT WOS:000396375600010 PM 28279336 ER PT J AU Schaefer, IM Wang, YX Liang, CW Bahri, N Quattrone, A Doyle, L Marino-Enriquez, A Lauria, A Zhu, MJ Debiec-Rychter, M Grunewald, S Hechtman, JF Dufresne, A Antonescu, CR Beadling, C Sicinska, ET van de Rijn, M Demetri, GD Ladanyi, M Corless, CL Heinrich, MC Raut, CP Bauer, S Fletcher, JA AF Schaefer, Inga-Marie Wang, Yuexiang Liang, Cher-wei Bahri, Nacef Quattrone, Anna Doyle, Leona Marino-Enriquez, Adrian Lauria, Alexandra Zhu, Meijun Debiec-Rychter, Maria Grunewald, Susanne Hechtman, Jaclyn F. Dufresne, Armelle Antonescu, Cristina R. Beadling, Carol Sicinska, Ewa T. van de Rijn, Matt Demetri, George D. Ladanyi, Marc Corless, Christopher L. Heinrich, Michael C. Raut, Chandrajit P. Bauer, Sebastian Fletcher, Jonathan A. TI MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation SO NATURE COMMUNICATIONS LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; NEUROFIBROMATOSIS TYPE-1; FUNCTION MUTATIONS; C-KIT; MYC; PROGRAMS AB KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in similar to 70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs. C1 [Schaefer, Inga-Marie; Wang, Yuexiang; Liang, Cher-wei; Bahri, Nacef; Quattrone, Anna; Doyle, Leona; Marino-Enriquez, Adrian; Lauria, Alexandra; Zhu, Meijun; Dufresne, Armelle; Fletcher, Jonathan A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 20 Shattuck St,Thorn 528, Boston, MA 02115 USA. [Quattrone, Anna; Debiec-Rychter, Maria] Katholieke Univ Leuven, Dept Human Genet, Herestr 49,Box 602, B-3000 Leuven, Belgium. [Quattrone, Anna; Debiec-Rychter, Maria] Univ Hosp Leuven, Herestr 49,Box 602, B-3000 Leuven, Belgium. [Grunewald, Susanne; Bauer, Sebastian] Univ Duisburg Essen, Sarcoma Ctr, Western German Canc Ctr, Sch Med, Hufelandstr 55, D-45122 Essen, Germany. [Hechtman, Jaclyn F.; Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10065 USA. [Beadling, Carol; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, Dept Pathol, 3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. [Sicinska, Ewa T.] Harvard Med Sch, Dana Farber Canc Inst, Dept Oncol Pathol, 450 Brookline Ave, Boston, MA 02215 USA. [van de Rijn, Matt] Stanford Univ, Dept Pathol, Med Ctr, 300 Pasteur Dr, Stanford, CA 94305 USA. [Demetri, George D.] Harvard Med Sch, Ludwig Ctr Harvard, 450 Brookline Ave, Boston, MA 02215 USA. [Demetri, George D.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Hlth Care Syst, Knight Canc Inst, 3181 Soutwest Sam Jackson Pk Rd, Portland, OR 97239 USA. [Raut, Chandrajit P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Wang, Yuexiang] Changzheng Hosp Joint Ctr Translat Med, Inst Translat Med CAS SMMU, 320 Yueyang Rd, Shanghai 200025, Peoples R China. [Wang, Yuexiang] Shanghai Jiao Tong Univ, Chinese Acad Sci, Sch Med, Key Lab Stem Cell Biol,Inst Hlth Sci,SIBS, 320 Yueyang Rd, Shanghai 200025, Peoples R China. [Wang, Yuexiang] Collaborat Innovat Ctr Syst Biomed, 320 Yueyang Rd, Shanghai 200025, Peoples R China. [Liang, Cher-wei] Natl Taiwan Univ Hosp, Dept & Grad Inst Pathol, 7 Zhong Shan South Rd, Taipei 10002, Taiwan. [Liang, Cher-wei] Natl Taiwan Univ, Coll Med, 7 Zhong Shan South Rd, Taipei 10002, Taiwan. RP Fletcher, JA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 20 Shattuck St,Thorn 528, Boston, MA 02115 USA. EM jfletcher@partners.org FU US National Institutes of Health [1P50CA127003, 1P50CA168512]; GIST Cancer Research Fund; Life Raft Group; Deutsche Krebshilfe; VA Merit Review [1I01BX000338-01, 2I01BX000338-05]; V Foundation Translational Research FX We thank Raymond DiDonato, PhD, from Agilent Technologies, for HaloPlex targeted cancer gene panel design and for other helpful advice with the HaloPlex analyses, and Jason Hornick, MD, PhD for assistance with the p16 IHC studies. This work was supported by grants from the US National Institutes of Health, including 1P50CA127003 (J.A.F. and G.D.D.), 1P50CA168512 (J.A.F. and A. M.-E.), the GIST Cancer Research Fund (J.A.F., M.C.H., C.L.C., C.R.A.), the Life Raft Group (J.A.F., M.v.d.R., M.C.H., C.L.C, S.B.), the Deutsche Krebshilfe (I. M.S.), the VA Merit Review Grants 1I01BX000338-01 and 2I01BX000338-05 (M.C.H.) and the V Foundation Translational Research Grant (M.C.H.). NR 25 TC 0 Z9 0 U1 0 U2 0 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 MAR 8 PY 2017 VL 8 AR 14674 DI 10.1038/ncomms14674 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0CV UT WOS:000395678800001 PM 28270683 ER PT J AU Charidimou, A Tirschwell, DL AF Charidimou, Andreas Tirschwell, David L. TI Early case fatality in intracerebral hemorrhage Sophistication of care, application globally SO NEUROLOGY LA English DT Editorial Material ID MANAGEMENT; GUIDELINES C1 [Charidimou, Andreas] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol,J Philip Kistler Stroke Res Ctr, Boston, MA 02115 USA. [Tirschwell, David L.] Univ Washington, Sch Med, Dept Neurol, UW Med,Harborview Comprehens Stroke Ctr, Seattle, WA USA. RP Charidimou, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol,J Philip Kistler Stroke Res Ctr, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk NR 12 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 MAR 7 PY 2017 VL 88 IS 10 BP 926 EP 927 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EP4ID UT WOS:000397343300006 PM 28159887 ER PT J AU Khera, AV Won, HH Peloso, GM O'Dushlaine, C Liu, D Stitziel, NO Natarajan, P Nomura, A Emdin, CA Gupta, N Borecki, IB Asselta, R Duga, S Merlini, PA Correa, A Kessler, T Wilson, JG Bown, MJ Hall, AS Braund, PS Carey, DJ Murray, MF Kirchner, HL Leader, JB Lavage, DR Manus, JN Hartzel, DN Samani, NJ Schunkert, H Marrugat, J Elosua, R McPherson, R Farrall, M Watkins, H Lander, ES Rader, DJ Danesh, J Ardissino, D Gabriel, S Willer, C Abecasis, GR Saleheen, D Dewey, FE Kathiresan, S AF Khera, Amit V. Won, Hong-Hee Peloso, Gina M. O'Dushlaine, Colm Liu, Dajiang Stitziel, Nathan O. Natarajan, Pradeep Nomura, Akihiro Emdin, Connor A. Gupta, Namrata Borecki, Ingrid B. Asselta, Rosanna Duga, Stefano Merlini, Piera Angelica Correa, Adolfo Kessler, Thorsten Wilson, James G. Bown, Matthew J. Hall, Alistair S. Braund, Peter S. Carey, David J. Murray, Michael F. Kirchner, H. Lester Leader, Joseph B. Lavage, Daniel R. Manus, J. Neil Hartzel, Dustin N. Samani, Nilesh J. Schunkert, Heribert Marrugat, Jaume Elosua, Roberto McPherson, Ruth Farrall, Martin Watkins, Hugh Lander, Eric S. Rader, Daniel J. Danesh, John Ardissino, Diego Gabriel, Stacey Willer, Cristen Abecasis, Goncalo R. Saleheen, Danish Dewey, Frederick E. Kathiresan, Sekar CA Myocardial Infarction Genetics DiscovEHR Study Grp CARDIoGRAM Exome Consortium Global Lipids Genetics Consortium TI Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OF-FUNCTION MUTATIONS; MYOCARDIAL-INFARCTION; HEART-DISEASE; NONFASTING TRIGLYCERIDES; MENDELIAN RANDOMIZATION; RISK; VARIANTS; CHOLESTEROL; POPULATION; DEFICIENCY AB IMPORTANCE The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. OBJECTIVE To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. EXPOSURES Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. MAIN OUTCOMES AND MEASURES Circulating lipid levels and CAD. RESULTS Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6mg/dL; 95% CI, 4.6-34.6mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 x 10(-22)) per 1-SD increase in triglycerides. CONCLUSIONS AND RELEVANCE The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease. C1 [Khera, Amit V.; Peloso, Gina M.; Natarajan, Pradeep; Nomura, Akihiro; Emdin, Connor A.; Gupta, Namrata; Lander, Eric S.; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Khera, Amit V.; Natarajan, Pradeep; Nomura, Akihiro; Emdin, Connor A.; Kathiresan, Sekar] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA. [Khera, Amit V.; Natarajan, Pradeep; Nomura, Akihiro; Emdin, Connor A.; Kathiresan, Sekar] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Samsung Med Ctr, Seoul, South Korea. [Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Dushlaine, Colm; Borecki, Ingrid B.; Dewey, Frederick E.] Regeneron Genet Ctr, Tarrytown, NY USA. [Liu, Dajiang] Penn State Coll Med, Dept Publ Hlth Sci, Inst Personalized Med, Hershey, PA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Dept Biomed Sci, Milan, Italy. [Asselta, Rosanna; Duga, Stefano] Humanitas Clin & Res Ctr, Milan, Italy. [Merlini, Piera Angelica] Osped Niguarda Ca Granda, Milan, Italy. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Kessler, Thorsten] Munich Heart Alliance, Munich, Germany. [Kessler, Thorsten; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, Deutsch Zentrum Herz Kreislauf Forsch, Munich, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Bown, Matthew J.; Braund, Peter S.; Samani, Nilesh J.] Univ Leicester, NIHR Leicester Cardiovasc Biomed Res Unit, Dept Cardiovasc Sci, Leicester, Leics, England. [Hall, Alistair S.] Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England. [Carey, David J.; Murray, Michael F.; Kirchner, H. Lester; Leader, Joseph B.; Lavage, Daniel R.; Manus, J. Neil; Hartzel, Dustin N.] Geisinger Hlth Syst, Danville, PA USA. [Marrugat, Jaume; Elosua, Roberto] Hosp Mar, Cardiovasc Epidemiol & Genet, Res Inst, Barcelona, Spain. [McPherson, Ruth] Univ Ottawa, Inst, Ottawa, ON, Canada. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Rader, Daniel J.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England. [Danesh, John; Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Willer, Cristen] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Kathiresan, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.; Kathiresan, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA.; Kathiresan, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. EM skathiresan1@mgh.harvard.edu FU ACCF/Merck Cardiovascular Research Fellowship from the American College of Cardiology Foundation; Merck; John S. Ladue Memorial Fellowship at Harvard Medical School; KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst - National Institutes of Health [TR001100]; National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [2016R1C1B2007920]; National Heart, Lung, and Blood Institute [K01HL125751, HL109946, HL127564, R01 HL127564, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, RC2 HL103010, RC2 HL102923, RC2 HL102924, RC2 HL102925, RC2 HL102926]; National Institutes of Health [K08 HL114642, R01 HL131961, 5U54HG003067]; Regeneron Genetics Center; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; Canada Foundation for Innovation; core award [090532/Z/09/Z]; Institutional Strategic Support Fund from the Wellcome Trust; British Heart Foundation Centre of Research Excellence [RE/13/1/30181]; UK Medical Research Council; British Heart Foundation; UK National Institute for Health Research; European Commission Framework Programme; Massachusetts General Hospital; Donovan Family Foundation; Wellcome Trust; EU Framework 6; Pfizer; Novartis; UK Medical Research Council [MR/L003120/1]; British Heart Foundation [RG/13/13/30194]; UK National Institute for Health Research Cambridge Biomedical Research Centre; European Research Council [268834]; European Commission Framework Programme 7 [HEALTH-F2-2012-279233]; National Institute on Minority Health and Health Disparities; Spanish Ministry of Economy and Innovation through the Carlos III Health Institute [Red Investigacion Cardiovascular RD12/0042, PI09/90506]; European Funds for Development (ERDF-FEDER); Catalan Research and Technology Innovation Interdepartmental Commission [2014SGR240]; British Heart Foundation (British Heart Foundation Family Heart Study) [RG2000010]; UK Aneurysm Growth Study [CS/14/2/30841]; National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science) [IS_BRU_0211_20033]; German Federal Ministry of Education and Research; FP7 European Union project CVgenes@target [261123]; Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes) [12CVD02]; Deutsche Forschungsgemeinschaft [SFB 1123]; Italian Ministry of Health [RFPS-2007-3-644382]; Programma di ricerca Regione-Universita Strategic Programmes from the Regione Emilia-Romagna FX Dr Khera was supported by an ACCF/Merck Cardiovascular Research Fellowship from the American College of Cardiology Foundation and Merck, a John S. Ladue Memorial Fellowship at Harvard Medical School, and KL2/Catalyst Medical Research Investigator Training award TR001100 from Harvard Catalyst funded by the National Institutes of Health. DrWon was supported by grant 2016R1C1B2007920 from the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning. Dr Peloso was supported by grant K01HL125751 from the National Heart, Lung, and Blood Institute. Dr Stitziel was supported by grants K08 HL114642 and R01 HL131961 from the National Institutes of Health. Drs Carey, Murray, and Kirchner and Messrs Leader, Lavage, Manus, and Hartzel were supported by the Regeneron Genetics Center. Dr McPherson was supported by grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, and the Canada Foundation for Innovation. Dr Farrall was supported by core award 090532/Z/09/Z and the Institutional Strategic Support Fund from the Wellcome Trust and grant RE/13/1/30181 from the British Heart Foundation Centre of Research Excellence. Dr Lander was supported by grant 5U54HG003067 from the National Institutes of Health. Dr Danesh was supported by grants from the UK Medical Research Council, the British Heart Foundation, the UK National Institute for Health Research, and the European Commission Framework Programme. Dr Willer was supported by grants HL109946 and HL127564 from the National Heart, Lung, and Blood Institute. Dr Abecasis was supported by a grant from the National Institutes of Health. Dr Kathiresan was supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the National Heart, Lung, and Blood Institute. Field work, genotyping, and standard clinical chemistry assays in the Pakistan Risk of Myocardial Infarction Study (PROMIS) were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The Jackson Heart Study was supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The Registre Gironi del COR (Gerona Heart Registry; REGICOR) study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular RD12/0042, PI09/90506), by the European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240).; Samples for the cohort in the Leicester Myocardial Infarction study were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The South German Myocardial Infarction study was supported by the German Federal Ministry of Education and Research in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces" and SFB 1123. The Atherosclerosis, Thrombosis, and Vascular Biology Italian Study (ATVB) was supported by grant RFPS-2007-3-644382 from the Italian Ministry of Health and by Programma di ricerca Regione-Universita 2010-2012 Area 1 Strategic Programmes from the Regione Emilia-Romagna. Funding for the Exome Sequencing Project Early-Onset Myocardial Infarction study was provided by grants RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP) from the National Heart, Lung, and Blood Institute. Exome sequencing was performed through grants RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO) from the National Heart, Lung, and Blood Institute. Exome sequencing in ATVB, the Precocious Coronary Artery Disease study (PROCARDIS), the Ottawa Heart Study, PROMIS, South German Myocardial Infarction study, and the Jackson Heart Study was supported by grant 5U54HG003067 from the National Institutes of Health (Drs Lander and Gabriel). The DiscovEHR study was supported in part by the Regeneron Genetics Center. NR 37 TC 0 Z9 0 U1 3 U2 3 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 MAR 7 PY 2017 VL 317 IS 9 BP 937 EP 946 DI 10.1001/jama.2017.0972 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EM8DM UT WOS:000395541500013 PM 28267856 ER PT J AU Bibbins-Domingo, K Grossman, DC Curry, SJ Barry, MJ Davidson, KW Doubeni, CA Epling, J Garcia, FAR Kemper, AR Krist, AH Kurth, AE Landefeld, CS Mangione, CM Phillips, WR Phipps, MG Silverstein, M Simon, M Siu, AL Tseng, CW AF Bibbins-Domingo, Kirsten Grossman, David C. Curry, Susan J. Barry, Michael J. Davidson, Karina W. Doubeni, Chyke A. Epling, Johnw., Jr. Garcia, Francisco A. R. Kemper, Alex R. Krist, Alex H. Kurth, Ann E. Landefeld, C. Seth Mangione, Carol M. Phillips, William R. Phipps, Maureen G. Silverstein, Michael Simon, Melissa Siu, Albert L. Tseng, Chien-Wen CA US Preventive Serv Task Force TI Screening for Gynecologic Conditions With Pelvic Examination US Preventive Services Task Force Recommendation Statement SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OVARIAN-CANCER; CLINICAL MANIFESTATIONS; BACTERIAL VAGINOSIS; ASYMPTOMATIC WOMEN AB IMPORTANCE Many conditions that can affect women's health are often evaluated through pelvic examination. Although the pelvic examination is a common part of the physical examination, it is unclear whether performing screening pelvic examinations in asymptomatic women has a significant effect on disease morbidity and mortality. OBJECTIVE To issue a new US Preventive Services Task Force(USPSTF) recommendation on screening for gynecologic conditions with pelvic examination for conditions other than cervical cancer, gonorrhea, and chlamydia, for which the USPSTF has already made specific recommendations. EVIDENCE REVIEW The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of performing screening pelvic examinations in asymptomatic, nonpregnant adult women 18 years and older who are not at increased risk for any specific gynecologic condition. FINDINGS Overall, the USPSTF found inadequate evidence on screening pelvic examinations for the early detection and treatment of a range of gynecologic conditions in asymptomatic, nonpregnant adult women. CONCLUSIONS AND RECOMMENDATION The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of performing screening pelvic examinations in asymptomatic, nonpregnant adult women. (I statement) This statement does not apply to specific disorders for which the USPSTF already recommends screening (ie, screening for cervical cancer with a Papanicolaou smear, screening for gonorrhea and chlamydia). C1 [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossman, David C.] Grp Hlth Res Inst, Seattle, WA USA. [Curry, Susan J.] Univ Iowa, Iowa City, IA USA. [Barry, Michael J.] Harvard Med Sch, Boston, MA USA. [Davidson, Karina W.] Columbia Univ, New York, NY USA. [Doubeni, Chyke A.] Univ Penn, Philadelphia, PA 19104 USA. [Epling, Johnw., Jr.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Garcia, Francisco A. R.] Pima Cty Dept Hlth, Tucson, AZ USA. [Kemper, Alex R.] Duke Univ, Durham, NC USA. [Krist, Alex H.] Fairfax Family Practice Residency, Fairfax, VA USA. [Krist, Alex H.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Kurth, Ann E.] Yale Univ, New Haven, CT USA. [Landefeld, C. Seth] Univ Alabama Birmingham, Birmingham, AL USA. [Mangione, Carol M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Phillips, William R.] Univ Washington, Seattle, WA 98195 USA. [Phipps, Maureen G.] Brown Univ, Providence, RI 02912 USA. [Silverstein, Michael] Boston Univ, Boston, MA 02215 USA. [Simon, Melissa] Northwestern Univ, Evanston, IL USA. [Siu, Albert L.] Mt Sinai Hosp, New York, NY 10029 USA. [Siu, Albert L.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Tseng, Chien-Wen] Univ Hawaii Manoa, Honolulu, HI 96822 USA. RP Bibbins-Domingo, K (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM chair@uspstf.net FU USPSTF FX The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF. NR 23 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 MAR 7 PY 2017 VL 317 IS 9 BP 947 EP 953 DI 10.1001/jama.2017.0807 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA EM8DM UT WOS:000395541500014 ER PT J AU Balasubramanian, P Kumar, R Williams, C Itri, V Wang, SX Lu, S Hessell, AJ Haigwood, NL Sinangil, F Higgins, KW Liu, L Li, LZ Nyambi, P Gorny, MK Totrov, M Nadas, A Kong, XP Zolla-Pazner, S Hioe, CE AF Balasubramanian, Preetha Kumar, Rajnish Williams, Constance Itri, Vincenza Wang, Shixia Lu, Shan Hessell, Ann J. Haigwood, Nancy L. Sinangil, Faruk Higgins, Keith W. Liu, Lily Li, Liuzhe Nyambi, Phillipe Gorny, Miroslaw K. Totrov, Maxim Nadas, Arthur Kong, Xiang-Peng Zolla-Pazner, Susan Hioe, Catarina E. TI Differential induction of anti-V3 crown antibodies with cradle- and ladle-binding modes in response to HIV-1 envelope vaccination SO VACCINE LA English DT Article DE HIV; HIV envelope; V3; Mimotopes; Antibodies ID V3 LOOP; TYPE-1 GP120; NEUTRALIZING ANTIBODIES; V3-SPECIFIC ANTIBODIES; HIV-1-INFECTED HUMANS; MONOCLONAL-ANTIBODIES; BROAD NEUTRALIZATION; IMMUNE-RESPONSE; INFECTION; EPITOPES AB The V3 loop in the HIV envelope gp120 is one of the immunogenic sites targeted by Abs. The V3 crown in particular has conserved structural elements recognized by cross-reactive neutralizing Abs, indicating its potential contribution in protection against HIV. Crystallographic analyses of anti-V3 crown mAbs in complex with the V3 peptides have revealed that these mAbs recognize the conserved sites on the V3 crown via two distinct strategies: a cradle-binding mode (V3C) and a ladle-binding (V3L) mode. However, almost all of the anti-V3 crown mAbs studied in the past were isolated from chronically HIV-infected individuals. The extents to which the two types of anti-V3 crown Abs are generated by vaccination are unknown. This study analyzed the prevalence of V3C-type and V3L-type Ab responses in HIV-infected individuals and in HIV envelope-immunized humans and animals using peptide mimotopes that distinguish the two Ab types. The results show that both V3L-type and V3C-type Abs were generated by the vast majority of chronically HIV-infected humans, although the V3L-type were more prevalent. In contrast, only one of the two V3 Ab types was elicited in vaccinated humans or animal models, irrespective of HIV-1 envelope clades, envelope constructs (oligomeric or monomeric), and protocols (DNA plus protein or protein alone) used for vaccinations. The V3C-type Abs were produced by vaccinated humans. macaques, and rabbits, whereas the V3L-type Abs were made by mice. The V3C-type and V3L-type Abs generated by the vaccinations were able to mediate virus neutralization. These data indicate the restricted repertoires and the species-specific differences in the functional V3-specific Ab responses induced by the HIV envelope vaccines. The study implies the need for improving immunogen designs and vaccination strategies to broaden the diversity of Abs in order to target the different conserved epitopes in the V3 loop and, by extension, in the entire HIV envelope. Published by Elsevier Ltd. C1 [Balasubramanian, Preetha] NYU, Sch Med, Sackler Inst Grad Biomed Sci, New York, NY 10016 USA. [Balasubramanian, Preetha; Kumar, Rajnish; Itri, Vincenza; Zolla-Pazner, Susan; Hioe, Catarina E.] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA. [Kumar, Rajnish; Hioe, Catarina E.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Williams, Constance; Liu, Lily; Li, Liuzhe; Nyambi, Phillipe; Gorny, Miroslaw K.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Wang, Shixia; Lu, Shan] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Hessell, Ann J.; Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Sinangil, Faruk; Higgins, Keith W.] Global Solut Infect Dis, San Francisco, CA USA. [Totrov, Maxim] Molsoft LLC, 3366 N Torrey Pines Ct, La Jolla, CA 92037 USA. [Nadas, Arthur] NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. [Kong, Xiang-Peng] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. RP Hioe, CE (reprint author), Dept Med, Div Infect Dis, One Gustave L Levy Pl,Box 1090, New York, NY 10029 USA. EM catarina.hioe@mssm.edu FU Henry M. Jackson Foundation for the Advancement of Military Medicine - USA; NIH [R21 AI114520, HIVRAD P01 AI100151]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX This work was supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine - USA (SZP, CEH), NIH grants R21 AI114520 (CEH) and HIVRAD P01 AI100151 (XPK, SZP) and by research funds from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (VA Merit Review and Research Career Scientist - CEH). NR 49 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 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAR 7 PY 2017 VL 35 IS 10 BP 1464 EP 1473 DI 10.1016/j.vaccine.2016.11.107 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EM9DK UT WOS:000395611300015 PM 28185743 ER PT J AU Bax, JJ Delgado, V Sogaard, P Singh, JP Abraham, WT Borer, JS Dickstein, K Gras, D Brugada, J Robertson, M Ford, I Krum, H Holzmeister, J Ruschitzka, F Gorcsan, J AF Bax, Jeroen J. Delgado, Victoria Sogaard, Peter Singh, Jagmeet P. Abraham, William T. Borer, Jeffrey S. Dickstein, Kenneth Gras, Daniel Brugada, Josep Robertson, Michele Ford, Ian Krum, Henry Holzmeister, Johannes Ruschitzka, Frank Gorcsan, John TI Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Global longitudinal strain; Prognosis; Cardiac resynchronization therapy; Narrow QRS complex ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL-INFARCTION; EJECTION FRACTION; ESC GUIDELINES; SCAR BURDEN; DYSFUNCTION; FIBROSIS; CARDIOMYOPATHY; ASSOCIATION; PREDICTOR AB Aim Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. Methods and results Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4-and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2-10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04-1.17, P< 0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (< 6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P = 0.009) whereas, no differences were observed in patients with LV GLS > 6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P = 0.62). Conclusion Low LV GLS is associated with poor outcome in heart failure patients with QRS width <130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes. C1 [Bax, Jeroen J.; Delgado, Victoria] Leiden Univ, Med Ctr, Dept Cardiol, Albinusdreef 2, NL-2300 RC Leiden, Netherlands. [Sogaard, Peter] Aalborg Univ, Fredrik Bajers Vej 7-D3, DK-9220 Aalborg, Denmark. [Singh, Jagmeet P.] Harvard Med Sch, Corrigan Minehan Heart Ctr, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. [Abraham, William T.] Ohio State Univ, Med Ctr, Davis Heart & Lung Res Inst, Div Cardiovasc Med, 473 West 12th Ave,Room 110P, Columbus, OH 43210 USA. [Borer, Jeffrey S.] SUNY Downstate Coll Med, Div Cardiovasc Med, 450 Clarkson Ave,Sixth Floor, Brooklyn, NY USA. [Borer, Jeffrey S.] SUNY Downstate Coll Med, Div Cardiovasc Med, Howard Gilman Inst, 450 Clarkson Ave,Sixth Floor, Brooklyn, NY USA. [Borer, Jeffrey S.] SUNY Downstate Coll Med, Div Cardiovasc Med, Ron & Jean Schiavone Inst, 450 Clarkson Ave,Sixth Floor, Brooklyn, NY USA. [Dickstein, Kenneth] Univ Bergen, Stavanger Univ Hosp, Postboks 8600 Forus, N-4036 Stavanger, Norway. [Gras, Daniel] Nouvelles Clin Nantaises, 2-4 Rue Eric Tabarly, F-44200 Nantes, France. [Brugada, Josep] Univ Barcelona, Hosp Clin, Thorax Inst, Cardiol Dept, Villarroel 170, E-08036 Barcelona, Spain. [Robertson, Michele; Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Krum, Henry] Monash Univ, Monash Ctr Cardiovasc Res & Educ Therapeut, Clayton, Vic 3800, Australia. [Holzmeister, Johannes; Ruschitzka, Frank] Univ Zurich Hosp, Clin Cardiol, Moussonstr 4, CH-8091 Zurich, Switzerland. [Gorcsan, John] Univ Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA 15260 USA. RP Bax, JJ (reprint author), Leiden Univ, Med Ctr, Dept Cardiol, Albinusdreef 2, NL-2300 RC Leiden, Netherlands. EM j.j.bax@lumc.nl NR 22 TC 2 Z9 2 U1 0 U2 0 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 MAR 7 PY 2017 VL 38 IS 10 BP 720 EP 726 DI 10.1093/eurheartj/ehw506 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO5ZP UT WOS:000396771800001 ER PT J AU Wasfy, JH Zigler, CM Choirat, C Wang, Y Dominici, F Yeh, RW AF Wasfy, Jason H. Zigler, Corwin Matthew Choirat, Christine Wang, Yun Dominici, Francesca Yeh, Robert W. TI Readmission Rates After Passage of the Hospital Readmissions Reduction Program SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; 30-DAY MORTALITY-RATES; MEDICARE BENEFICIARIES; HEART-FAILURE; PERFORMANCE; OUTCOMES; ENGLAND; PAY AB Background: Whether hospitals with the highest riskstandardized readmission rates (RSRRs) subsequently experienced the greatest improvement after passage of the Medicare Hospital Readmissions Reduction Program (HRRP) is unknown. Objective: To evaluate whether passage of the HRRP was followed by acceleration in improvement in 30-day RSRRs after hospitalizations for acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia and whether the lowestperforming hospitals had faster acceleration in improvement after passage of the law than hospitals that were already performing well. Design: Pre-post analysis stratified by hospital performance groups. Setting: U.S. acute care hospitals. Patients: 15 170 008 Medicare patients discharged alive from 2000 to 2013. Intervention: Passage of the HRRP. Measurements: 30-day readmission rates after hospitalization for AMI, CHF, or pneumonia for hospitals in the highestperformance (0% penalty), average-performance (>0% and <0.50% penalty), low-performance (>= 0.50% and <0.99% penalty), and lowest-performance (>= 0.99% penalty) groups. Results: Of 2868 hospitals serving 1 109 530 Medicare discharges annually, 30.1% were highest performers, 44.0% were average performers, 16.8% were low performers, and 9.0% were lowest performers. After controlling for prelaw trends, an additional 67.6 (95% CI, 66.6 to 68.4), 74.8 (CI, 74.0 to 75.4), 85.4 (CI, 84.0 to 86.8), and 95.1 (CI, 92.6 to 97.5) readmissions per 10 000 discharges were found to have been averted per year in the highest-, average-, low-, and lowest-performance groups, respectively, after passage of the law. Limitation: Inability to distinguish between improvement caused by the magnitude of the penalty or by different levels of health improvement in different patient populations. Conclusion: After passage of the HRRP, 30-day RSRRs for myocardial infarction, heart failure, and pneumonia decreased more rapidly than before the law's passage. Improvement was most marked for hospitals with the lowest prelaw performance. C1 [Wasfy, Jason H.] Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Dominici, Francesca] Harvard TH Chan Sch Publ Hlth, Off Dean, 655 Huntington Ave, Boston, MA 02115 USA. [Yeh, Robert W.] Beth Israel Deaconess Med Ctr, Smith Ctr Outcomes Res Cardiol, 375 Longwood Ave, Boston, MA 02215 USA. [Zigler, Corwin Matthew; Choirat, Christine; Wang, Yun; Dominici, Francesca] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. RP Dominici, F (reprint author), Harvard TH Chan Sch Publ Hlth, Off Dean, 655 Huntington Ave, Boston, MA 02115 USA.; Yeh, RW (reprint author), Beth Israel Deaconess Med Ctr, Smith Ctr Outcomes Res Cardiol, 375 Longwood Ave, Boston, MA 02215 USA.; Dominici, F (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. EM jwasfy@mgh.harvard.edu FU National Institutes of Health FX National Institutes of Health. NR 25 TC 0 Z9 0 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 MAR 7 PY 2017 VL 166 IS 5 BP 324 EP + DI 10.7326/M16-0185 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EO1BO UT WOS:000396432800005 PM 28024302 ER PT J AU Sales, VM Ferguson-Smith, AC Patti, ME AF Sales, Vicencia Micheline Ferguson-Smith, Anne C. Patti, Mary-Elizabeth TI Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations SO CELL METABOLISM LA English DT Review ID HIGH-FAT DIET; LOW-BIRTH-WEIGHT; DNA METHYLATION; EARLY-LIFE; GLUCOSE-INTOLERANCE; PRENATAL EXPOSURE; GENE-EXPRESSION; MAMMALIAN DNA; TRANSGENERATIONAL INHERITANCE; MITOCHONDRIAL DYSFUNCTION AB Both human and animal studies indicate that environmental exposures experienced during early life can robustly influence risk for adult disease. Moreover, environmental exposures experienced by parents during either intrauterine or postnatal life can also influence the health of their offspring, thus initiating a cycle of disease risk across generations. In this Perspective, we focus on epigenetic mechanisms in germ cells, including DNA methylation, histone modification, and non-coding RNAs, which collectively may provide a non-genetic molecular legacy of prior environmental exposures and influence transcriptional regulation, developmental trajectories, and adult disease risk in offspring. C1 [Sales, Vicencia Micheline; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, Integrat Physiol & Metab, One Joslin Pl,Sixth Floor, Boston, MA 02215 USA. [Sales, Vicencia Micheline; Patti, Mary-Elizabeth] Harvard Med Sch, One Joslin Pl,Sixth Floor, Boston, MA 02215 USA. [Ferguson-Smith, Anne C.] Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England. RP Patti, ME (reprint author), Joslin Diabet Ctr, Div Res, Integrat Physiol & Metab, One Joslin Pl,Sixth Floor, Boston, MA 02215 USA.; Patti, ME (reprint author), Harvard Med Sch, One Joslin Pl,Sixth Floor, Boston, MA 02215 USA. EM mary.elizabeth.patti@joslin.harvard.edu FU Harvard Epigenetics Grant; NIH [R01 DK106193, P30 DK036836]; Wellcome Trust [WT095606]; MRC [MR/J001597/1] FX We would like to acknowledge support from the Harvard Epigenetics Grant, NIH R01 DK106193 (to M.-E.P. and A.C.F.-S.), P30 DK036836 (Joslin DRC), and Wellcome Trust WT095606 and MRC MR/J001597/1 (to A.C.F.-S.). NR 136 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 7 PY 2017 VL 25 IS 3 BP 559 EP 571 DI 10.1016/j.cmet.2017.02.016 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EN9YO UT WOS:000396355700014 PM 28273478 ER PT J AU Fan, Y Hanai, J Le, PT Bi, RY Maridas, D DeMambro, V Figueroa, CA Kir, S Zhou, XD Mannstadt, M Baron, R Bronson, RT Horowitz, MC Wu, JY Bilezikian, JP Dempster, DW Rosen, CJ Lanske, B AF Fan, Yi Hanai, Jun-ichi Le, Phuong T. Bi, Ruiye Maridas, David DeMambro, Victoria Figueroa, Carolina A. Kir, Serkan Zhou, Xuedong Mannstadt, Michael Baron, Roland Bronson, Roderick T. Horowitz, Mark C. Wu, Joy Y. Bilezikian, John P. Dempster, David W. Rosen, Clifford J. Lanske, Beate TI Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate SO CELL METABOLISM LA English DT Article ID INHIBITS ADIPOCYTE DIFFERENTIATION; OSTEOBLASTIC CELLS; MINERAL DENSITY; ADIPOSE-TISSUE; STEM-CELLS; PROTEIN; OSTEOPOROSIS; EXPRESSION; RECEPTOR; ADIPOGENESIS AB Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1(+)RANKL(+) marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH's therapeutic action through its ability to direct mesenchymal cell fate. C1 [Fan, Yi; Baron, Roland; Lanske, Beate] Harvard Sch Dent Med, Div Bone & Mineral Res, Boston, MA 02115 USA. [Fan, Yi; Bi, Ruiye; Zhou, Xuedong] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China. [Hanai, Jun-ichi] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Hanai, Jun-ichi] Harvard Med Sch, Boston, MA 02215 USA. [Le, Phuong T.; Maridas, David; DeMambro, Victoria; Figueroa, Carolina A.; Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA. [Bi, Ruiye; Mannstadt, Michael; Baron, Roland; Lanske, Beate] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bi, Ruiye; Mannstadt, Michael; Baron, Roland; Lanske, Beate] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Kir, Serkan] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Bronson, Roderick T.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [Horowitz, Mark C.] Yale Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06510 USA. [Wu, Joy Y.] Stanford Univ, Sch Med, Div Endocrinol, Stanford, CA 94305 USA. [Bilezikian, John P.] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10032 USA. [Dempster, David W.] Columbia Univ, Dept Pathol, Coll Phys & Surg, New York, NY 10032 USA. RP Lanske, B (reprint author), Harvard Sch Dent Med, Div Bone & Mineral Res, Boston, MA 02115 USA.; Rosen, CJ (reprint author), Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA.; Lanske, B (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA.; Lanske, B (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02114 USA. EM rosenc@mmc.org; beate_lanske@hsdm.harvard.edu FU NIH/NIGMS [P30GM106391]; NIH [DK097105, DK100584, DK092759-06]; Dean's Scholarship from Harvard School of Dental Medicine; State Key Laboratory of Oral Diseases Open Funding [SKLOD2015OF01]; Fujifilm cooperation; Eli Lilly FX We thank Drs. Noriko Ide, William N. Addison, and Tadatoshi Sato for help with experimental protocols and Mr. Hao Wang for assistance with animal care. We also thank Dr. T.J. Martin for discussing the data and providing valuable input. This work was supported by grants from the NIH/NIGMS P30GM106391, NIH DK097105 (B.L.), DK100584 (M.M.), and DK092759-06 (C.J.R.), Dean's Scholarship from Harvard School of Dental Medicine (Y.F.), and State Key Laboratory of Oral Diseases Open Funding (SKLOD2015OF01). J.-i.H. obtains salary support from Fujifilm cooperation, R.B. is on the advisory board of Eli Lilly and Radius Health, and D.W.D. obtains research support, consulting fees, and honoraria for speaking at Eli Lilly. NR 47 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 7 PY 2017 VL 25 IS 3 BP 661 EP 672 DI 10.1016/j.cmet.2017.01.001 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EN9YO UT WOS:000396355700022 PM 28162969 ER PT J AU Lindner, SM Fordyce, CB Hellkamp, AS Lokhnygina, Y Piccini, JP Breithardt, G Mahaffey, KW Singer, DE Hacke, W Halperin, JL Hankey, GJ Berkowitz, SD Nessel, CC Becker, RC Fox, KAA Patel, MR AF Lindner, Samuel M. Fordyce, Christopher B. Hellkamp, Anne S. Lokhnygina, Yuliya Piccini, Jonathan P. Breithardt, Gnter Mahaffey, Kenneth W. Singer, Daniel E. Hacke, Werner Halperin, Jonathan L. Hankey, Graeme J. Berkowitz, Scott D. Nessel, Christopher C. Becker, Richard C. Fox, Keith A. A. Patel, Manesh R. CA ROCKET AF Steering Comm TI Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin A ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis SO CIRCULATION LA English DT Letter DE atrial fibrillation; renal function ID SYSTEMIC EMBOLISM; OUTCOMES C1 [Lindner, Samuel M.; Fordyce, Christopher B.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Piccini, Jonathan P.; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Fordyce, Christopher B.] Univ British Columbia, Div Cardiol, Vancouver, BC, Canada. [Breithardt, Gnter] Univ Munster, Dept Cardiovasc Med, Munster, Germany. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. [Hacke, Werner] Ruprecht Karls Univ Heidelberg, Heidelberg, Germany. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Parsippany, NJ USA. [Nessel, Christopher C.] Janssen Res & Dev LLC, Raritan, NJ USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Patel, MR (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Med, Rm 0311 Terrace Level,2400 Pratt St, Durham, NC 27705 USA. EM manesh.patel@duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Johnson Johnson; Bayer FX ROCKET AF was funded by Johnson & Johnson and Bayer. NR 5 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 7 PY 2017 VL 135 IS 10 BP 1001 EP 1003 DI 10.1161/CIRCULATIONAHA.116.024666 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EN1KP UT WOS:000395769200021 PM 28264892 ER PT J AU Brugada, J Delnoy, PP Brachmann, J Reynolds, D Padeletti, L Noelker, G Kantipudi, C Lopez, JMR Dichtl, W Borri-Brunetto, A Verhees, L Ritter, P Singh, JP AF Brugada, Josep Delnoy, Peter Paul Brachmann, Johannes Reynolds, Dwight Padeletti, Luigi Noelker, Georg Kantipudi, Charan Rubin Lopez, Jose Manuel Dichtl, Wolfgang Borri-Brunetto, Alberto Verhees, Luc Ritter, Philippe Singh, Jagmeet P. CA RESPOND CRT Investigators TI Contractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial SO EUROPEAN HEART JOURNAL LA English DT Article DE SonR; AV and VV optimization; CRT optimization; Cardiac contractility; RESPOND; HF hospitalization; Adaptive CRT ID CHRONIC HEART-FAILURE; PEAK ENDOCARDIAL ACCELERATION; HEMODYNAMIC SENSOR; AUTOMATIC OPTIMIZATION; CLINICAL-OUTCOMES; EUROPEAN-SOCIETY; TASK-FORCE; LEAD; LONG; CARDIOMYOPATHY AB Aims Although cardiac resynchronization therapy (CRT) is effective in patients with systolic heart failure (HF) and a wide QRS interval, a substantial proportion of patients remain non-responsive. The SonR contractility sensor embedded in the right atrial lead enables individualized automatic optimization of the atrioventricular (AV) and interventricular (VV) timings. The RESPOND-CRT study investigated the safety and efficacy of the contractility sensor system in HF patients undergoing CRT. Methods and results RESPOND-CRT was a prospective, randomized, double-blinded, multicentre, non-inferiority trial. Patients were randomized (2: 1, respectively) to receive weekly, automatic CRT optimization with SonR vs. an Echo-guided optimization of AV and VV timings. The primary efficacy endpoint was the rate of clinical responders (patients alive, without adjudicated HF-related events, with improvement in New York Heart Association class or quality of life), at 12 months. The study randomized 998 patients. Responder rates were 75.0% in the SonR arm and 70.4% in the Echo arm (mean difference, 4.6%; 95% CI, -1.4% to 10.6%; P<0.001 for non-inferiority margin -10.0%) (Table 2). At an overall mean follow-up of 5486190 days SonR was associated with a 35% risk reduction in HF hospitalization (hazard ratio, 0.65; 95% CI, 0.46-0.92; log-rank P = 0.01). Conclusion Automatic AV and VV optimization using the contractility sensor was safe and as effective as Echo-guided AV and VV optimization in increasing response to CRT. C1 [Brugada, Josep] Univ Barcelona, Cardiovasc Inst, Hosp Clin, Barcelona, Spain. [Delnoy, Peter Paul] Isala Klinieken Zwolle, Zwolle, Netherlands. [Brachmann, Johannes] Coburg Hosp, Coburg, Germany. [Reynolds, Dwight] Univ Oklahoma, Oklahoma City, OK USA. [Padeletti, Luigi] Univ Florence, Florence, Italy. [Padeletti, Luigi] IRCCS Multimed, Milan, Italy. [Noelker, Georg] Herz & Diabet Zentrum, Bad Oeynhausen, Germany. [Kantipudi, Charan] Piedmont Heart Inst, Atlanta, GA USA. [Rubin Lopez, Jose Manuel] Hosp Univ Cent Asturias, Oviedo, Spain. [Dichtl, Wolfgang] Med Univ Innsbruck, Dept Internal Med 3, Innsbruck, Austria. [Borri-Brunetto, Alberto] LivaNova Cardiac Rhythm Management, Saluggia, Italy. [Verhees, Luc] LivaNova, Clamart, France. [Ritter, Philippe] Univ Hosp Bordeaux, Pessac, France. [Singh, Jagmeet P.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Brugada, J (reprint author), Univ Barcelona, Cardiovasc Inst, Hosp Clin, Barcelona, Spain. EM jbrugada@clinic.ub.es FU Sorin CRM SAS (LivaNova), Clamart, France FX The RESPOND-CRT study has been funded by Sorin CRM SAS (LivaNova), Clamart, France. NR 31 TC 2 Z9 2 U1 1 U2 1 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 MAR 7 PY 2017 VL 38 IS 10 BP 730 EP 738 DI 10.1093/eurheartj/ehw526 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO2FB UT WOS:000396510900006 ER PT J AU Chopyk, J Chattopadhyay, S Kulkarni, P Smyth, EM Hittle, LE Paulson, JN Pop, M Buehler, SS Clark, PI Mongodin, EF Sapkota, AR AF Chopyk, Jessica Chattopadhyay, Suhana Kulkarni, Prachi Smyth, Eoghan M. Hittle, Lauren E. Paulson, Joseph N. Pop, Mihai Buehler, Stephanie S. Clark, Pamela I. Mongodin, Emmanuel F. Sapkota, Amy R. TI Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE cigarettes; tobacco; bacteria; bacterial community composition; microbiome; storage conditions; tobacco-specific nitrosamines; 16S rRNA gene ID FLUE-CURED TOBACCO; STAPHYLOCOCCUS-AUREUS; PANTOEA-AGGLOMERANS; BURLEY TOBACCO; HEALTHY-ADULTS; N-NITROSAMINES; SMOKE; PRODUCTS; LEAVES; TEMPERATURE AB Tobacco products, specifically cigarettes, are home to microbial ecosystems that may play an important role in the generation of carcinogenic tobacco-specific nitrosamines (TSNAs), as well as the onset of multiple adverse human health effects associated with the use of these products. Therefore, we conducted time-series experiments with five commercially available brands of cigarettes that were either commercially mentholated, custom-mentholated, user-mentholated, or non-mentholated. To mimic user storage conditions, the cigarettes were incubated for 14 days under three different temperatures and relative humidities (i.e., pocket, refrigerator, and room). Overall, 360 samples were collected over the course of 2 weeks and total DNA was extracted, PCR amplified for the V3V4 hypervariable region of the 16S rRNA gene and sequenced using Illumina MiSeq. A subset of samples (n = 32) was also analyzed via liquid chromatography with tandem mass spectrometry for two TSNAs: N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Comparative analyses of the five tobacco brands revealed bacterial communities dominated by Pseudomonas, Pantoea, and Bacillus, with Pseudomonas relatively stable in abundance regardless of storage condition. In addition, core bacterial operational taxonomic units (OTUs) were identified in all samples and included Bacillus pumilus, Rhizobium sp., Sphingomonas sp., unknown Enterobacteriaceae, Pantoea sp., Pseudomonas sp., Pseudomonas oryzihabitans, and P. putida. Additional OTUs were identified that significantly changed in relative abundance between day 0 and day 14, influenced by brand and storage condition. In addition, small but statistically significant increases in NNN levels were observed in user- and commercially mentholated brands between day 0 and day 14 at pocket conditions. These data suggest that manufacturing and user manipulations, such as mentholation and storage conditions, may directly impact the microbiome of cigarette tobacco as well as the levels of carcinogens. C1 [Chopyk, Jessica; Chattopadhyay, Suhana; Kulkarni, Prachi; Smyth, Eoghan M.; Sapkota, Amy R.] Univ Maryland, Sch Publ Hlth, Maryland Inst Appl Environm Hlth, College Pk, MD 20742 USA. [Smyth, Eoghan M.; Hittle, Lauren E.] Univ Maryland, Inst Genome Sci, Baltimore, MD 21201 USA. [Smyth, Eoghan M.; Hittle, Lauren E.; Mongodin, Emmanuel F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Paulson, Joseph N.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Paulson, Joseph N.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Pop, Mihai] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Buehler, Stephanie S.] Publ Hlth Ctr Tobacco Res, Columbus, OH USA. [Clark, Pamela I.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, College Pk, MD 20742 USA. RP Sapkota, AR (reprint author), Univ Maryland, Sch Publ Hlth, Maryland Inst Appl Environm Hlth, College Pk, MD 20742 USA. EM ars@umd.edu FU National Cancer Institute [P50CA180523]; Food and Drug Administration, Center for Tobacco Products [P50CA180523] FX Research reported in this publication was supported by grant number P50CA180523, from the National Cancer Institute and Food and Drug Administration, Center for Tobacco Products awarded to the University of Maryland. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. NR 66 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 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD MAR 7 PY 2017 VL 8 AR 358 DI 10.3389/fmicb.2017.00358 PG 14 WC Microbiology SC Microbiology GA EM8OA UT WOS:000395569500001 PM 28326071 ER PT J AU Ibrahim, NE Januzzi, AJL Magaret, CA Gaggin, HK Rhyne, RF Gandhi, PU Kelly, N Simon, ML Motiwala, SR Belcher, AM van Kimmenade, RRJ AF Ibrahim, Nasrien E. Januzzi, A. James L., Jr. Magaret, Craig A. Gaggin, Hanna K. Rhyne, Rhonda F. Gandhi, Parul U. Kelly, Noreen Simon, Mandy L. Motiwala, Shweta R. Belcher, Arianna M. van Kimmenade, Roland R. J. TI A Clinical and Biomarker Scoring System to Predict the Presence of Obstructive Coronary Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE diagnosis; myocardial infarction; negative predictive value; positive predictive value; stenosis ID INJURY MOLECULE-1 KIM-1; RISK SCORE; MIDKINE; MODEL; MICE AB BACKGROUND Noninvasive models to predict the presence of coronary artery disease (CAD) may help reduce the societal burden of CAD. OBJECTIVES From a prospective registry of patients referred for coronary angiography, the goal of this study was to develop a clinical and biomarker score to predict the presence of significant CAD. METHODS In a training cohort of 649 subjects, predictors of >= 70% stenosis in at least 1 major coronary vessel were identified from >200 candidate variables, including 109 biomarkers. The final model was then validated in a separate cohort (n = 278). RESULTS The scoring system consisted of clinical variables (male sex and previous percutaneous coronary intervention) and 4 biomarkers (midkine, adiponectin, apolipoprotein C-I, and kidney injury molecule-1). In the training cohort, elevated scores were predictive of >= 70% stenosis in all subjects (odds ratio [ OR]: 9.74; p < 0.001), men (OR: 7.88; p < 0.001), women (OR: 24.8; p < 0.001), and those with no previous CAD (OR: 8.67; p < 0.001). In the validation cohort, the score had an area under the receiver-operating characteristic curve of 0.87 (p < 0.001) for coronary stenosis >= 70%. Higher scores were associated with greater severity of angiographic stenosis. At optimal cutoff, the score had 77% sensitivity, 84% specificity, and a positive predictive value of 90% for >= 70% stenosis. Partitioning the score into 5 levels allowed for identifying or excluding CAD with > 90% predictive value in 42% of subjects. An elevated score predicted incident acute myocardial infarction during 3.6 years of follow up (hazard ratio: 2.39; p < 0.001). CONCLUSIONS We described a clinical and biomarker score with high accuracy for predicting the presence of anatomically significant CAD. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases; NCT00842868) (C) 2017 by the American College of Cardiology Foundation. C1 [Ibrahim, Nasrien E.; Januzzi, A. James L., Jr.; Gaggin, Hanna K.; Simon, Mandy L.; Belcher, Arianna M.] Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. [Januzzi, A. James L., Jr.; Gaggin, Hanna K.] Harvard Clin Res Inst, Cardiometab Trials, Boston, MA USA. [Magaret, Craig A.; Rhyne, Rhonda F.] Prevencio Inc, Kirkland, WA USA. [Gandhi, Parul U.] Yale Univ, Cardiol, New Haven, CT USA. [Kelly, Noreen; Motiwala, Shweta R.] Brigham & Womens Hosp, Cardiol, 75 Francis St, Boston, MA 02115 USA. [van Kimmenade, Roland R. J.] Radboud Univ Nijmegen, Med Ctr, Dept Cardiol, Nijmegen, Netherlands. RP Januzzi, AJL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Prevencio, Inc.; Dennis and Marilyn Barry Fellowship in Cardiology; Hutter Family Professorship in Cardiology; Siemens; Singulex; Cardiology; Prevencio; Ruth and James Clark Fund for Cardiac Research Innovation; Roche; Portola FX This work was supported by a grant from Prevencio, Inc. Dr. Ibrahim is supported by the Dennis and Marilyn Barry Fellowship in Cardiology. Dr. Januzzi is supported in part by the Hutter Family Professorship in Cardiology; has received grant support from Siemens, Singulex, and Prevencio; consulting income from Roche Diagnostics, Critical Diagnostics, Sphingotec, Phillips, and Novartis; and participates in clinical endpoint committees/data safety monitoring boards for Novartis, Amgen, Janssen, and Boehringer Ingelheim. Dr. Gaggin is supported in part by the Ruth and James Clark Fund for Cardiac Research Innovation; and has received grant support from Roche and Portola; consulting income from Roche Diagnostics, American Regent, Amgen, Boston Heart Diagnostics, and Critical Diagnostics; and research payments for clinical endpoint committees for EchoSense and RadioMeter. Mr. Magaret is a consultant to Prevencio, Inc. Ms. Rhyne is an employee of Prevencio, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Ibrahim and Januzzi contributed equally to this work. Sanjay Kaul, MD, served as Guest Editor for this paper. NR 18 TC 1 Z9 1 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 MAR 7 PY 2017 VL 69 IS 9 BP 1147 EP 1156 DI 10.1016/j.jacc.2016.12.021 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9ZY UT WOS:000396359300007 PM 28254177 ER PT J AU Pollack, TM Duong, HT Pham, TT Do, CD Colby, D AF Pollack, Todd M. Duong, Hao T. Pham, Thuy T. Do, Cuong D. Colby, Donn TI Cigarette smoking is associated with high HIV viral load among adults presenting for antiretroviral therapy in Vietnam SO PLOS ONE LA English DT Article ID DISEASE PROGRESSION; ALCOHOL-CONSUMPTION; INFECTED PATIENTS; HEPATITIS-B; VIRUS LOAD; CELL COUNT; SET-POINT; IMPACT; COHORT; TUBERCULOSIS AB High HIV viral load (VL >100,000 cp/ml) is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART) at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Out of 636 patients, 62.7% were male, 72.9% were >= 30 years old, and 28.3% had a history of drug injection. Median CD4 was 132 cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having >= 5 drinks per event. Overall 53.0% had a VL >100,000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45), while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66). Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100,000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of tobacco use among HIV-infected patients. C1 [Pollack, Todd M.; Duong, Hao T.; Pham, Thuy T.] Partnership Hlth Adv Vietnam HAIVN, Hanoi, Vietnam. [Pollack, Todd M.] Harvard Med Sch, BIDMC, Boston, MA 02115 USA. [Pham, Thuy T.; Do, Cuong D.] BMH, Dept Infect Dis, Hanoi, Vietnam. [Colby, Donn] HCMC, Ctr Appl Res Men & Community Hlth CARMAH, Hanoi, Vietnam. [Colby, Donn] Thai Red Cross AIDS Res Ctr, SEARCH, Bangkok, Thailand. RP Pollack, TM (reprint author), Partnership Hlth Adv Vietnam HAIVN, Hanoi, Vietnam.; Pollack, TM (reprint author), Harvard Med Sch, BIDMC, Boston, MA 02115 USA. EM todd@haivn.org FU Roche Molecular Systems, Inc. (RMS); [L974] FX This study was funded by a research grant from Roche Molecular Systems, Inc. (RMS); contract No. L974. RMS developed the COBAS (R) AmpliPrep/COBAS (R) TaqMan (R) HIV-1 Test which was used in the study for measuring plasma HIV viral load. RMS has had no role in the study design; collection, analysis, and interpretation of data, writing of the paper, and/or decision to submit for publication. NR 51 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 MAR 7 PY 2017 VL 12 IS 3 AR e0173534 DI 10.1371/journal.pone.0173534 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5QM UT WOS:000396060600042 PM 28267790 ER PT J AU Eustache, E Gerbasi, ME Fawzi, MCS Fils-Aime, JR Severe, J Raviola, GJ Legha, R Darghouth, S Grelotti, DJ Therosme, T Pierre, EL Affricot, E Alcindor, Y Stack, MB Becker, AE AF Eustache, E. Gerbasi, M. E. Fawzi, M. C. Smith Fils-Aime, J. R. Severe, J. Raviola, G. J. Legha, R. Darghouth, S. Grelotti, D. J. Therosme, T. Pierre, E. L. Affricot, E. Alcindor, Y. Stack, M. B. Becker, A. E. TI Mental health training for secondary school teachers in Haiti: a mixed methods, prospective, formative research study of feasibility, acceptability, and effectiveness in knowledge acquisition SO GLOBAL MENTAL HEALTH LA English DT Article DE Haiti; school-based; task sharing; teachers; training ID MIDDLE-INCOME COUNTRIES; INTERVENTIONS; DISABILITY; EARTHQUAKE; CHALLENGES; DISORDERS; IMPACT; INDIA; CARE AB Background Engagement and training of educators in student mental health holds promise for promoting access to care as a task sharing strategy but has not been well-studied in low-income regions. Methods We used a prospective and convergent mixed methods design to evaluate a customized school mental health 21/2 day training for teachers in rural Haiti (n = 22) as the initial component of formative research developing a schoolbased intervention to promote student mental health. Training prepared teachers to respond to student mental health needs by providing psychoeducational and practical support to facilitate access to care. We examined level of participation and evaluated feasibility, acceptability, and perceived effectiveness by calculating mean scores on self-report Likert-style items eliciting participant experience. We examined effectiveness of the training on improving mental health knowledge and attitudes by comparing mean scores on an assessment administered pre- and post-training. Finally, we examined self-report written open-ended responses and focus group discussion (FGD) interview data bearing on perceived feasibility, acceptability, and effectiveness to contextualize participant ratings of training and to identify recommendations for enhancing the utility of mental health training locally for educators. Results Mean scores of knowledge and attitudes significantly improved between the pre- test and post-tests; e.g., knowledge improved from 58% correct at baseline to 68% correct on the second post-test (p = 0.039). Mean ratings of the training were favorable across all categories and FGD data demonstrated widespread participant endorsement of training acceptability and effectiveness; participants recommended extending the duration and number of training sessions. Conclusions Findings support feasibility, acceptability, and a limited scope of effectiveness of brief mental health training for secondary school teachers in Haiti. Further development of approaches to engage teachers in promoting school mental health through training is warranted. C1 [Eustache, E.; Fils-Aime, J. R.; Therosme, T.; Pierre, E. L.; Affricot, E.; Alcindor, Y.] Zanmi Lasante, Mental Hlth & Psychosocial Serv, Mirebalais, Haiti. [Gerbasi, M. E.; Fawzi, M. C. Smith; Severe, J.; Raviola, G. J.; Stack, M. B.; Becker, A. E.] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Severe, J.] Tufts Univ, Sch Med, Dept Psychiat, Baystate Med Ctr, Springfield, MA 01199 USA. [Raviola, G. J.] Partners Hlth, Boston, MA USA. [Raviola, G. J.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Legha, R.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Darghouth, S.; Becker, A. E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Grelotti, D. J.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Eustache, E (reprint author), Zanmi Lasante, Mental Hlth & Psychosocial Serv, Mirebalais, Haiti. EM e.eustache@pih.org FU National Institute of Mental Health of the National Institutes of Health [R21MH093298] FX Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award number R21MH093298 (Co-PIs, Becker and Eustache). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful to the leadership of Zanmi Lasante as well as at the four schools who so generously accommodated the planning and implementation of the mental health training and its accompanying school-based pilot study. We thank Kate Boyd, Shin Daimyo, Georges Alexis, Elysee Noesil, Ernst Origene, Handy Petit-Homme, and other colleagues at Partners In Health as well as Claire Pernar at HMS for their support of the planning, management, and implementation of the study and trainings. We express here our profound gratitude to the teacher study participants for their time and generous feedback, and from whom we learned so much. NR 29 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2054-4251 J9 GLOB MENT HEALTH JI Glob. Ment. Health PD MAR 6 PY 2017 VL 4 AR e4 DI 10.1017/gmh.2016.29 PG 16 WC Psychiatry SC Psychiatry GA EN1CF UT WOS:000395747300001 ER PT J AU Liao, YF Sassi, S Halvorsen, S Feng, Y Shen, J Gao, Y Cote, G Choy, E Harmon, D Mankin, H Hornicek, F Duan, ZF AF Liao, Yunfei Sassi, Slim Halvorsen, Stefan Feng, Yong Shen, Jacson Gao, Yan Cote, Gregory Choy, Edwin Harmon, David Mankin, Henry Hornicek, Francis Duan, Zhenfeng TI Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11 SO SCIENTIFIC REPORTS LA English DT Article ID PROSTATE-CANCER; BREAST-CANCER; CELL-CYCLE; KINASE 11; BICALUTAMIDE; GROWTH; SURVIVAL; THERAPY; PROLIFERATION; PROGRESSION AB Osteosarcoma is the most common bone cancer in children and adolescents. Previously, we have found that cyclin-dependent kinase 11 (CDK11) signaling was essential for osteosarcoma cell growth and survival. Subsequently, CDK11 siRNA gene targeting, expression profiling, and network reconstruction of differentially expressed genes were performed between CDK11 knock down and wild type osteosarcoma cells. Reconstructed network of the differentially expressed genes pointed to the AR as key to CDK11 signaling in osteosarcoma. CDK11 increased transcriptional activation of AR gene in osteosarcoma cell lines. AR protein was highly expressed in various osteosarcoma cell lines and patient tumor tissues. Tissue microarray analysis showed that the disease-free survival rate for patients with high-expression of AR was significantly shorter than for patients with low-expression of AR. In addition, AR gene expression knockdown via siRNA greatly inhibited cell growth and viability. Similar results were found in osteosarcoma cells treated with AR inhibitor. These findings suggest that CDK11 is involved in the regulation of AR pathway and AR can be a potential novel prognostic marker and therapeutic target for osteosarcoma treatment. C1 [Liao, Yunfei; Sassi, Slim; Feng, Yong; Shen, Jacson; Gao, Yan; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. [Liao, Yunfei; Sassi, Slim; Feng, Yong; Shen, Jacson; Gao, Yan; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng] Harvard Med Sch, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. [Liao, Yunfei] Huazhong Univ Sci & Technol, Wuhan Union Hosp, Dept Endocrinol, Tongji Med Coll, 1277 Jie Fang Ave, Wuhan 430022, Peoples R China. [Sassi, Slim; Halvorsen, Stefan] Massachusetts Gen Hosp, CCIB, Boston, MA 02139 USA. [Feng, Yong] Huazhong Univ Sci & Technol, Wuhan Union Hosp, Dept Orthopaed Surg, Tongji Med Coll, 1277 Jie Fang Ave, Wuhan 430022, Peoples R China. [Cote, Gregory; Choy, Edwin; Harmon, David] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Cote, Gregory; Choy, Edwin; Harmon, David] Harvard Med Sch, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA.; Duan, ZF (reprint author), Harvard Med Sch, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH) [UO1, CA 151452-01]; Sarcoma SPORE/NIH; Academic Enrichment Fund of MGH Orthopaedics FX This work was supported, in part, by the Gattegno and Wechsler funds, the Kenneth Stanton Fund. Dr. Duan is supported, in part, through a grant from the Sarcoma Foundation of America (SFA), a grant from the National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452-01, a pilot grant from Sarcoma SPORE/NIH, and a grant from an Academic Enrichment Fund of MGH Orthopaedics. NR 51 TC 0 Z9 0 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 MAR 6 PY 2017 VL 7 AR 43941 DI 10.1038/srep43941 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0ZG UT WOS:000395739400001 PM 28262798 ER PT J AU Collins, RL Brand, H Redin, CE Hanscom, C Antolik, C Stone, MR Glessner, JT Mason, T Pregno, G Dorrani, N Mandrile, G Giachino, D Perrin, D Walsh, C Cipicchio, M Costello, M Stortchevoi, A An, JY Currall, BB Seabra, CM Ragavendran, A Margolin, L Martinez-Agosto, JA Lucente, D Levy, B Sanders, SJ Wapner, RJ Quintero-Rivera, F Kloosterman, W Talkowski, ME AF Collins, Ryan L. Brand, Harrison Redin, Claire E. Hanscom, Carrie Antolik, Caroline Stone, Matthew R. Glessner, Joseph T. Mason, Tamara Pregno, Giulia Dorrani, Naghmeh Mandrile, Giorgia Giachino, Daniela Perrin, Danielle Walsh, Cole Cipicchio, Michelle Costello, Maura Stortchevoi, Alexei An, Joon-Yong Currall, Benjamin B. Seabra, Catarina M. Ragavendran, Ashok Margolin, Lauren Martinez-Agosto, Julian A. Lucente, Diane Levy, Brynn Sanders, Stephan J. Wapner, Ronald J. Quintero-Rivera, Fabiola Kloosterman, Wigard Talkowski, Michael E. TI Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome SO GENOME BIOLOGY LA English DT Article DE Structural variation; Inversion; Complex chromosomal rearrangement; Chromoanagenesis; Chromothripsis; Autism; Neurodevelopmental disorders; Copynumber variation; Whole-genome sequencing; Germline mutation ID COPY NUMBER VARIATION; BALANCED CHROMOSOME REARRANGEMENTS; GENERATION SEQUENCING DATA; PROTEIN-CODING GENES; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; CANCER GENOMES; PRENATAL-DIAGNOSIS; POLYMORPHIC INVERSIONS; DISEASE SUSCEPTIBILITY AB Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. Results: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at similar to 5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. Conclusions: These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease. C1 [Collins, Ryan L.; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R.; Glessner, Joseph T.; Stortchevoi, Alexei; Currall, Benjamin B.; Seabra, Catarina M.; Ragavendran, Ashok; Lucente, Diane; Talkowski, Michael E.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Genom Med, Boston, MA 02114 USA. [Collins, Ryan L.; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R.; Glessner, Joseph T.; Stortchevoi, Alexei; Currall, Benjamin B.; Seabra, Catarina M.; Ragavendran, Ashok; Lucente, Diane; Talkowski, Michael E.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA. [Collins, Ryan L.; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R.; Glessner, Joseph T.; Stortchevoi, Alexei; Currall, Benjamin B.; Seabra, Catarina M.; Ragavendran, Ashok; Lucente, Diane; Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Collins, Ryan L.; Talkowski, Michael E.] Harvard Med Sch, Div Med Sci, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA. [Collins, Ryan L.; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R.; Glessner, Joseph T.; Mason, Tamara; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; Currall, Benjamin B.; Seabra, Catarina M.; Ragavendran, Ashok; Margolin, Lauren; Lucente, Diane; Talkowski, Michael E.] Broad Inst MIT & Harvard, Program Populat & Med Genet, Cambridge, MA 02142 USA. [Collins, Ryan L.; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R.; Glessner, Joseph T.; Mason, Tamara; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; Currall, Benjamin B.; Seabra, Catarina M.; Ragavendran, Ashok; Margolin, Lauren; Talkowski, Michael E.] Broad Inst MIT & Harvard, Genom Platform, Cambridge, MA 02142 USA. [Pregno, Giulia; Mandrile, Giorgia; Giachino, Daniela] Univ Torino, Dept Clin & Biol Sci, Med Genet Unit, Orbassano, Italy. [Dorrani, Naghmeh; Martinez-Agosto, Julian A.; Quintero-Rivera, Fabiola] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Dorrani, Naghmeh; Martinez-Agosto, Julian A.; Quintero-Rivera, Fabiola] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Clin Genom Ctr, Los Angeles, CA 90095 USA. [An, Joon-Yong; Sanders, Stephan J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94103 USA. [Seabra, Catarina M.] Univ Porto, GABBA Program, P-4099002 Oporto, Portugal. [Levy, Brynn] Columbia Univ, Dept Pathol, New York, NY 10032 USA. [Wapner, Ronald J.] Columbia Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, Med Ctr, New York, NY 10032 USA. [Kloosterman, Wigard] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, NL-3584 CG Utrecht, Netherlands. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Genom Med, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Talkowski, ME (reprint author), Harvard Med Sch, Div Med Sci, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Program Populat & Med Genet, Cambridge, MA 02142 USA.; Talkowski, ME (reprint author), Broad Inst MIT & Harvard, Genom Platform, Cambridge, MA 02142 USA. EM talkowski@chgr.mgh.harvard.edu FU Simons Foundation for Autism Research (SFARI) [346042]; Nancy Lurie Marks Family Foundation; March of Dimes; Charles Hood Foundation; NARSAD; National Institutes of Health [R00MH095867, HD081256, GM061354]; Simons Foundation; Ruth L. Kirschstein NRSA training grant from the National Institutes of Health (NHGRI) [T32HG002295-14] FX Funding for this work was provided by the Simons Foundation for Autism Research (SFARI #346042), the Nancy Lurie Marks Family Foundation, the March of Dimes, the Charles Hood Foundation, NARSAD, and the National Institutes of Health (R00MH095867, HD081256, GM061354) to MET. The principal investigators of the Simons Simplex Collection (SSC), which is sponsored by the Simons Foundation, collected the samples in the SSC. No funding body played a role in the study design, analysis, or interpretation of data. RLC is supported by a Ruth L. Kirschstein NRSA training grant from the National Institutes of Health (NHGRI #T32HG002295-14) to the PhD Program in Bioinformatics and Integrative Genomics of Harvard Medical School. MET is the supported as the MGH Desmond and Ann Heathwood Research Scholar. NR 114 TC 1 Z9 1 U1 0 U2 0 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 MAR 6 PY 2017 VL 18 AR 36 DI 10.1186/s13059-017-1158-6 PG 21 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EP0YG UT WOS:000397112000001 PM 28260531 ER PT J AU Lefebure, M Tothill, RW Kruse, E Hawkins, ED Shortt, J Matthews, GM Gregory, GP Martin, BP Kelly, MJ Todorovski, I Doyle, MA Lupat, R Li, J Schroeder, J Wall, M Craig, S Poortinga, G Cameron, D Bywater, M Kats, L Gearhart, MD Bardwell, VJ Dickins, RA Hannan, RD Papenfuss, AT Johnstone, RW AF Lefebure, Marcus Tothill, Richard W. Kruse, Elizabeth Hawkins, Edwin D. Shortt, Jake Matthews, Geoffrey M. Gregory, Gareth P. Martin, Benjamin P. Kelly, Madison J. Todorovski, Izabela Doyle, Maria A. Lupat, Richard Li, Jason Schroeder, Jan Wall, Meaghan Craig, Stuart Poortinga, Gretchen Cameron, Don Bywater, Megan Kats, Lev Gearhart, Micah D. Bardwell, Vivian J. Dickins, Ross A. Hannan, Ross D. Papenfuss, Anthony T. Johnstone, Ricky W. TI Genomic characterisation of E mu-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene SO NATURE COMMUNICATIONS LA English DT Article ID B-CELL LYMPHOMA; TRANSGENIC MICE; STRUCTURAL VARIATION; SOMATIC MUTATIONS; SEQUENCING DATA; HUMAN CANCER; COPY NUMBER; RNA-SEQ; LEUKEMIA; MODEL AB The E mu-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising E mu-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of E mu-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis. C1 [Lefebure, Marcus; Tothill, Richard W.; Kruse, Elizabeth; Shortt, Jake; Gregory, Gareth P.; Martin, Benjamin P.; Kelly, Madison J.; Todorovski, Izabela; Doyle, Maria A.; Lupat, Richard; Li, Jason; Craig, Stuart; Poortinga, Gretchen; Cameron, Don; Bywater, Megan; Kats, Lev; Hannan, Ross D.; Papenfuss, Anthony T.; Johnstone, Ricky W.] Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia. [Lefebure, Marcus; Tothill, Richard W.; Kats, Lev; Papenfuss, Anthony T.; Johnstone, Ricky W.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. [Tothill, Richard W.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Hawkins, Edwin D.; Schroeder, Jan; Papenfuss, Anthony T.] Walter Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Shortt, Jake] Monash Hlth, Sch Clin Sci, Fac Med Nursing & Hlth Sci, Clayton, Vic 3168, Australia. [Matthews, Geoffrey M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wall, Meaghan] St Vincents Hosp, Victorian Canc Cytogenet Serv, Fitzroy, Vic 3065, Australia. [Wall, Meaghan] Univ Melbourne, Dept Med, St Vincents Hosp, Parkville, Vic 3052, Australia. [Gearhart, Micah D.; Bardwell, Vivian J.] Univ Minnesota, Masonic Canc Ctr, Ctr Dev Biol, Minneapolis, MN 55455 USA. [Gearhart, Micah D.; Bardwell, Vivian J.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Dickins, Ross A.] Monash Univ, Australian Ctr Blood Dis, Alfred Hosp, AMREP Bldg,Commercial Rd, Melbourne, Vic 3004, Australia. [Hannan, Ross D.] Australian Natl Univ, John Curtin Sch Med Res, Canc Biol & Therapeut Dept, Canberra, ACT 0200, Australia. RP Tothill, RW; Johnstone, RW (reprint author), Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia.; Tothill, RW; Johnstone, RW (reprint author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia. EM Richard.Tothill@petermac.org; Ricky.Johnstone@petermac.org FU Leukaemia Foundation of Australia; Arrow Bone Marrow Transplant Foundation; National Health and Medical Research Council Australia; Cancer Council Victoria; Victorian Cancer Agency; Australian Cancer Research Foundation; Peter MacCallum Cancer Centre Foundation; National Institutes of Health FX We thank Charles Mullighan and Ari Melnick for helpful discussion and Jerry Pelletier for providing us with the pCIG-constructs. We thank members of the Peter Mac Molecular Genomics Core Facility for their contribution. We acknowledge the following funding agencies: Leukaemia Foundation of Australia, Arrow Bone Marrow Transplant Foundation, National Health and Medical Research Council Australia, Cancer Council Victoria, Victorian Cancer Agency, Australian Cancer Research Foundation, Peter MacCallum Cancer Centre Foundation, National Institutes of Health. NR 51 TC 0 Z9 0 U1 0 U2 0 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 MAR 6 PY 2017 VL 8 BP 1 EP 10 AR 14581 DI 10.1038/ncomms14581 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM7OM UT WOS:000395502000001 PM 28262675 ER PT J AU Alver, BH Kim, KH Lu, P Wang, XF Manchester, HE Wang, WS Haswell, JR Park, PJ Roberts, CWM AF Alver, Burak H. Kim, Kimberly H. Lu, Ping Wang, Xiaofeng Manchester, Haley E. Wang, Weishan Haswell, Jeffrey R. Park, Peter J. Roberts, Charles W. M. TI The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers SO NATURE COMMUNICATIONS LA English DT Article ID CHIP-SEQ; CELL IDENTITY; SUPER-ENHANCERS; SNF COMPLEX; BRG1; TRANSCRIPTION; GENOME; P300; PLURIPOTENCY; ACETYLATION C1 [Alver, Burak H.; Park, Peter J.] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Kim, Kimberly H.; Lu, Ping; Wang, Xiaofeng; Manchester, Haley E.; Wang, Weishan; Haswell, Jeffrey R.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Kim, Kimberly H.; Lu, Ping; Wang, Xiaofeng; Manchester, Haley E.; Wang, Weishan; Haswell, Jeffrey R.; Roberts, Charles W. M.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02215 USA. [Kim, Kimberly H.; Lu, Ping; Wang, Xiaofeng; Manchester, Haley E.; Wang, Weishan; Haswell, Jeffrey R.; Roberts, Charles W. M.] Harvard Med Sch, Dept Pediat, Boston, MA 02215 USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA. [Roberts, Charles W. M.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Kim, Kimberly H.] Pfizer, Dept Oncol Target Discovery, Pearl River, NY 10965 USA. RP Park, PJ (reprint author), Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.; Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA.; Roberts, CWM (reprint author), Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02215 USA.; Roberts, CWM (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02215 USA.; Roberts, CWM (reprint author), St Jude Childrens Res Hosp, Ctr Comprehens Canc, 332 N Lauderdale St, Memphis, TN 38105 USA.; Roberts, CWM (reprint author), St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM peter_park@hms.harvard.edu; charles.roberts@stjude.org OI Alver, Burak/0000-0002-5019-7652 FU US National Institutes of Health [R01CA172152, R01CA113794, K99CA197640]; National Cancer Center; Rally Foundation for Childhood Cancer Research; Truth 365; St. Baldrick's Foundation; Avalanna Fund; Cure AT/RT Now Foundation; Garrett B. Smith Foundation; Miles for Mary; ALSAC/St. Jude FX We thank members of the Roberts and Park laboratories for assistance and discussion. In particular, we thank Soohyun Lee and Ryan Lee for careful reading of the manuscript. This work was supported by the US National Institutes of Health grants R01CA172152 (C.W.M.R.) and R01CA113794 (C.W.M.R.). K.H.K. was supported by an award from National Cancer Center. X.W. was supported by the Pathway to Independence Award from the US National Institutes of Health (K99CA197640), a postdoctoral fellowship from the Rally Foundation for Childhood Cancer Research and The Truth 365, and a research grant from the St. Baldrick's Foundation. The Avalanna Fund, the Cure AT/RT Now Foundation, the Garrett B. Smith Foundation, Miles for Mary, and ALSAC/St. Jude (C.W.M.R.) provided additional support. NR 48 TC 0 Z9 0 U1 1 U2 1 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 MAR 6 PY 2017 VL 8 AR 14648 DI 10.1038/ncomms14648 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM7PF UT WOS:000395503900001 PM 28262751 ER PT J AU Desai, RJ Bateman, BT Huybrechts, KF Patorno, E Hernandez-Diaz, S Park, Y Dejene, SZ Cohen, J Mogun, H Kim, SC AF Desai, Rishi J. Bateman, Brian T. Huybrechts, Krista F. Patorno, Elisabetta Hernandez-Diaz, Sonia Park, Yoonyoung Dejene, Sara Z. Cohen, Jacqueline Mogun, Helen Kim, Seoyoung C. TI Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID SYSTEMIC GLUCOCORTICOID THERAPY; RHEUMATOID-ARTHRITIS; CROHNS-DISEASE; BOWEL-DISEASE; UNITED-STATES; OUTCOMES; LUPUS; RECOMMENDATIONS; PREDICTORS; MANAGEMENT AB OBJECTIVE To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor alpha (TNF) inhibitors in pregnancy. DESIGN Observational cohort study. SETTING Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US. PARTICIPANTS 4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. EXPOSURE FOR OBSERVATIONAL STUDIES Exposure was classified into steroid, non-biologic, or TNF inhibitors on first filled prescription during pregnancy. Because TNF inhibitors are not used to treat systemic lupus erythematosus, patients with this condition were excluded from comparisons involving TNF inhibitors. MAIN OUTCOME MEASURE The main outcome was occurrence of serious infections during pregnancy, defined by hospital admission for bacterial or opportunistic infections. Hazard ratios were derived using Cox proportional hazard regression models after adjustment for confounding with propensity score fine stratification. A logistic regression model was used to conduct a dose-response analysis among women filling at least one steroid prescription. RESULTS 71 out of 4961 pregnant women (0.2%) treated with immunosuppressive agents experienced serious infections. The crude incidence rates of serious infections per 100 person years among 2598 steroid users, 1587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose-response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose= 0.019, P= 0.02). CONCLUSIONS Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy. C1 [Desai, Rishi J.; Bateman, Brian T.; Huybrechts, Krista F.; Patorno, Elisabetta; Dejene, Sara Z.; Mogun, Helen; Kim, Seoyoung C.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Desai, Rishi J.; Bateman, Brian T.; Huybrechts, Krista F.; Patorno, Elisabetta; Dejene, Sara Z.; Mogun, Helen; Kim, Seoyoung C.] Harvard Med Sch, Boston, MA 02120 USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Hernandez-Diaz, Sonia; Park, Yoonyoung; Cohen, Jacqueline] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Desai, RJ (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA.; Desai, RJ (reprint author), Harvard Med Sch, Boston, MA 02120 USA. EM rdesai@bwh.harvard.edu OI Kim, Seoyoung/0000-0002-2517-3579 FU Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital; Harvard Medical School FX The investigators conducted the research independently through funding from internal sources of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School. NR 36 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 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAR 6 PY 2017 VL 356 AR j895 DI 10.1136/bmj.j895 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EO1BH UT WOS:000396432100009 PM 28264814 ER PT J AU Helluy, X Sauter, M Ye, YX Lykowsky, G Kreutner, J Yilmaz, A Jahns, R Boivin, V Kandolf, R Jakob, PM Hiller, KH Klingel, K AF Helluy, Xavier Sauter, Martina Ye, Yu-Xiang Lykowsky, Gunthard Kreutner, Jakob Yilmaz, Ali Jahns, Roland Boivin, Valerie Kandolf, Reinhard Jakob, Peter M. Hiller, Karl-Heinz Klingel, Karin TI In vivo T2*weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis SO PLOS ONE LA English DT Article ID COXSACKIEVIRUS B3-INDUCED MYOCARDITIS; ADENINE-NUCLEOTIDE TRANSLOCATOR; RESONANCE; CARDIOMYOPATHY; SUSCEPTIBILITY; REPLICATION; EXPRESSION; INFARCTION; INFECTION; DIAGNOSIS AB Objective Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis. Results Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2* w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast. Conclusion This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of tissue damage free of MR contrast agents. C1 [Helluy, Xavier; Ye, Yu-Xiang] Univ Wurzburg, Inst Phys, Dept Expt Phys V, Wurzburg, Germany. [Sauter, Martina; Kandolf, Reinhard; Klingel, Karin] Univ Hosp Tuebingen, Inst Pathol & Neuropathol, Dept Mol Pathol, Tubingen, Germany. [Ye, Yu-Xiang] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ye, Yu-Xiang] Harvard Med Sch, Boston, MA USA. [Lykowsky, Gunthard; Kreutner, Jakob; Jakob, Peter M.; Hiller, Karl-Heinz] Res Ctr Magnet Resonance Bavaria MRB, Wurzburg, Germany. [Yilmaz, Ali] Univ Hosp Munster, Dept Cardiol & Angiol, Munster, Germany. [Jahns, Roland] Univ Hosp Wurzburg, Comprehens Heart Failure Ctr, Wurzburg, Germany. [Jahns, Roland] Univ Hosp Wurzburg, Interdisziplinary Bank Biomat & Data Ibdw, Wurzburg, Germany. [Boivin, Valerie] Univ Wurzburg, Inst Pharmacol & Toxicol, Wurzburg, Germany. [Hiller, Karl-Heinz] Fraunhofer Inst Integrated Circuits, Magnet Resonance & XRay Imaging Dept, Wurzburg, Germany. RP Klingel, K (reprint author), Univ Hosp Tuebingen, Inst Pathol & Neuropathol, Dept Mol Pathol, Tubingen, Germany. EM Karin.Klingel@med.uni-tuebingen.de FU German Federal Ministry of Education and Research [01EZ0818, 13EZ0817]; Deutsche Herzstiftung e.V. FX This work was financially supported by a grant from the German Federal Ministry of Education and Research (WN; grant-ID 01EZ0818 and 13EZ0817), and in part by the Deutsche Herzstiftung e.V. (Ye, Y-X). NR 25 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 MAR 6 PY 2017 VL 12 IS 3 AR e0172084 DI 10.1371/journal.pone.0172084 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5OE UT WOS:000396054300007 ER PT J AU Abramovitch, A Hallion, LS Reese, HE Woods, DW Peterson, A Walkup, JT Piacentini, J Scahill, L Deckersbach, T Wilhelm, S AF Abramovitch, Amitai Hallion, Lauren S. Reese, Hannah E. Woods, Douglas W. Peterson, Alan Walkup, John T. Piacentini, John Scahill, Lawrence Deckersbach, Thilo Wilhelm, Sabine TI Neurocognitive predictors of treatment response to randomized treatment in adults with tic disorders SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Tourette's disorder; Response inhibition; Executive function; Treatment; Neuropsychology ID OBSESSIVE-COMPULSIVE DISORDER; TOURETTE-SYNDROME; BEHAVIOR-THERAPY; CONTROLLED-TRIAL; INHIBITION; CHILDREN; METAANALYSIS; SEVERITY AB Tourette's disorder (TS) and chronic tic disorder (CTD) are neurodevelopmental disorders characterized by involuntary vocal and motor tics. Consequently, TS/CTD have been conceptualized as disorders of cognitive and motor inhibitory control. However, most neurocognitive studies have found comparable or superior inhibitory capacity among individuals with TS/CTD) relative to healthy controls. These findings have led to the hypothesis that individuals with TS/CTD develop increased inhibitory control due to the constant need to inhibit tics. However, the role of cognitive control in TS/CTD is not yet understood, particularly in adults. To examine the role of inhibitory control in TS/CTD, the present study investigated this association by assessing the relationship between inhibitory control and treatment response in a large sample of adults with TS/CTD. As part of a large randomized trial comparing behavior therapy versus supportive psychotherapy for TS/CTD, a battery of tests, including tests of inhibitory control was administered to 122 adults with TS/CTD at baseline. We assessed the association between neuropsychological test performance and change in symptom severity, as well as compared the performance of treatment responders and non-responders as defined by the Clinical Global Impression Scale. Results indicated that change in symptoms, and treatment response were not associated with neuropsychological performance on tests of inhibitory control, intellectual ability, or motor function, regardless of type of treatment The finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control may not be a clinically relevant facet of these disorders in adults. (C) 2016 Elsevier Inc. All rights reserved. C1 [Abramovitch, Amitai] Texas State Univ, Dept Psychol, San Marcos, TX 78666 USA. [Abramovitch, Amitai; Hallion, Lauren S.; Reese, Hannah E.; Deckersbach, Thilo; Wilhelm, Sabine] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Abramovitch, Amitai; Hallion, Lauren S.; Reese, Hannah E.; Deckersbach, Thilo; Wilhelm, Sabine] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Hallion, Lauren S.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Hallion, Lauren S.] Inst Living, Anxiety Disorders Ctr, Hartford, CT USA. [Reese, Hannah E.] Bowdoin Coll, Dept Psychol, Brunswick, ME 04011 USA. [Woods, Douglas W.] Marquette Univ, Dept Psychol, Milwaukee, WI 53233 USA. [Peterson, Alan] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Walkup, John T.] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Piacentini, John] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Scahill, Lawrence] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Scahill, Lawrence] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. RP Abramovitch, A (reprint author), Texas State Univ, Dept Psychol, San Marcos, TX 78666 USA. EM abramovitch@txstate.edu OI Abramovitch, Amitai/0000-0001-9640-0970 FU National Institute of Mental Health (NIMH) [5R01MH069877, R01MH069874, RO1MH069875] FX This work was supported by grants from the National Institute of Mental Health (NIMH) to Drs. Wilhelm (5R01MH069877), Scahill (R01MH069874), and Peterson (RO1MH069875) with subcontracts to Drs. Piacentini and Woods. NR 39 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 0278-5846 EI 1878-4216 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD MAR 6 PY 2017 VL 74 BP 9 EP 14 DI 10.1016/j.pnpbp.2016.11.002 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EJ0JO UT WOS:000392894700002 PM 27864156 ER PT J AU Bauer, EM Ben-Artzi, A Duffy, EL Elashoff, DA Vangala, SS Fitzgerald, J Ranganath, VK AF Bauer, Erin M. Ben-Artzi, Ami Duffy, Erin L. Elashoff, David A. Vangala, Sitaram S. Fitzgerald, John Ranganath, Veena K. TI Joint-specific assessment of swelling and power Doppler in obese rheumatoid arthritis patients SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Ultrasound; Obesity; Outcome measures; Rheumatoid arthritis ID BODY-MASS INDEX; ANTITUMOR NECROSIS FACTOR; DISEASE-ACTIVITY; TREATMENT RESPONSE; AMERICAN-COLLEGE; CONTROLLED-TRIAL; ASSOCIATION; ULTRASOUND; THERAPY; PROGRESSION AB Background: Clinical swollen joint examination of the obese rheumatoid arthritis (RA) patient can be difficult. Musculoskeletal Ultrasound (MSUS) has higher sensitivity than physical examination for swollen joints (SJ). The purpose of this study was to determine the joint-specific association between power Doppler (PDUS) and clinical SJ in RA across body mass index (BMI) categories. Methods: Cross-sectional clinical and laboratory data were collected on 43 RA patients. PDUS was performed on 9 joints (wrist, metacarpalphalangeal 2-5, proximal interphalgeal 2/3 and metatarsalphalangeal 2/5). DAS28 and clinical disease activity index (CDAI) were calculated. Patients were categorized by BMI: <25, 25-30, and >30. Demographic and clinical characteristics were compared across BMI groups with Kruskal-Wallis test and chi-square tests. Joint-level associations between PDUS and clinically SJ were evaluated with mixed effects logistic regression models. Results: While demographics and clinically-determined disease activity were similar among BMI groups, PDUS scores significantly differed (p = 0.02). Using PDUS activity as the reference standard for synovitis and clinically SJ as the test, the positive predictive value of SJ was significantly lower in higher BMI groups (0.71 in BMI < 25, 0.58 in BMI 25-30 and 0.44 in BMI < 30) (p = 0.02). The logistic model demonstrated that increased BMI category resulted in decreased likelihood of PDUS positivity (OR 0.52, p = 0.03). Conclusions: This study suggests that in an obese RA patient, a clinically assessed SJ is less likely to represent true synovitis (as measured by PDUS). Disease activity in obese RA patients may be overestimated by CDAI/DAS28 calculations and clinicians when considering change in therapy. C1 [Bauer, Erin M.; Duffy, Erin L.; Elashoff, David A.; Vangala, Sitaram S.; Fitzgerald, John; Ranganath, Veena K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Bauer, Erin M.] US Dept Vet Affairs, Los Angeles, CA USA. [Ben-Artzi, Ami] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Ranganath, VK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM vranganath@mednet.ucla.edu FU National Institutes of Health [NIAMS K23 AR057818-02]; National Center for Advancing Translational Sciences through UCLA CTSI [UL1TR000124] FX This work was supported by Grant and National Institutes of Health Award (NIAMS K23 AR057818-02) to Veena K. Ranganath and supported by the National Center for Advancing Translational Sciences through UCLA CTSI Grant UL1TR000124. NR 39 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 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD MAR 4 PY 2017 VL 18 AR 99 DI 10.1186/s12891-017-1406-7 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EM7AZ UT WOS:000395465100002 PM 28259162 ER PT J AU Tsai, AC Mendenhall, E Trostle, JA Kawachi, I AF Tsai, Alexander C. Mendenhall, Emily Trostle, James A. Kawachi, Ichiro TI Co-occurring epidemics, syndemics, and population health SO LANCET LA English DT Editorial Material ID SUFFICIENT CAUSE INTERACTIONS; EDUCATIONAL-ATTAINMENT; PARTNER VIOLENCE; LIFE EXPECTANCY; HIV RISK; CONTEXT; WOMEN; DISEASE; AIDS; INTERVENTIONS C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.; Kawachi, Ichiro] Harvard Univ, Harvard Med Sch, Boston, MA 02115 USA. [Tsai, Alexander C.; Kawachi, Ichiro] Harvard Univ, Harvard Ctr Populat & Dev Studies, Boston, MA 02115 USA. [Kawachi, Ichiro] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Mendenhall, Emily] Georgetown Univ, Edmund A Walsh Sch Foreign Serv, Washington, DC USA. [Trostle, James A.] Trinity Coll, Dept Anthropol, Hartford, CT 06106 USA. [Trostle, James A.] Univ Chile, Fac Med, Sch Publ Hlth, Santiago, Chile. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, MGH Global Hlth, Boston, MA 02114 USA. EM actsai@partners.org FU US National Institutes of Health [K23MH096620]; US National Science Foundation [EAR-1360330] FX We thank, without implicating, Brian T Chan, Jessica F Magidson, Mark J Siedner, and Atheendar S Venkataramani for their helpful comments on drafts of this manuscript. ACT acknowledges salary support from the US National Institutes of Health (K23MH096620). JAT acknowledges grant support from the US National Science Foundation (EAR-1360330). The funders had no role in the analysis or interpretation of the evidence, in writing the manuscript, or in the decision to submit the manuscript for publication. NR 54 TC 3 Z9 3 U1 1 U2 1 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 MAR 4 PY 2017 VL 389 IS 10072 BP 978 EP 982 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EM4DL UT WOS:000395263400037 PM 28271848 ER PT J AU Chen, CF Bikson, M Chou, LW Shan, CL Khadka, N Chen, WS Fregni, F AF Chen, Chiun-Fan Bikson, Marom Chou, Li-Wei Shan, Chunlei Khadka, Niranjan Chen, Wen-Shiang Fregni, Felipe TI Higher-order power harmonics of pulsed electrical stimulation modulates corticospinal contribution of peripheral nerve stimulation SO SCIENTIFIC REPORTS LA English DT Article ID SPINAL-CORD STIMULATION; HIGH-FREQUENCY STIMULATION; RANDOM NOISE STIMULATION; EPILEPTIFORM ACTIVITY; MUSCLE FATIGUE; ALTERNATING-CURRENT; AFFERENT-FIBERS; MOTOR CORTEX; PAIN; DURATION AB It is well established that electrical-stimulation frequency is crucial to determining the scale of induced neuromodulation, particularly when attempting to modulate corticospinal excitability. However, the modulatory effects of stimulation frequency are not only determined by its absolute value but also by other parameters such as power at harmonics. The stimulus pulse shape further influences parameters such as excitation threshold and fiber selectivity. The explicit role of the power in these harmonics in determining the outcome of stimulation has not previously been analyzed. In this study, we adopted an animal model of peripheral electrical stimulation that includes an amplitude-adapted pulse train which induces force enhancements with a corticospinal contribution. We report that the electrical-stimulation-induced force enhancements were correlated with the amplitude of stimulation power harmonics during the amplitude-adapted pulse train. In an exploratory analysis, different levels of correlation were observed between force enhancement and power harmonics of 20-80 Hz (r = 0.4247, p = 0.0243), 100-180 Hz (r = 0.5894, p = 0.0001), 200-280 Hz (r = 0.7002, p < 0.0001), 300-380 Hz (r = 0.7449, p < 0.0001), 400-480 Hz (r = 0.7906, p < 0.0001), 500-600 Hz (r = 0.7717, p < 0.0001), indicating a trend of increasing correlation, specifically at higher order frequency power harmonics. This is a pilot, but important first demonstration that power at high order harmonics in the frequency spectrum of electrical stimulation pulses may contribute to neuromodulation, thus warrant explicit attention in therapy design and analysis. C1 [Chen, Chiun-Fan; Shan, Chunlei; Fregni, Felipe] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Spaulding Neuromodulat Ctr, Boston, MA 02115 USA. [Chen, Chiun-Fan; Shan, Chunlei; Fregni, Felipe] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chen, Chiun-Fan] Loyola Univ Chicago, Engn Sci, Chicago, IL USA. [Bikson, Marom; Khadka, Niranjan] CUNY City Coll, Dept Biomed Engn, New York, NY 10031 USA. [Chou, Li-Wei] Natl Yang Ming Univ, Dept Phys Therapy & Assist Technol, Taipei, Taiwan. [Shan, Chunlei] Shanghai Univ Tradit Chinese Med, Sch Rehabil Sci, Shanghai, Peoples R China. [Chen, Wen-Shiang] Natl Taiwan Univ, Coll Med, Dept Phys Med & Rehabil, Taipei, Taiwan. [Chen, Wen-Shiang] Natl Taiwan Univ Hosp, Taipei, Taiwan. RP Fregni, F (reprint author), Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Spaulding Neuromodulat Ctr, Boston, MA 02115 USA.; Fregni, F (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM Fregni.Felipe@mgh.harvard.edu FU Ministry of Science and Technology, Taipei, Taiwan [103-2917-I-564-059] FX This study was supported in part by a grant from Ministry of Science and Technology, Taipei, Taiwan (103-2917-I-564-059) to C.F.C NR 51 TC 0 Z9 0 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 MAR 3 PY 2017 VL 7 AR 43619 DI 10.1038/srep43619 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8YI UT WOS:000396285500001 PM 28256638 ER PT J AU Shenoy, VN Gifford, HS Kao, JT AF Shenoy, Vivek N. Gifford, Hanson S. Kao, John T. TI A Novel Implant System for Unloading the Medial Compartment of the Knee by Lateral Displacement of the Iliotibial Band SO ORTHOPAEDIC JOURNAL OF SPORTS MEDICINE LA English DT Article DE medial osteoarthritis; knee; treatment gap; unloading; moment arm; extracapsular ID HIGH TIBIAL OSTEOTOMY; CRUCIATE LIGAMENT RECONSTRUCTIONS; SIMULATED MUSCLE LOADS; DOUBLE-BUNDLE; OSTEOARTHRITIS; KINEMATICS; REDUCTION; FLEXION; SINGLE; FORCES AB Background: Medial knee osteoarthritis (OA) typically occurs with excessive mechanical load within the medial compartment, resulting in degeneration of the articular cartilage. Purpose: A novel extracapsular implant (Latella Knee Implant) has been developed to unload the medial compartment of the knee. The implant displaces the iliotibial band (ITB) over the lateral femoral condyle, thereby increasing its effective moment arm, resulting in a transfer of load from the medial compartment to the lateral compartment of the knee. A cadaveric study was performed to evaluate the effect of altering the moment arm of the ITB on knee biomechanics. Study Design: Controlled laboratory study. Methods: A 6-degrees-of-freedom robotic testing system was utilized to measure medial and lateral compartment loads in 8 fresh-frozen cadaveric knees at various ITB loads and knee flexion angles. Measurements were made with and without the implant in place. The system measured the compartment forces at flexion angles between 0 degrees and 30 degrees under 3 simulated loading conditions (300 N quadriceps, 100 N hamstrings, and [1] 0 N ITB, [2] 50 N ITB, [3] 100 N ITB). Results: Lateral displacement of the ITB between 15 and 20 mm resulted in medial compartment unloading between 34% and 65%. Conclusion: Unloading the medial compartment with this novel implant has the potential to address the treatment gap for patients with medial knee OA. Clinical Relevance: Currently, there exists a treatment gap for patients with medial compartment OA who have exhausted conservative management but whose disease and symptoms do not warrant more invasive surgical procedures. An extracapsular implant to unload the medial compartment could fill this treatment gap by providing patients and surgeons with a less invasive option for early to mid-stage OA. Unloading the medial compartment may alleviate pain and improve function, allowing patients with early-stage medial OA to remain active longer prior to considering more invasive options such as arthroplasty. C1 [Shenoy, Vivek N.; Gifford, Hanson S.; Kao, John T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shenoy, Vivek N.] Cotera Inc, 199 Jefferson Dr, Menlo Pk, CA 94025 USA. [Gifford, Hanson S.] The Foundry LLC, Menlo Pk, CA USA. [Kao, John T.] SOAR Med Associates, San Jose, CA USA. RP Shenoy, VN (reprint author), Cotera Inc, 199 Jefferson Dr, Menlo Pk, CA 94025 USA. EM vivek@thefoundry.com FU Cotera, Inc. FX One or more of the authors has declared the following potential conflict of interest or source of funding: V.N.S. has received consulting fees from, is employed by, owns stock in, is a board member of, is a patent holder of patents owned by, and receives royalties from Cotera, Inc. V.N.S.'s spouse owns stock in Cotera, Inc. H.S.G. receives consulting fees from, owns stock in, is a board member of, is a patent holder of patents owned by, and receives royalties from Cotera, Inc. H.S.G.'s parents, children, and siblings own stock in Cotera, Inc. J.T.K. receives consulting fees from and owns stock options in Cotera, Inc. NR 41 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 2325-9671 J9 ORTHOP J SPORTS MED JI Orthop. J. Sports Med. PD MAR 3 PY 2017 VL 5 IS 3 AR 2325967117693614 DI 10.1177/2325967117693614 PG 9 WC Sport Sciences SC Sport Sciences GA EP6CH UT WOS:000397465100001 PM 28321432 ER PT J AU Nielson, JL Cooper, SR Yue, JK Sorani, MD Inoue, T Yuh, EL Mukherjee, P Petrossian, TC Paquette, J Lum, PY Carlsson, GE Vassar, MJ Lingsma, HF Gordon, WA Valadka, AB Okonkwo, DO Manley, GT Ferguson, AR AF Nielson, Jessica L. Cooper, Shelly R. Yue, John K. Sorani, Marco D. Inoue, Tomoo Yuh, Esther L. Mukherjee, Pratik Petrossian, Tanya C. Paquette, Jesse Lum, Pek Y. Carlsson, Gunnar E. Vassar, Mary J. Lingsma, Hester F. Gordon, Wayne A. Valadka, Alex B. Okonkwo, David O. Manley, Geoffrey T. Ferguson, Adam R. CA TRACK-TBI Investigators TI Uncovering precision phenotype-biomarker associations in traumatic brain injury using topological data analysis SO PLOS ONE LA English DT Article ID COMMON DATA ELEMENTS; TRANSFORMING RESEARCH; CLINICAL KNOWLEDGE; POLYMORPHISM; COMT; CLASSIFICATION; PREDICTION; PROTEIN AB Background Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-ana-tomical and molecular mechanisms. Complete integration of these diverse data for TBI diag-nosis and patient stratification remains an unmet challenge. Methods and findings The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural sub-groups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-iden-tified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-trau-matic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2). Conclusions TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust method for patient stratifica-tion and treatment planning targeting identified biomarkers in future clinical trials in TBI patients. C1 [Nielson, Jessica L.; Cooper, Shelly R.; Yue, John K.; Inoue, Tomoo; Vassar, Mary J.; Manley, Geoffrey T.; Ferguson, Adam R.] Zuckerberg San Francisco Gen Hosp, Brain & Spinal Injury Ctr BASIC, San Francisco, CA 94110 USA. [Nielson, Jessica L.; Cooper, Shelly R.; Yue, John K.; Sorani, Marco D.; Inoue, Tomoo; Vassar, Mary J.; Manley, Geoffrey T.; Ferguson, Adam R.] Univ Calif San Francisco, Dept Neurol Surg, Weill Inst Neurosci, San Francisco, CA 94143 USA. [Cooper, Shelly R.; Yuh, Esther L.; Mukherjee, Pratik] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Petrossian, Tanya C.; Paquette, Jesse; Lum, Pek Y.; Carlsson, Gunnar E.] Ayasdi Inc, Palo Alto, CA USA. [Lingsma, Hester F.] Erasmus MC, Publ Hlth, Rotterdam, Netherlands. [Gordon, Wayne A.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Valadka, Alex B.] Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA USA. [Okonkwo, David O.] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA USA. [Ferguson, Adam R.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA 94121 USA. RP Manley, GT; Ferguson, AR (reprint author), Zuckerberg San Francisco Gen Hosp, Brain & Spinal Injury Ctr BASIC, San Francisco, CA 94110 USA.; Manley, GT; Ferguson, AR (reprint author), Univ Calif San Francisco, Dept Neurol Surg, Weill Inst Neurosci, San Francisco, CA 94143 USA.; Ferguson, AR (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA 94121 USA. EM manleyg@neurosurg.ucsf.edu; adam.ferguson@ucsf.edu OI Yue, John/0000-0001-9694-7722 FU Department of Defense (DoD) [W81XWH-131-0441]; National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [NS067092, NS069409, NS069409-0251]; Craig H. Neilsen Foundation (ARF); Wings for Life Foundation (ARF) FX This work was funded by the following: Department of Defense (DoD) grant W81XWH-131-0441 (GTM): http://cdmrp.army.mil/funding/phtbi.shtml; National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) grants NS067092 (ARF), NS069409 (GTM) and NS069409-0251 (GTM): http://www.runds.nih.govt/; Craig H. Neilsen Foundation (ARF): http://chnfoundation.org/; and Wings for Life Foundation (ARF): http://www.wingsforlrie.com/en/. NR 41 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 MAR 3 PY 2017 VL 12 IS 3 AR e0169490 DI 10.1371/journal.pone.0169490 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5BR UT WOS:000396021100002 PM 28257413 ER PT J AU Hicks, DF Goossens, N Blas-Garcia, A Tsuchida, T Wooden, B Wallace, MC Nieto, N Lade, A Redhead, B Cederbaum, AI Dudley, JT Fuchs, BC Lee, YA Hoshida, Y Friedman, SL AF Hicks, Daniel F. Goossens, Nicolas Blas-Garcia, Ana Tsuchida, Takuma Wooden, Benjamin Wallace, Michael C. Nieto, Natalia Lade, Abigale Redhead, Benjamin Cederbaum, Arthur I. Dudley, Joel T. Fuchs, Bryan C. Lee, Youngmin A. Hoshida, Yujin Friedman, Scott L. TI Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells SO SCIENTIFIC REPORTS LA English DT Article ID RECEPTOR BLOCKING DRUG; GENE-EXPRESSION; LIVER FIBROSIS; DOUBLE-BLIND; HEPATOCELLULAR-CARCINOMA; CYCLIC-AMP; PATHWAYS; FAMILY; TRIAL; CHEMOTHERAPY AB We have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4. To identify proteins mediating apigenin's effect, we next overlapped a 122-gene signature unique to HSCs with a list of 160 genes encoding proteins that are known to interact with apigenin, which identified C1QTNF2, encoding for Complement C1q tumor necrosis factor-related protein 2, a secreted adipocytokine with metabolic effects in liver. To validate its disease relevance, C1QTNF2 expression is reduced during hepatic stellate cell activation in culture and in a mouse model of alcoholic liver injury in vivo, and its expression correlates with better clinical outcomes in patients with hepatitis C cirrhosis (n = 216), suggesting it may have a protective role in cirrhosis progression. These findings reinforce the value of computational approaches to drug discovery for hepatic fibrosis, and identify C1QTNF2 as a potential mediator of apigenin's anti-fibrotic activity. C1 [Hicks, Daniel F.; Goossens, Nicolas; Blas-Garcia, Ana; Tsuchida, Takuma; Wooden, Benjamin; Wallace, Michael C.; Lade, Abigale; Lee, Youngmin A.; Hoshida, Yujin; Friedman, Scott L.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Tisch Canc Inst, Div Liver Dis,Dept Med,Liver Canc Program, New York, NY 10029 USA. [Goossens, Nicolas] Univ Hosp Geneva, Div Gastroenterol & Hepatol, Geneva, Switzerland. [Blas-Garcia, Ana] Univ Valencia, FISABIO, Dept Pharmacol, Valencia, Spain. [Tsuchida, Takuma] Mitsubishi Tanabe Pharma Corp, Div Res, Saitama, Japan. [Wallace, Michael C.] Univ Western Australia, West Leederville, WA, Australia. [Nieto, Natalia] Univ Illinois, Dept Pathol, Chicago, IL USA. [Redhead, Benjamin; Dudley, Joel T.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Cederbaum, Arthur I.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Fuchs, Bryan C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. RP Hoshida, Y; Friedman, SL (reprint author), Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Tisch Canc Inst, Div Liver Dis,Dept Med,Liver Canc Program, New York, NY 10029 USA. EM yujin.hoshida@mssm.edu; scott.friedman@mssm.edu FU Icahn School of Medicine Medical Student Research Office [JCI-2012-15124]; Fundacion Juan Esplugues; FISABIO [UGP-14-153]; Nuovo-Soldati Cancer Research Foundation; Geneva University Hospital; NIH/NIDDK [DK099558]; European Union [ERC-2014-AdG-671231HEPCIR]; Irma T. Hirschl Trust; US Department of Defense [W81XWH-16-1-0363]; NIH [DK56621, AA020709] FX Funding from Icahn School of Medicine Medical Student Research Office to D.F.H. Juan de la Cierva contract (JCI-2012-15124, Ministerio de Economia y Competitividad) and Fundacion Juan Esplugues and FISABIO (UGP-14-153) to A.B.G. FLAGS foundation, the Nuovo-Soldati Cancer Research Foundation, and an advanced training grant from Geneva University Hospital to N.G. NIH/NIDDK DK099558, European Union ERC-2014-AdG-671231HEPCIR, Irma T. Hirschl Trust, and US Department of Defense (W81XWH-16-1-0363) to Y.H., and NIH DK56621 and AA020709 to S.L.F. NR 45 TC 0 Z9 0 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 MAR 3 PY 2017 VL 7 AR 42563 DI 10.1038/srep42563 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM4JV UT WOS:000395280200001 PM 28256512 ER PT J AU Walsh, BK Smallwood, C Rettig, J Kacmarek, RM Thompson, J Arnold, JH AF Walsh, Brian K. Smallwood, Craig Rettig, Jordan Kacmarek, Robert M. Thompson, John Arnold, John H. TI Daily Goals Formulation and Enhanced Visualization of Mechanical Ventilation Variance Improves Mechanical Ventilation Score SO RESPIRATORY CARE LA English DT Article DE mechanical ventilation; quality; safety; health-care quality; ICU; critical care; computer decision support; visualization of data ID LOWER TIDAL VOLUMES; ARTERY-BYPASS SURGERY; INTENSIVE-CARE-UNIT; ACUTE LUNG INJURY; RANDOMIZED-TRIAL; SEDATION PROTOCOL; WEANING PROTOCOL; DURATION; OUTCOMES; IMPLEMENTATION AB BACKGROUND: The systematic implementation of evidence-based practice through the use of guidelines, checklists, and protocols mitigates the risks associated with mechanical ventilation, yet variation in practice remains prevalent. Recent advances in software and hardware have allowed for the development and deployment of an enhanced visualization tool that identifies mechanical ventilation goal variance. Our aim was to assess the utility of daily goal establishment and a computer-aided visualization of variance. METHODS: This study was composed of 3 phases: a retrospective observational phase (baseline) followed by 2 prospective sequential interventions. Phase I intervention comprised daily goal establishment of mechanical ventilation. Phase II intervention was the setting and monitoring of daily goals of mechanical ventilation with a web-based data visualization system (T3). A single score of mechanical ventilation was developed to evaluate the outcome. RESULTS: The baseline phase evaluated 130 subjects, phase I enrolled 31 subjects, and phase II enrolled 36 subjects. There were no differences in demographic characteristics between cohorts. A total of 171 verbalizations of goals of mechanical ventilation were completed in phase I. The use of T3 increased by 87% from phase I. Mechanical ventilation score improved by 8.4% in phase I and 11.3% in phase II from baseline (P =.032). The largest effect was in the low risk V-T category, with a 40.3% improvement from baseline in phase I, which was maintained at 39% improvement from baseline in phase II (P =.01). mechanical ventilation score was 9% higher on average in those who survived. CONCLUSIONS: Daily goal formation and computer- enhanced visualization of mechanical ventilation variance were associated with an improvement in goal attainment by evidence of an improved mechanical ventilation score. Further research is needed to determine whether improvements in mechanical ventilation score through a targeted, process-oriented intervention will lead to improved patient outcomes. (C) 2017 Daedalus Enterprises C1 [Walsh, Brian K.; Smallwood, Craig; Rettig, Jordan; Thompson, John; Arnold, John H.] Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesiol Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Med Sch, Boston, MA USA. RP Walsh, BK (reprint author), Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesiol Perioperat & Pain Med, 300 Longwood Ave,Bader 634, Boston, MA 02115 USA. FU Draeger Medical; GE Healthcare; Covidien; Venner Medical FX Dr Rettig, Dr Walsh, Mr Smallwood, and Dr Arnold have received research support from Draeger Medical. Dr Walsh has received research support from GE Healthcare. Dr Kacmarek is a consultant for Covidien and OrangeMed and has received research grants from Covidien and Venner Medical. Mr. Thompson has disclosed no conflicts of interest. NR 49 TC 1 Z9 1 U1 0 U2 0 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 MAR 2 PY 2017 VL 62 IS 3 BP 268 EP 278 DI 10.4187/respcare.04873 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EL9WT UT WOS:000394971500003 PM 28073993 ER PT J AU He, K Palen, BN Mattox, EA Parsons, EC AF He, Ken Palen, Brian N. Mattox, Elizabeth A. Parsons, Elizabeth C. TI Veteran Preferences Regarding Wireless Management of Positive Airway Pressure for Obstructive Sleep Apnea at a Tertiary Health-Care System SO RESPIRATORY CARE LA English DT Article DE sleep apnea syndrome; CPAP; patient preference; telehealth; telemedicine; e-health; home health monitoring; technology ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE; HIGH-RISK; ADHERENCE; PROGRAM; POPULATION; ADULTS; DIAGNOSIS; MEDICINE; ACCESS AB BACKGROUND: Timely monitoring of obstructive sleep apnea (OSA) therapy can be a challenge amid conflicting pressures of rising patient volume and shortage of sleep medicine providers. Positive airway pressure (PAP) devices with wireless modem technology have the potential to improve patient access to care and streamline work load, yet little is known about patient attitudes toward telehealth integration among veterans with sleep apnea. As part of a larger quality improvement initiative at the Veterans Affairs (VA) Puget Sound Health Care System, we elicited veterans' preferences toward modem versus traditional PAP data download, including patient attitudes and factors affecting those preferences. METHODS: We conducted an anonymous survey of veterans without previous CPAP experience presenting for initial device setup and training at VA Puget Sound PAP clinics. Surveys assessed subject demographics, PAP download preferences (modem vs mail), and Likert- type scale ratings of importance placed on factors including convenience and information privacy. Using multinomial logistic regression, we examined the association between convenience rating and download preference, adjusting for information privacy rating, age, and commute time. RESULTS: Of 444 surveys analyzed, respondents were primarily male with a mean age of 52 y. Most respondents reported taking >= 30 min to commute to the PAP clinic. Convenience was rated as the most important factor affecting download preferences. Veteran preferences regarding PAP download method were mixed, with 47% preferring modem, 38% preferring memory card mail- in, and 15% undecided. A higher rating of convenience was significantly associated with modem preference, both before and after adjustment for information privacy rating, commute time, and veteran age (adjusted relative risk ratio 1.67, P <.001, 95% CI 1.40-1.99). CONCLUSIONS: PAP data download preferences were mixed among new veteran users. Veterans placed a high value on the potentially competing concerns of convenience and information privacy. Veterans preferring modem factored convenience as important in their decision making, independent of privacy concerns. C1 [Palen, Brian N.; Parsons, Elizabeth C.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [He, Ken; Palen, Brian N.; Mattox, Elizabeth A.; Parsons, Elizabeth C.] Vet Affairs Puget Sound Hlth Care Syst, 1600 S Columbian Way,S-111 Pulm, Seattle, WA 98108 USA. RP Parsons, EC (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1600 S Columbian Way,S-111 Pulm, Seattle, WA 98108 USA. EM Elizabeth.parsons@va.gov NR 43 TC 0 Z9 0 U1 1 U2 1 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 MAR 2 PY 2017 VL 62 IS 3 BP 357 EP 362 DI 10.4187/respcare.05002 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EL9WT UT WOS:000394971500013 PM 27879382 ER PT J AU Kacmarek, RM Walsh, BK AF Kacmarek, Robert M. Walsh, Brian K. TI The Respiratory Therapy Profession Is at a Crossroads SO RESPIRATORY CARE LA English DT Editorial Material ID DIRECTORS; EDUCATION; CARE C1 [Kacmarek, Robert M.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Walsh, Brian K.] Amer Assoc Resp Care, Irving, TX USA. [Walsh, Brian K.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM rkacmarek@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 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 MAR 2 PY 2017 VL 62 IS 3 BP 384 EP 386 DI 10.4187/respcare.05484 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EL9WT UT WOS:000394971500018 PM 28246282 ER PT J AU Lajnef, T O'Reilly, C Combrisson, E Chaibi, S Eichenlaub, JB Ruby, PM Aguera, PE Samet, M Kachouri, A Frenette, S Carrier, J Jerbi, K AF Lajnef, Tarek O'Reilly, Christian Combrisson, Etienne Chaibi, Sahbi Eichenlaub, Jean-Baptiste Ruby, Perrine M. Aguera, Pierre-Emmanuel Samet, Mounir Kachouri, Abdennaceur Frenette, Sonia Carrier, Julie Jerbi, Karim TI Meet Spinky: An Open-Source Spindle and K-Complex Detection Toolbox Validated on the Open-Access Montreal Archive of Sleep Studies (MASS) SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE spindles; K-complex; automatic detection; sleep-EEG; spinky; open-source; toolbox; TQWT ID SUPPORT VECTOR MACHINES; EYE-MOVEMENT SLEEP; AUTOMATIC DETECTION; PARKINSONS-DISEASE; WAVELET TRANSFORM; MOTOR SEQUENCE; DECISION-TREE; EEG; SLOW; BENCHMARKING AB Sleep spindles and K-complexes are among the most prominent micro-events observed in electroencephalographic (EEG) recordings during sleep. These EEG microstructures are thought to be hallmarks of sleep-related cognitive processes. Although tedious and time-consuming, their identification and quantification is important for sleep studies in both healthy subjects and patients with sleep disorders. Therefore, procedures for automatic detection of spindles and K-complexes could provide valuable assistance to researchers and clinicians in the field. Recently, we proposed a framework for joint spindle and K-complex detection (Lajnef et al., 2015a) based on a Tunable Q-factor Wavelet Transform (TQWT; Selesnick, 2011a) and morphological component analysis (MCA). Using a wide range of performance metrics, the present article provides critical validation and benchmarking of the proposed approach by applying it to open-access EEG data from the Montreal Archive of Sleep Studies (MASS; O'Reilly et al., 2014). Importantly, the obtained scores were compared to alternative methods that were previously tested on the same database. With respect to spindle detection, our method achieved higher performance than most of the alternative methods. This was corroborated with statistic tests that took into account both sensitivity and precision (i. e., Matthew's coefficient of correlation (MCC), F1, Cohen k). Our proposed method has been made available to the community via an open-source tool named Spinky (for spindle and K-complex detection). Thanks to a GUI implementation and access to Matlab and Python resources, Spinky is expected to contribute to an open-science approach that will enhance replicability and reliable comparisons of classifier performances for the detection of sleep EEG microstructure in both healthy and patient populations. C1 [Lajnef, Tarek; Combrisson, Etienne; Carrier, Julie; Jerbi, Karim] Univ Montreal, Dept Psychol, Montreal, PQ, Canada. [Lajnef, Tarek; Frenette, Sonia; Carrier, Julie] Hop Sacre Coeur, Ctr Adv Res Sleep Med, Montreal, PQ, Canada. [O'Reilly, Christian] Ecole Polytech Fed Lausanne, Blue Brain Project, Geneva, Switzerland. [Combrisson, Etienne] Univ Claude Bernard Lyon 1, Interuniv Lab Human Movement Biol, Villeurbanne, France. [Combrisson, Etienne; Ruby, Perrine M.; Aguera, Pierre-Emmanuel] Univ Lyon 1, Lyon Neurosci Res Ctr, DYCOG Lab, INSERM U1028,UMR 5292, Lyon, France. [Chaibi, Sahbi; Samet, Mounir; Kachouri, Abdennaceur] Univ Sfax, LETI Lab Sfax, Natl Engn Sch ENIS, Sfax, Tunisia. [Eichenlaub, Jean-Baptiste] Harvard Med Sch, Dept Neurol, Massachusetts Gen Hosp, Boston, MA USA. [Jerbi, Karim] CRIUGM, Montreal, PQ, Canada. [Jerbi, Karim] Univ Montreal, Dept Psychol, Ctr Rech Neuropsychol & Cognit CERNEC, Montreal, PQ, Canada. [Jerbi, Karim] Int Lab Res Brain Mus & Sound, BRAMS, Montreal, PQ, Canada. RP Lajnef, T (reprint author), Univ Montreal, Dept Psychol, Montreal, PQ, Canada.; Lajnef, T (reprint author), Hop Sacre Coeur, Ctr Adv Res Sleep Med, Montreal, PQ, Canada. EM lajnef.tarek@gmail.com FU Natural Sciences and Engineering Research Council (NSERC) of Canada; EDST doctoral program; LETI Laboratory, Sfax, Tunisia; Ecole Doctorale Inter-Disciplinaire Sciences-Sante (EDISS), Lyon, France; NSERC of Canada; Fyssen Foundation; Canada Research Chairs program; NSERC [RGPIN-2015-04854, RGPIN-2016-05149]; LABEX CORTEX of Universite de Lyon [ANR-11-LABX-0042, ANR-11-IDEX-0007] FX The authors would like to acknowledge that this work greatly benefited from the open access TQWT toolbox developed and made available online by Dr Ivan Selesnick (New York University, NY, USA). TL was supported in part by a fellowship based on funding from Natural Sciences and Engineering Research Council (NSERC) of Canada, and by travel funds from EDST doctoral program and the LETI Laboratory, Sfax, Tunisia. EC was supported in part by a PhD Scholarship by the Ecole Doctorale Inter-Disciplinaire Sciences-Sante (EDISS), Lyon, France, and by PhD funding from the NSERC of Canada. J-BE was supported by the Fyssen Foundation. KJ acknowledges funding from the Canada Research Chairs program and a Discovery Grant (RGPIN-2015-04854) awarded by NSERC. JC was supported by an NSERC Grant (RGPIN-2016-05149). This work was partly performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of Universite de Lyon, within the program ANR-11-IDEX-0007. The authors are grateful to Golnoush Alamian for her invaluable help proofreading the manuscript. NR 59 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 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD MAR 2 PY 2017 VL 11 AR 15 DI 10.3389/fninf.2017.00015 PG 13 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA EM0WH UT WOS:000395037900002 PM 28303099 ER PT J AU Stone, RM AF Stone, Richard M. TI 3+7+FLT3 inhibitors: 1+1 not equal 2 SO BLOOD LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; CONTROLLED-TRIAL; CHEMOTHERAPY; SORAFENIB; YOUNGER; PLACEBO; FLT3 AB In this issue of Blood, Knapper et al analyzed 2 consecutive randomized Medical Research Council (MRC) trials in newly diagnosed patients with mutant FMS-like tyrosine kinase-3 (FLT3) acute myeloid leukemia (AML) and suggested no benefit for the addition of the kinase inhibitor lestaurtinib to chemotherapy. 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 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 MAR 2 PY 2017 VL 129 IS 9 BP 1061 EP 1062 DI 10.1182/blood-2016-12-754473 PG 2 WC Hematology SC Hematology GA EP1JZ UT WOS:000397142500002 PM 28254820 ER PT J AU Gusella, JF AF Gusella, James F. TI 2016 William Allan Award: Human Disease Research: Genetic Cycling and Re-cycling SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID SOMATIC MAMMALIAN-CELLS; HUNTINGTONS-DISEASE; FAMILIAL DYSAUTONOMIA; REPEAT EXPANSION; DETERMINES AGE; DNA MARKERS; CURT STERN; REGION; LOCALIZATION; DIAGNOSIS C1 [Gusella, James F.] Harvard Med Sch, Dept Chem, Boston, MA 02115 USA. [Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. RP Gusella, JF (reprint author), Harvard Med Sch, Dept Chem, Boston, MA 02115 USA.; Gusella, JF (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM gusella@helix.mgh.harvard.edu NR 46 TC 0 Z9 0 U1 0 U2 0 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 MAR 2 PY 2017 VL 100 IS 3 BP 387 EP 394 DI 10.1016/j.ajhg.2017.01.008 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EN2PH UT WOS:000395851900003 PM 28257685 ER PT J AU Nguyen, HD Yadav, T Giri, S Saez, B Graubert, TA Zou, L AF Nguyen, Hai Dang Yadav, Tribhuwan Giri, Sumanprava Saez, Borja Graubert, Timothy A. Zou, Lee TI Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1 SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTIONAL PAUSE SITES; SINGLE-STRANDED-DNA; GENOME INSTABILITY; FORK PROGRESSION; RNA/DNA HYBRIDS; ATR ACTIVATION; HUMAN GENES; RPA-SSDNA; B-CELLS AB R loop, a transcription intermediate containing RNA: DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA: DNA hybrids, plays an important role in R loop suppression. Here we show that replication protein A (RPA), an ssDNA-binding protein, interacts with RNaseH1 and colocalizes with both RNaseH1 and R loops in cells. In vitro, purified RPA directly enhances the association of RNaseH1 with RNA: DNA hybrids and stimulates the activity of RNaseH1 on R loops. An RPA binding-defective RNaseH1 mutant is not efficiently stimulated by RPA in vitro, fails to accumulate at R loops in cells, and loses the ability to suppress R loops and associated genomic instability. Thus, in addition to sensing DNA damage and replication stress, RPA is a sensor of R loops and a regulator of RNaseH1, extending the versatile role of RPA in suppression of genomic instability. C1 [Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava; Saez, Borja; Graubert, Timothy A.; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM zou.lee@mgh.harvard.edu FU NIH [P41 RR-01081, GM076388, CA197779]; Medical Discovery Fund; Jim and Ann Orr Massachusetts General Hospital Research Scholar Award; Evans Foundation [201407] FX We thank Drs. R. Bradley, R. Crouch, M.A. Lee-Kirsch, and S. Leppla for reagents, Dr. A. Marechal for characterizations of reagents, and members of the Zou and Dyson labs for helpful discussions. The molecular graphic image in Figure 4C was produced using the University of California at San Francisco (UCSF) Chimera package from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH P41 RR-01081). H.D.N. is partly supported by a postdoctoral fellowship from the Medical Discovery Fund. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research and was supported by a Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. This work is supported by grants from the NIH (GM076388 and CA197779 to L.Z.) and the Evans Foundation (201407 to T.G.). NR 62 TC 0 Z9 0 U1 3 U2 3 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 MAR 2 PY 2017 VL 65 IS 5 BP 832 EP + DI 10.1016/j.molcel.2017.01.029 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EO1BD UT WOS:000396431700008 PM 28257700 ER PT J AU Maus, MV AF Maus, Marcela V. TI IMMUNOLOGY T-cell tweaks to target tumours SO NATURE LA English DT Editorial Material AB Immune cells known as T cells can destroy tumour cells, but their clinical use requires complex preparation and the cells can lose effectiveness over time. A new approach might improve the efficiency of T-cell therapy. See Letter p. 113 C1 [Maus, Marcela V.] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. [Maus, Marcela V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Maus, MV (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02114 USA.; Maus, MV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM mvmaus@mgh.harvard.edu NR 12 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 2 PY 2017 VL 543 IS 7643 BP 48 EP 49 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0AA UT WOS:000395671500029 PM 28225762 ER PT J AU Geha, R Peters, M Gill, RM Dhaliwal, G AF Geha, Rabih Peters, Marion Gill, Ryan M. Dhaliwal, Gurpreet TI Histology Rings True SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID Q-FEVER; HEPATIC GRANULOMAS; DIAGNOSIS; DISEASE C1 [Peters, Marion] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Geha, Rabih; Peters, Marion; Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Gill, Ryan M.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Geha, R (reprint author), 505 Parnassus Ave,Rm 987, San Francisco, CA 94143 USA. EM rabih.geha@ucsf.edu FU Philips Healthcare FX Dr. Peters reports receiving honoraria from Merck, Roche, Johnson & Johnson, Gilead Sciences, Abbott, and Genentech; Dr. Gill, receiving consulting fees from Philips Healthcare; and Dr. Dhaliwal, receiving honoraria from the ISMIE Mutual Insurance and Physicians' Reciprocal Insurers. No other potential conflict of interest relevant to this article was reported. NR 13 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 MAR 2 PY 2017 VL 376 IS 9 BP 870 EP 875 DI 10.1056/NEJMcps1609391 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JK UT WOS:000395627500012 ER PT J AU Hong, TS Allen, JN Shellito, PC AF Hong, Theodore S. Allen, Jill N. Shellito, Paul C. TI Case 39-2016: A Man with a History of Prostate Cancer and Recent Rectal Bleeding REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hong, Theodore S.; Allen, Jill N.; Shellito, Paul C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 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 MAR 2 PY 2017 VL 376 IS 9 BP 898 EP 898 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JK UT WOS:000395627500032 PM 28273412 ER PT J AU Corleis, B Lisanti, AC Korner, C Schiff, AE Rosenberg, ES Allen, TM Altfeld, M Kwon, DS AF Corleis, Bjorn Lisanti, Antonella C. Koerner, Christian Schiff, Abigail E. Rosenberg, Eric S. Allen, Todd M. Altfeld, Marcus Kwon, Douglas S. TI Early type I Interferon response induces upregulation of human beta-defensin 1 during acute HIV-1 infection SO PLOS ONE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; TOLL-LIKE RECEPTOR-3; ANTIMICROBIAL PEPTIDES; INNATE IMMUNITY; EPITHELIAL-CELLS; HUMAN BETA-DEFENSIN-3; HOST-DEFENSE; INHIBIT HIV; T-CELLS; EXPRESSION AB HIV-1 is able to evade innate antiviral responses during acute infection to establish a chronic systemic infection which, in the absence of antiretroviral therapy (ART), typically progresses to severe immunodeficiency. Understanding these early innate immune responses against HIV-1 and their mechanisms of failure is relevant to the development of interventions to better prevent HIV-1 transmission. Human beta defensins (HBDs) are antibacterial peptides but have recently also been associated with control of viral replication. HBD1 and 2 are expressed in PBMCs as well as intestinal tissue, but their expression in vivo during HIV-1 infection has not been characterized. We demonstrate that during acute HIV-1 infection, HBD1 but not HBD2 is highly upregulated in circulating monocytes but returns to baseline levels during chronic infection. HBD1 expression in monocytes can be induced by HIV-1 in vitro, although direct infection may not entirely account for the increase in HBD1 during acute infection. We provide evidence that HIV-1 triggers antiviral IFN-alpha responses, which act as a potent inducer of HBD1. Our results show the first characterization of induction of an HBD during acute and chronic viral infection in humans. HBD1 has been reported to have low activity against HIV-1 compared to other defensins, suggesting that in vivo induced defensins may not significantly contribute to the robust early antiviral response against HIV1. These data provide important insight into the in vivo kinetics of HBD expression, the mechanism of HBD1 induction by HIV-1, and the role of HBDs in the early innate response to HIV-1 during acute infection. C1 [Corleis, Bjorn; Lisanti, Antonella C.; Koerner, Christian; Schiff, Abigail E.; Allen, Todd M.; Altfeld, Marcus; Kwon, Douglas S.] Harvard Med Sch, Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02115 USA. [Rosenberg, Eric S.; Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Koerner, Christian] Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. RP Kwon, DS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02115 USA.; Kwon, DS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM dkwon@mgh.harvard.edu FU National Institute of Allergy and Infectious Disease [P01 AI074415, R01DK101354]; Burroughs Wellcome Fund FX This work was funded in part with federal funds from the National Institute of Allergy and Infectious Disease through P01 AI074415 (TMA and MA) and R01DK101354 (DSK). DSK is funded by an award from the Burroughs Wellcome Fund. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 72 TC 0 Z9 0 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 MAR 2 PY 2017 VL 12 IS 3 AR e0173161 DI 10.1371/journal.pone.0173161 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN4XX UT WOS:000396011300085 PM 28253319 ER PT J AU Wang, ZW Xiao, XY Ge, RB Li, JJ Johnson, CW Rassoulian, C Olumi, AF AF Wang, Zongwei Xiao, Xingyuan Ge, Rongbin Li, Jijun Johnson, Cameron W. Rassoulian, Cyrus Olumi, Aria F. TI Metformin inhibits the proliferation of benign prostatic epithelial cells SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-I; SIGNALING PATHWAY; CYCLE PROGRESSION; CANCER-CELLS; HYPERPLASIA; INSULIN; EXPRESSION; RISK; RECEPTOR; D1 AB Objective Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate affecting elderly men throughout the world. Epidemiologic studies have shown that diabetes significantly increases the risk of developing BPH, although whether anti-diabetic medications preventing the development of BPH remains to be defined. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial cell proliferation through paracrine mechanisms. Here, we seek to understand if metformin, a first line medication for the treatment of type 2 diabetes, inhibits the proliferation of benign prostatic epithelial cells through reducing the expression of IGF-1 receptor (IGF-1R) and regulating cell cycle. Methods BPE cell lines BPH-1 and P69, murine fibroblasts3T3 and primary human prostatic fibroblasts were cultured and tested in this study. Cell proliferation and the cell cycle were analyzed by MTS assay and flow cytometry, respectively. The expression of IGF-1R was determined by western-blot and immunocytochemistry. The level of IGF-1 secretion in culture medium was measured by ELISA. Results Metformin (0.5-10mM, 6-48h) significantly inhibited the proliferation of BPH-1 and P69 cells in a dose-dependent and time-dependent manner. Treatment with metformin for 24 hours lowered the G(2)/M cell population by 43.24% in P69 cells and 24.22% in BPH-1 cells. On the other hand, IGF-1 (100ng/mL, 24h) stimulated the cell proliferation (increased by 28.81% in P69 cells and 20.95% in BPH-1 cells) and significantly enhanced the expression of IGF-1R in benign prostatic epithelial cells. Metformin (5mM) abrogated the proliferation of benign prostatic epithelial cells induced by IGF-1. In 3T3 cells, the secretion of IGF-1 was significantly inhibited by metformin from 574.31pg/ml to 197.61pg/ml. The conditioned media of 3T3 cells and human prostatic fibroblasts promoted the proliferation of epithelial cells and the expression of IGF-1R in epithelial cells. Metformin abrogated the proliferation of benign prostatic epithelial cells promoted by 3T3 conditioned medium. Conclusions Our study demonstrates that metformin inhibits the proliferation of benign prostatic epithelial cells by suppressing the expression of IGF-1R and IGF-1 secretion in stromal cells. Metformin lowers the G2/M cell population and simultaneously increases the G0/G1 population. Findings here might have significant clinical implications in management of BPH patients treated with metformin. C1 [Wang, Zongwei; Xiao, Xingyuan; Johnson, Cameron W.; Rassoulian, Cyrus; Olumi, Aria F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02115 USA. [Xiao, Xingyuan] Huazhong Univ Sci & Technol, Wuhan Union Hosp, Dept Urol, Wuhan, Peoples R China. [Ge, Rongbin] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Li, Jijun] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai, Peoples R China. RP Wang, ZW (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02115 USA. EM zwang0@mgh.harvard.edu FU NIH/National Institute for Diabetes and Digestive and Kidney Diseases [NIH/R01 DK091353] FX NIH/National Institute for Diabetes and Digestive and Kidney Diseases (NIH/R01 DK091353) to AFO. NR 39 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 MAR 2 PY 2017 VL 12 IS 3 AR e0173335 DI 10.1371/journal.pone.0173335 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN4XX UT WOS:000396011300101 PM 28253329 ER PT J AU Baciewicz, AM Lee, C Ben-Ari, A Kim, H Lee, AT AF Baciewicz, Anne M. Lee, Calvin Ben-Ari, Alon Kim, Hojoong Lee, Alex T. TI Intravenous Tissue Plasminogen Activator Administration for Ischemic Stroke 1 Hour After Epidural Catheter Removal: A Case Report SO A & A CASE REPORTS LA English DT Article ID ASSOCIATION; GUIDELINES; MEDICINE; SOCIETY AB Anticoagulation after a recent neuraxial procedure poses risk for development of spinal hematoma. Clinical evidence supports prompt IV tissue plasminogen activator administration after onset of ischemic stroke. There is an absence of data regarding emergency fibrinolytic therapy for patients experiencing a stroke with recent neuraxial procedures, resulting in highly disparate, nonevidence-based guidelines. This report describes a patient who developed ischemic stroke when receiving postoperative epidural analgesia. Tissue plasminogen activator was emergently administered 1 hour after epidural catheter removal with a favorable recovery. The patient and his family reviewed the manuscript, and written consent to publish this case report was obtained from the patient. C1 [Baciewicz, Anne M.] Univ Washington, Dept Pharm, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Lee, Calvin] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Ben-Ari, Alon; Lee, Alex T.] Univ Washington, Dept Anesthesiol & Pain Med, VA Puget Sound Hlth Care Syst, 1660 Columbian Way S-112-Anes, Seattle, WA 98108 USA. [Kim, Hojoong] Univ Washington, Dept Neurol, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Lee, AT (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, VA Puget Sound Hlth Care Syst, 1660 Columbian Way S-112-Anes, Seattle, WA 98108 USA. EM alex.lee@va.gov NR 9 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 2325-7237 J9 A A CASE REP JI A A Case Rep. PD MAR 1 PY 2017 VL 8 IS 5 BP 113 EP 115 DI 10.1213/XAA.0000000000000443 PG 3 WC Anesthesiology SC Anesthesiology GA EN3HQ UT WOS:000395900000006 PM 28079666 ER PT J AU Katolik, A Clark, NE Tago, N Montemayor, EJ Hart, PJ Damha, MJ AF Katolik, Adam Clark, Nathaniel E. Tago, Nobuhiro Montemayor, Eric J. Hart, P. John Damha, Masad J. TI Fluorescent Branched RNAs for High-Throughput Analysis of Dbr1 Enzyme Kinetics and Inhibition SO ACS CHEMICAL BIOLOGY LA English DT Article ID LARIAT-DEBRANCHING ENZYME; SOLID-PHASE SYNTHESIS; MANGANESE-DEPENDENT PHOSPHODIESTERASE; TY1; OLIGORIBONUCLEOTIDES; RETROTRANSPOSITION; MECHANISMS; LINKAGES; SEQUENCE; DESIGN AB We have developed fluorescent 2',S' branched RNAs (bRNA) that permit real time monitoring of RNA lariat (intron) debranching enzyme (Dbrl) kinetics. These compounds contain fluorescein (FAM) on the 5' arm of the bRNA that is quenched by a dabcyl moiety on the 2 arm. Dbrl-mediated hydrolysis of the 2',S' linkage induces a large increase in fluorescence, providing a convenient assay for Dbrl hydrolysis. We show that unlabeled bRNAs with non-native 2',5'- phosphodiester linkages, such as phosphoramidate or phosphorothioate, can inhibit Dbrl-mediated debranching with IC50 values in the low nanomolar range. In addition to measuring kinetic parameters of the debranching enzyme, these probes can be used for high throughput screening (HTS) of chemical libraries with the aim of identifying Dbrl inhibitors, compounds that may be useful in treating neurodegenerative diseases and retroviral infections. C1 [Katolik, Adam; Tago, Nobuhiro; Damha, Masad J.] McGill Univ, Dept Chem, 801 Sherbrooke St West, Montreal, PQ H3A 0B8, Canada. [Clark, Nathaniel E.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biochem, 433 Babcock Dr, Madison, WI 53706 USA. [Montemayor, Eric J.] Univ Wisconsin, Dept Biomol Chem, 433 Babcock Dr, Madison, WI 53706 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Damha, MJ (reprint author), McGill Univ, Dept Chem, 801 Sherbrooke St West, Montreal, PQ H3A 0B8, Canada.; Clark, NE; Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA.; Hart, PJ (reprint author), South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. EM clarkn@uthscsa.edu; pjh@biochem.uthscsa.edu; masad.damha@mcgill.ca FU National Sciences and Engineering Research Council of Canada; Department of Veterans Affairs [1 I01 BX002580]; Robert A. Welch Foundation [AQ-1399]; Judith and Jean Pape Adams Charitable Foundation; National Science Foundation [DBI-0905865]; National Institutes of Health [T32 AG021890]; Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from a Japan Society for the Promotion of Science (JSPS) FX This work was supported in part by grants from the National Sciences and Engineering Research Council of Canada (to M.J.D.), Department of Veterans Affairs (1 I01 BX002580, to PJ.H.), the Robert A. Welch Foundation (AQ-1399, to PJ.H.), the Judith and Jean Pape Adams Charitable Foundation (to PJ.H.), the National Science Foundation (DBI-0905865, to E.J.M.), the National Institutes of Health (T32 AG021890, to N.E.C. and EJ.M.), and a Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from a Japan Society for the Promotion of Science (JSPS to N.T.). NR 33 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAR PY 2017 VL 12 IS 3 BP 622 EP 627 DI 10.1021/acschembio.6b00971 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP0LB UT WOS:000397077700005 PM 28055181 ER PT J AU Tyler, MW Zaldivar-Diez, J Haggarty, SJ AF Tyler, Marshall W. Zaldivar-Diez, Josefa Haggarty, Stephen J. TI Classics in Chemical Neuroscience: Haloperidol SO ACS CHEMICAL NEUROSCIENCE LA English DT Review DE Haloperidol; antipsychotic; schizophrenia; dopamine; pharmacology; history ID NEUROLEPTIC MALIGNANT SYNDROME; INDUCED WEIGHT-GAIN; NMDA RECEPTOR HYPOFUNCTION; DOPAMINE HYPOTHESIS; ANTIPSYCHOTIC-DRUGS; SCHIZOPHRENIC-PATIENTS; PYRIDINIUM METABOLITE; ATYPICAL ANTIPSYCHOTICS; INTRAVENOUS HALOPERIDOL; NEUROTRANSMITTER UPTAKE AB The discovery of haloperidol catalyzed a breakthrough in our understanding of the biochemical basis of schizophrenia, improved the treatment of psychosis, and facilitated deinstitutionalization. In doing so, it solidified the role for chemical neuroscience as a means to elucidate the molecular underpinnings of complex neuropsychiatric disorders. In this Review, we will cover aspects of haloperidol's synthesis, manufacturing, metabolism, pharmacology, approved and off-label indications, and adverse effects. We will also convey the fascinating history of this classic molecule and the influence that it has had on the evolution of neuropsychopharmacology and neuroscience. C1 [Tyler, Marshall W.; Zaldivar-Diez, Josefa; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Genom Med, Harvard Med Sch, Chem Neurobiol Lab,Chem Biol Program, Boston, MA 02114 USA. [Zaldivar-Diez, Josefa] CSIC, Ctr Investigac Biol, Madrid 28040, Spain. RP Tyler, MW; Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Ctr Genom Med, Harvard Med Sch, Chem Neurobiol Lab,Chem Biol Program, Boston, MA 02114 USA. EM mwtyler@mgh.harvard.edu; shaggarty@mgh.harvard.edu NR 135 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2017 VL 8 IS 3 BP 444 EP 453 DI 10.1021/acschemneuro.7b00018 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA EO6MT UT WOS:000396807900006 PM 28170220 ER PT J AU Schroeder, FA Gilbert, TM Feng, NP Taillon, BD Volkow, ND Innis, RB Hooker, JM Lipska, BK AF Schroeder, Frederick A. Gilbert, Tonya M. Feng, Ningping Taillon, Brendan D. Volkow, Nora D. Innis, Robert B. Hooker, Jacob M. Lipska, Barbara K. TI Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Epigenetics; chromatin; schizophrenia; mood disorders unipolar; mood disorders bipolar; neuropsychiatry ID AGE-RELATED-CHANGES; MESSENGER-RNA; PSYCHIATRIC-DISORDERS; HISTONE ACETYLATION; HUMAN BRAIN; ABNORMALITIES; CONNECTIVITY; INHIBITION; SYSTEM; MICE AB Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder, and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. We used >700 well-characterized samples from patients diagnosed with schizophrenia (n = 175), major depressive disorder (n = 135), and bipolar disorder (n = 61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of beta-2-microglobulin, beta-glucuronidase, and beta-actin. In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p < 10(-4)). HDAC2 was significantly upregulated in major depressive disorder samples by 17% versus controls (p = 0.002). Neither smoking history nor therapeutic drugs impacted HDAC2 levels and no HDAC1 patient-control differences were observed. In caudate, HDAC levels were unchanged between patient and control groups. In control DLPFC, age fetal week 14 to 97 years (n = 326), both HDAC1 and HDAC2 levels sharply declined around birth and stabilized thereafter. Using by far the largest postmortem sample set on this topic, our major finding (decreased HDAC2 transcript) showed notable specificity in disease (schizophrenia but not major depressive disorder), HDAC subtype (HDAC2 but not HDAC1) and brain region (DLPFC but not caudate). These differences shape understanding of regional components of neural circuitry in the diseased brain and set a benchmark to quantify HDAC density and distribution using in vivo neuroimaging tools. C1 [Schroeder, Frederick A.; Gilbert, Tonya M.; Taillon, Brendan D.; Hooker, Jacob M.] Harvard Med Sch, Athinoula Martinos Ctr, Dept Radiol, Massachusetts Gen Hosp, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. [Feng, Ningping; Lipska, Barbara K.] Natl Inst Hlth, Human Brain Collect Core, Div Intramural Res Programs, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD 20892 USA. [Innis, Robert B.] Natl Inst Hlth, Mol Imaging Branch, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. RP Schroeder, FA (reprint author), Harvard Med Sch, Athinoula Martinos Ctr, Dept Radiol, Massachusetts Gen Hosp, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM fschroeder@mgh.harvard.edu RI Lipska, Barbara/E-4569-2017 FU National Institute of Mental Health; Molecular Imaging Branch [ZIAMH002795]; Harvard/MGH Nuclear Medicine Training Program from the Department of Energy [DE-SC0008430]; National Institute of Drug Abuse of the National Institutes of Health [R0IDA030321]; Brain and Behavior Research Foundation Independent Investigator Award FX Research was supported by the National Institute of Mental Health through programmatic funding to the Human Brain Collection Core (B.K.L.) and Molecular Imaging Branch (Project ZIAMH002795 to R.B.I.), by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy under Grant DE-SC0008430 (to T.M.G.), and by the National Institute of Drug Abuse of the National Institutes of Health under Grant Number R0IDA030321 and the Brain and Behavior Research Foundation Independent Investigator Award (J.M.H.). NR 41 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2017 VL 8 IS 3 BP 662 EP 668 DI 10.1021/acschemneuro.6b00372 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA EO6MT UT WOS:000396807900025 PM 27959513 ER PT J AU Hu, KZ Patnaik, D Collier, TL Lee, KN Gao, H Swoyer, MR Rotstein, BH Krishnan, HS Liang, SH Wang, J Yan, ZQ Hooker, JM Vasdev, N Haggarty, SJ Ngai, MY AF Hu, Kongzhen Patnaik, Debasis Collier, Thomas Lee Lee, Katarzyna Gao, Han Swoyer, Matthew Rotstein, Benjamin krishnan, Hema Liang, Steven Wang, Jin Yan, Zhiqiang Hooker, Jacob M. Vasdev, Neil Haggarty, Stephen J. Ngai, Ming-Yu TI Development of [F-18]Maleimide-Based Glycogen Synthase Kinase-3 beta Ligands for Positron Emission Tomography Imaging SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Glycogen synthase kinase-3; PET imaging; radiofluorination; maleimide ID IN-VIVO; GSK-3-BETA INHIBITORS; ALZHEIMERS-DISEASE; PET; POTENT; CANCER; GSK3; RADIOSYNTHESIS; HYPERTROPHY; RADIOTRACER AB Dysregulation of glycogen synthase kinase-3 beta (GSK-3 beta) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3 beta radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3 beta and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3 beta inhibitors. Radiosynthesis of a potential GSK-3 beta tracer [F-18]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [F-18]-labeled GSK-3 beta radiotracers for PET imaging of the central nervous system is warranted. C1 [Hu, Kongzhen; Lee, Katarzyna; Gao, Han; Swoyer, Matthew; Wang, Jin; Ngai, Ming-Yu] SUNY Stony Brook, Dept Chem, New York, NY 11794 USA. [Hu, Kongzhen; Lee, Katarzyna; Gao, Han; Swoyer, Matthew; Wang, Jin; Ngai, Ming-Yu] SUNY Stony Brook, Inst Chem Biol & Drug Discovery, New York, NY 11794 USA. [Patnaik, Debasis; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Genom Med, Chem Neurobiol Lab, Dept Neurol, Boston, MA 02114 USA. [Patnaik, Debasis; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Genom Med, Chem Neurobiol Lab, Dept Psychiat, Boston, MA 02114 USA. [Patnaik, Debasis; Haggarty, Stephen J.] Harvard Med Sch, Boston, MA 02114 USA. [Collier, Thomas Lee; Rotstein, Benjamin; krishnan, Hema; Liang, Steven; Vasdev, Neil] Massachusetts Gen Hosp, Gordon Ctr Med Imaging & Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Collier, Thomas Lee; Rotstein, Benjamin; krishnan, Hema; Liang, Steven; Vasdev, Neil] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. [Hooker, Jacob M.] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Dept Radiol, Boston, MA 02114 USA. [Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hooker, Jacob M.] Harvard Med Sch, Charlestown, MA 02129 USA. [Yan, Zhiqiang] Chinese Acad Sci, Changchun Inst Appl Chem, State Key Lab Electroanalyt Chem, Changchun 130022, Kagawa, Peoples R China. [Hu, Kongzhen] Nanfang Hosp, Dept PET Ctr, Guangzhou, Guangdong, Peoples R China. RP Ngai, MY (reprint author), SUNY Stony Brook, Dept Chem, New York, NY 11794 USA.; Ngai, MY (reprint author), SUNY Stony Brook, Inst Chem Biol & Drug Discovery, New York, NY 11794 USA. EM ming-yu.ngai@stonybrook.edu FU National Institute of General Medical Sciences [R35GM119652]; National Institute on Aging of the National Institute of Health; Stony Brook University [R01AG054473]; National Natural Science Foundation of China [21403208]; NIH Chemical -Biology [T32GM092714]; Tau Consortium; National Institute on Drug Abuse [DA038000] FX This work was partially supported by National Institute of General Medical Sciences (R35GM119652 to M.-Y.N.) and National Institute on Aging of the National Institute of Health and (R01AG054473 to N.V.), start-up funds from Stony Brook University (M.-Y.N.), and National Natural Science Foundation of China (Grant no. 21403208 to Z.Y.). K.N.L. received a graduate fellowship from an NIH Chemical -Biology training grant (T32GM092714). S.J.H. received support from the Tau Consortium. S.H.L is a recipient of NIH career development award from the National Institute on Drug Abuse (DA038000). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 43 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD MAR PY 2017 VL 8 IS 3 BP 287 EP 292 DI 10.1021/acsmedthernle11.6b00405 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EN9CG UT WOS:000396297700006 PM 28337318 ER PT J AU Liang, YK de Wispelaere, M Carocci, M Liu, QS Wang, JH Yang, PL Gray, NS AF Liang, Yanke de Wispelaere, Melissanne Carocci, Margot Liu, Qingsong Wang, Jinhua Yang, Priscilla L. Gray, Nathanael S. TI Structure-Activity Relationship Study of QL47: A Broad-Spectrum Antiviral Agent SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Dengue virus; broad-spectrum antiviral; QL47; structure-activity relationship ID KINASE INHIBITORS; DENGUE VIRUS; B-CELL; DISCOVERY; CANCER; MTOR; REPLICATION; FLAVIVIRUS; INFECTION; POTENT AB Here we report the structure activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation. C1 [Liang, Yanke; Liu, Qingsong; Wang, Jinhua; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Liang, Yanke; Liu, Qingsong; Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [de Wispelaere, Melissanne; Carocci, Margot; Yang, Priscilla L.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Gray, NS (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Yang, PL (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM priscilla_yang@hms.harvard.edu; nathanael_gray@dfci.harvard.edu FU Linde program in chemical biology FX We gratefully acknowledge Dr. Tinghu Zhang for the synthesis of relevant tool compounds and helpful discussions; and Dr. Michael Cameron at the Scripps Research Institute for conducting in vitro mouse microsome study and in vivo tolerability study. This work was funded by the Linde program in chemical biology. NR 30 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD MAR PY 2017 VL 8 IS 3 BP 344 EP 349 DI 10.1021/acsmedchemlett.7b00008 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EN9CG UT WOS:000396297700016 PM 28337328 ER PT J AU Sjoerds, Z Stufflebeam, SM Veltman, DJ Van den Brink, W Penninx, BWJH Douw, L AF Sjoerds, Zsuzsika Stufflebeam, Steven M. Veltman, Dick J. Van den Brink, Wim Penninx, Brenda W. J. H. Douw, Linda TI Loss of brain graph network efficiency in alcohol dependence SO ADDICTION BIOLOGY LA English DT Article DE Alcohol dependence; brain network; functional connectivity; graph theory; resting-state fMRI; striatum ID DRUG-ADDICTION; RESTING BRAIN; CONNECTIVITY; SYSTEMS; STRIATUM; PSYCHIATRY; DISEASE; HABITS; HEALTH; REWARD AB Alcohol dependence (AD) is characterized by corticostriatal impairments in individual brain areas such as the striatum. As yet however, complex brain network topology in AD and its association with disease progression are unknown. We applied graph theory to resting-state functional magnetic resonance imaging (RS-fMRI) to examine weighted global efficiency and local (clustering coefficient, degree and eigenvector centrality) network topology and the functional role of the striatumin 24 AD patients compared with 20 matched healthy controls (HCs), and their association with dependence characteristics. Graph analyses were performed based on Pearson's correlations between RS-fMRI time series, while correcting for age, gender and head motion. We found no significant group differences between AD patients and HCs in network topology. Notably, within the patient group, but not in HCs, the whole-brain network showed reduced average cluster coefficient with more severe alcohol use, whereas longer AD duration within the patient group was associated with a global decrease in efficiency, degree and clustering coefficient. Additionally, within four a-priori chosen bilateral striatal nodes, alcohol use severity was associated with lower clustering coefficient in the left caudate. Longer AD duration was associated with reduced clustering coefficient in caudate and putamen, and reduced degree in bilateral caudate, but with increased eigenvector centrality in left posterior putamen. Especially changes in global network topology and clustering coefficient in anterior striatum remained strikingly robust after exploratory variations in network weight. Our results show adverse effects of AD on overall network integration and possibly on striatal efficiency, putatively contributing to the increasing behavioral impairments seen in chronically addicted patients. C1 [Sjoerds, Zsuzsika] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Sjoerds, Zsuzsika; Veltman, Dick J.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Sjoerds, Zsuzsika; Van den Brink, Wim] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, Amsterdam Inst Addict Res, NL-1012 WX Amsterdam, Netherlands. [Stufflebeam, Steven M.; Douw, Linda] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Douw, Linda] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Neurosci Campus Amsterdam, Amsterdam, Netherlands. RP Sjoerds, Z (reprint author), Max Planck Inst Human Cognit & Brain Sci, Max Planck Fellow Grp Cognit & Affect Control Beh, Room C211,Stephanstr 1A, D-04103 Leipzig, Germany. EM sjoerds.zs@gmail.com OI Sjoerds, Zsuzsika/0000-0001-9467-3772 FU Netherlands Organization for Health Research and Development (Zon-Mw) [31160004]; European Foundation for Alcohol Research (ERAB) [EXA1301]; Rubicon grant [825.11.002]; Veni grant from the Netherlands Organization for Health Research and Development (ZonMw) [31160004]; Netherlands Organization for Scientific Research (NWO); Branco Weiss Fellowship from Society in Science FX Data collection was funded by a grant (no. 31160004) from the Netherlands Organization for Health Research and Development (Zon-Mw), commissioned by the Netherlands Organization for Scientific Research (NWO). Travel costs for data analysis at the Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, U.S.A. were funded by an exchange award (no. EXA1301) of the European Foundation for Alcohol Research (ERAB) awarded to ZS. A part of this research was funded by a Rubicon grant 825.11.002 and by a Veni grant (no. 31160004) from the Netherlands Organization for Health Research and Development (ZonMw), both awarded to LD by the Netherlands Organization for Scientific Research (NWO). LD was also funded by a Branco Weiss Fellowship from Society in Science. NWO, ERAB and Society in Science had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 60 TC 2 Z9 2 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 EI 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2017 VL 22 IS 2 BP 523 EP 534 DI 10.1111/adb.12346 PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA EM0DH UT WOS:000394988500022 PM 26692359 ER PT J AU Yaremchuk, MJ AF Yaremchuk, Michael J. TI Commentary on: Chin Ups and Downs: Avoiding Bad Results in Chin Reoperation SO AESTHETIC SURGERY JOURNAL LA English DT Editorial Material C1 [Yaremchuk, Michael J.] Harvard Med Sch, Boston, MA USA. [Yaremchuk, Michael J.] Harvard Plast Surg Training Program, Boston, MA USA. [Yaremchuk, Michael J.] Massachusetts Gen Hosp, Craniofacial Surg, Boston, MA 02114 USA. RP Yaremchuk, MJ (reprint author), 170 Commonwealth Ave, Boston, MA 02116 USA. EM dr.y@dryaremchuk.com NR 1 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 1090-820X EI 1527-330X J9 AESTHET SURG J JI Aesthet. Surg. J. PD MAR 1 PY 2017 VL 37 IS 3 BP 264 EP 265 DI 10.1093/asj/sjw266 PG 2 WC Surgery SC Surgery GA EO9WF UT WOS:000397038100005 PM 28207066 ER PT J AU Lin, A Brook, J Grill, JD Teng, E AF Lin, Amy Brook, Jenny Grill, Joshua D. Teng, Edmond TI Participant-Informant Relationships Affect Quality of Life Ratings in Incipient and Clinical Alzheimer Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Informant; study partner; quality of life; mild cognitive impairment; Alzheimer disease ID MILD COGNITIVE IMPAIRMENT; QOL-AD SCALE; CAREGIVER BURDEN; OLDER ADULTS; DEMENTIA; PERSPECTIVES; PROGRESSION; DIAGNOSIS; VALIDITY; PEOPLE AB Objective: Clinical trials in incipient and clinical Alzheimer disease (AD) often include informant-reported outcomes. Whereas informant reports in AD dementia may be modulated by the nature of participant-informant relationships, whether informant type affects reporting at earlier disease stages is less certain. We sought to determine the effects of participant-informant relationships on informant assessments of quality of life (QOL), functional abilities, and behavioral symptoms in individuals with normal cognition (NC), mild cognitive impairment (MCI), and mild-to-moderate AD dementia. Design: Cross-sectional. Setting: Easton Center for Alzheimer Disease Research at the University of California, Los Angeles. Participants: A total of 399 individuals who met criteria for NC (N = 100), MCI [amnestic (N = 125) and nonamnestic (N = 61)], and AD (N = 113). Participants were subdivided into groups based on informantparticipant relationships (spouse versus other). Measurements: We examined informant effects on the Quality of Life-Alzheimer's Disease (QOL-AD) scale, the Functional Activities Questionnaire (FAQ), and the Neuropsychiatric Inventory (NPI). Results: After adjustments for demographic and cognitive factors, spouse informants reported higher participant QOL in the amnestic MCI and AD groups than did other informants. No informant effects were seen on QOL-AD ratings in the nonamnestic MCI or NC groups or on the FAQ or NPI in the MCI andAD groups. Conclusions: Participant-informant relationships may modulate informant responses on subjective measures such as the QOL-AD in both incipient and clinical AD. Clinical trials that use informant measures may need to address these effects. C1 [Lin, Amy] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Brook, Jenny] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Teng, Edmond] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Grill, Joshua D.] Univ Calif Irvine, Dept Psychiat & Human Behav, Inst Memory Impairments & Neurol Disorders, Irvine, CA 92717 USA. [Teng, Edmond] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Teng, E (reprint author), West Los Angeles VA Healthcare Ctr, Neurobehav Serv 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM eteng@mednet.ucla.edu FU National Institute on Aging [T35 AG026736, P50 AG16570]; California Alzheimer's Disease Centers; Sidell-Kagan Foundation FX This research was supported by the National Institute on Aging (T35 AG026736 [UCLA Medical Student Training in Aging Research Program] and P50 AG16570 [UCLA Alzheimer's Disease Research Center]), the California Alzheimer's Disease Centers, and the Sidell-Kagan Foundation. NR 39 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 BP 297 EP 307 DI 10.1016/j.jagp.2016.10.007 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1FZ UT WOS:000397132100015 PM 27818119 ER PT J AU McGrath, ER Espie, CA Power, A Murphy, AW Newell, J Kelly, C Duffy, N Gunning, P Gibson, I Bostock, S O'Donnell, MJ AF McGrath, Emer R. Espie, Colin A. Power, Alice Murphy, Andrew W. Newell, John Kelly, Caroline Duffy, Niamh Gunning, Patricia Gibson, Irene Bostock, Sophie O'Donnell, Martin J. TI Sleep to Lower Elevated Blood Pressure: A Randomized Controlled Trial (SLEPT) SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; hypertension; primary prevention; risk factors; sleep ID COGNITIVE-BEHAVIORAL THERAPY; CLINICAL EFFECTIVENESS TRIAL; PERSISTENT INSOMNIA; INSUFFICIENT SLEEP; FUNCTIONAL DATA; DURATION; INTERVENTION; HYPERTENSION; EXERCISE; EFFICACY AB BACKGROUND Impaired sleep quality is common and associated with an increased risk of cardiovascular disease (CVD), thought to be mediated through adverse effects on established vascular risk factors, particularly hypertension. We determined if a web-delivered sleep intervention (sleep-hygiene education, stimulus control, and cognitive behavioral therapy) reduces blood pressure compared to vascular risk factor education (standard care) alone. METHODS Phase II randomized, blinded, controlled trial of 134 participants without CVD with mild sleep impairment and blood pressure 130-160/< 110 mm Hg. The primary outcome was the difference in the mean change in 24-hour ambulatory systolic blood pressure (SBP) over 8 weeks between intervention and control groups. Secondary outcomes included measures of sleep quality and psychosocial health, namely Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS Participants in the sleep intervention group showed significantly greater improvements in sleep quality, including ISI [difference in mean improvement 2.8; 95% confidence interval (CI), 1.3-4.4], PSQI (1.1; 95% CI, 0.1-2.2), sleep condition indicator (0.8; 95% CI, 0.2-1.4), and psychosocial health, including BDI (2.0; 95% CI, 0.3-3.7) and BAI (1.4; 95% CI, 0.02-2.8). The mean improvement in 24-hour ambulatory SBP did not differ between the sleep intervention (0.9 mm Hg) and control (0.8 mm Hg) arms, (difference in mean improvement 0.1; 95% CI, -3.4 to 3.2). CONCLUSION A simple, low-cost, web-delivered sleep intervention is feasible and significantly improves sleep quality and measures of psychosocial health in individuals with mild sleep impairment but does not result in short-term improvements in blood pressure. C1 [McGrath, Emer R.; Murphy, Andrew W.; Kelly, Caroline; Duffy, Niamh; Gunning, Patricia; O'Donnell, Martin J.] Natl Univ Ireland, HRB Clin Res Facil, Galway, Ireland. [McGrath, Emer R.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [McGrath, Emer R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McGrath, Emer R.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. [Espie, Colin A.] Univ Oxford, Sleep & Circadian Neurosci Inst, Oxford, England. [Espie, Colin A.; Bostock, Sophie] Big Hlth Ltd, London, England. [Power, Alice; Gibson, Irene] Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res, Cork, Ireland. [Newell, John] Croi, West Ireland Cardiac Fdn, Galway, Ireland. [Bostock, Sophie] Univ Southampton, Dept Publ Hlth & Epidemiol, Southampton, Hants, England. RP McGrath, ER (reprint author), Natl Univ Ireland, HRB Clin Res Facil, Galway, Ireland.; McGrath, ER (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; McGrath, ER (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; McGrath, ER (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA. EM emcgrath2@partners.org NR 31 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAR PY 2017 VL 30 IS 3 BP 319 EP 327 DI 10.1093/ajh/hpw132 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO9SC UT WOS:000397027400019 ER PT J AU Reese, PP Bloom, RD Trofe-Clark, J Mussell, A Leidy, D Levsky, S Zhu, JS Yang, L Wang, WL Troxel, A Feldman, HI Volpp, K AF Reese, Peter P. Bloom, Roy D. Trofe-Clark, Jennifer Mussell, Adam Leidy, Daniel Levsky, Simona Zhu, Jingsan Yang, Lin Wang, Wenli Troxel, Andrea Feldman, Harold I. Volpp, Kevin TI Automated Reminders and Physician Notification to Promote Immunosuppression Adherence Among Kidney Transplant Recipients: A Randomized Trial SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Kidney transplantation; kidney transplant recipient (KTR); immunosuppression; tacrolimus; behavior change; adherence; compliance; automated reminder; medication reminder; wireless pill bottle; polypharmacy; end-stage renal disease (ESRD); tacrolimus trough level; allograft loss; randomized controlled trial ID PERCEIVED SOCIAL SUPPORT; MEDICATION ADHERENCE; ANTIRETROVIRAL THERAPY; RENAL-TRANSPLANTATION; MULTIDIMENSIONAL SCALE; FINANCIAL INCENTIVES; BLOOD-LEVELS; RISK-FACTOR; NONADHERENCE; REJECTION AB Background: Immunosuppression nonadherence increases the risk for kidney transplant loss after transplantation. Wireless-enabled pill bottles have created the opportunity to monitor medication adherence in real time. Reminders may help patients with poor memory or organization. Provision of adherence data to providers may motivate patients to improve adherence and help providers identify adherence barriers. Study Design: Randomized controlled trial. Setting & Participants: Kidney transplant recipients (n = 120) at a single center. Intervention: Participants were provided wireless pill bottles to store tacrolimus and record bottle openings. Participants were randomly assigned 1:1:1 to adherence monitoring with customized reminders (including alarms, texts, telephone calls, and/or e-mails), monitoring with customized reminders plus provider notification (every 2 weeks, providers received notification if adherence decreased to <90% during that period), or wireless pill bottle use alone (control). Outcomes: The main outcome was bottle-measured tacrolimus adherence during the last 90 days of the 180-day trial. A secondary outcome was tacrolimus whole-blood concentrations at routine clinical visits. Measurements: Adherence for the primary outcome was assessed via wireless pill bottle openings. Results: Mean participant age was 50 years; 60% were men,. and 40% were black. Mean adherence was 78%, 88%, and 55% in the reminders, reminders-plus-notification, and control arms (P < 0.001 for comparison of each intervention to control). Mean tacrolimus levels were not significantly different between groups. Limitations: The study did not assess clinical end points. Participants and study coordinators were not blinded to intervention arm. Conclusions: Provider notification and customized reminders appear promising in helping patients achieve better medication adherence, but these strategies require evaluation in trials powered to detect differences in clinical outcomes. (C) 2016 by the National Kidney Foundation, Inc. C1 [Reese, Peter P.; Bloom, Roy D.; Trofe-Clark, Jennifer; Feldman, Harold I.] Univ Penn, Renal Electrolyte & Hypertens Div, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Reese, Peter P.; Troxel, Andrea; Feldman, Harold I.] Univ Penn, Dept Biostat & Epidemiol, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Reese, Peter P.; Mussell, Adam; Leidy, Daniel; Troxel, Andrea; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Reese, Peter P.; Zhu, Jingsan; Yang, Lin; Wang, Wenli; Troxel, Andrea; Volpp, Kevin] Univ Penn, Leonard Davis Inst Ctr Hlth Incent & Behav Econ, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Trofe-Clark, Jennifer] Hosp Univ Penn, Dept Pharm Serv, 3400 Spruce St, Philadelphia, PA 19104 USA. [Levsky, Simona] Univ Penn, Sch Arts & Sci, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Volpp, Kevin] Perelman Sch Med, Dept Med, Philadelphia, PA USA. [Volpp, Kevin] Perelman Sch Med, Med Eth & Hlth Policy, Philadelphia, PA USA. [Volpp, Kevin] Univ Penn, Wharton Sch, Dept Hlth Care Management, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Volpp, Kevin] Cresencz Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Reese, PP (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM peter.reese@uphs.upenn.edu FU CVS Caremark; Merck, Sharpe, and Dohme; CVS Health; Humana; Weight Watchers; Hawaii Medical Services Association; Vitality Institute; Veloxis Pharma FX The University of Pennsylvania has received research support from CVS Caremark and Merck, Sharpe, and Dohme for other studies of medication adherence, which provided salary support to Drs Reese and Volpp. Dr Volpp is a principal at the behavioral economics consulting firm VAL Health and has received consulting income and research support from CVS Health and research support from Humana, Weight Watchers, the Hawaii Medical Services Association, and the Vitality Institute (not related to Vitality Inc, the manufacturer of the GlowCaps pill bottle). Dr Troxel has received consulting income from VAL Health and research support from the Vitality Institute, the Hawaii Medical Services Association, and Weight Watchers. After the trial interventions were completed, the University of Pennsylvania received research support from Veloxis Pharma, which provided salary support for Dr Trofe-Clark; she also received honorarium from Veloxis Pharma after this study was conducted. The other authors declare that they have no other relevant financial interests. NR 58 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2017 VL 69 IS 3 BP 400 EP 409 DI 10.1053/j.ajkd.2016.10.017 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EM0ZV UT WOS:000395047900013 PM 27940063 ER PT J AU Leung, LB Escarce, JJ AF Leung, Lucinda B. Escarce, Jose J. TI Consumer-Directed Health Plans: Do Doctors and Nurses Buy In? SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID CARE; SERVICES; COST C1 [Leung, Lucinda B.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Leung, Lucinda B.; Escarce, Jose J.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. RP Leung, LB (reprint author), UCLA Robert Wood Johnson Fdn, VA Clin Scholars Program, 10940 Wilshire Blvd,Ste 710, Los Angeles, CA 90024 USA. EM lleung@mednet.ucla.edu FU Robert Wood Johnson Foundation Clinical Scholars program; US Department of Veterans Affairs FX Support for this article was provided by the Robert Wood Johnson Foundation Clinical Scholars program and the US Department of Veterans Affairs. 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 or the US government. NR 16 TC 0 Z9 0 U1 0 U2 0 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD MAR PY 2017 VL 23 IS 3 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EO0OP UT WOS:000396398000004 ER PT J AU Smoller, JW AF Smoller, Jordan W. TI Anxiety Genetics: Dispatches From the Frontier SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE anxiety; disorder; anxiety disorders; genetic; genomewide; association; RDoC ID DEPRESSION; DISORDERS; RISK AB Anxiety disorders are the most common class of psychiatric disorders and incur an enormous burden in terms of economic costs, disability and personal suffering. Despite their public health importance and documented heritability, genetic research aimed at identifying the genetic contributions to these disorders has had limited success, particularly in comparison to recent advances in the genetics of other major psychiatric disorders. The major factor contributing to this lagging progress has been a dearth of well-powered genomic studies. As a result, the genetic basis of anxiety disorders remains a largely uncharted frontier. In this Special Issue, we bring together dispatches from this frontier, reflecting a range of strategies being pursued including genomewide common variant association studies, exome sequencing, genetic prediction of treatment response, cross-disorder genetic epidemiology, and the prospects for dissecting underlying anxiety domains using the RDoC framework. Overall, these efforts underscore the genetic and phenotypic complexity of pathologic anxiety and the urgent need for more powerful and comprehensive analyses if we are to make real progress in advancing this important frontier. (C) 2017 Wiley Periodicals, Inc. C1 [Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Smoller, JW (reprint author), Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM jsmoller@mgh.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR PY 2017 VL 174 IS 2 SI SI BP 117 EP 119 DI 10.1002/ajmg.b.32526 PG 3 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA EL9RG UT WOS:000394957100001 PM 28224734 ER PT J AU Stein, MB Chen, CY Jain, S Jensen, KP He, F Heeringa, SG Kessler, RC Maihofer, A Nock, MK Ripke, S Sun, XY Thomas, ML Ursano, RJ Smoller, JW Gelernter, J AF Stein, Murray B. Chen, Chia-Yen Jain, Sonia Jensen, Kevin P. He, Feng Heeringa, Steven G. Kessler, Ronald C. Maihofer, Adam Nock, Matthew K. Ripke, Stephan Sun, Xiaoying Thomas, Michael L. Ursano, Robert J. Smoller, Jordan W. Gelernter, Joel CA Army STARRS Collaborators TI Genetic Risk Variants for Social Anxiety SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE anxiety; extraversion; neuroticism; social anxiety; social phobia ID GENOME-WIDE ASSOCIATION; POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; WILLIAMS-SYNDROME; SEROTONIN SYNTHESIS; PHOBIA; HERITABILITY; METAANALYSIS; PERSONALITY; NEUROTICISM AB Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h(g)(2)=0.12, P=2.17x10(-4) in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P=1.55x10(-8); beta=0.073) and AFR (rs78924501, Chr 1: BP 88406905, P=3.58x10(-8); beta=0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (r(g)=-0.52, se=0.22, P=0.02) but not with neuroticism (r(g)=0.05, se=0.22, P=0.81) or with an anxiety disorder factor score (r(g)=0.02, se=0.32, P=0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. (C) 2017 Wiley Periodicals, Inc. C1 [Stein, Murray B.; Maihofer, Adam; Thomas, Michael L.] Univ Calif San Diego, Dept Psychiat, Mailcode 0855,9500 Gilman Dr, La Jolla, CA 92093 USA. [Stein, Murray B.; Jain, Sonia; He, Feng; Sun, Xiaoying] Univ Calif San Diego, Dept Family Med & Publ Hlth, Mailcode 0855,9500 Gilman Dr, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Chen, Chia-Yen; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chen, Chia-Yen; Smoller, Jordan W.] Harvard Med Sch, Boston, MA USA. [Chen, Chia-Yen; Ripke, Stephan; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Jensen, Kevin P.; Gelernter, Joel] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Jensen, Kevin P.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Ursano, Robert J.; Gelernter, Joel] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Gelernter, Joel] Yale Univ, Dept Genet, New Haven, CT USA. [Gelernter, Joel] Yale Univ, Dept Neurobiol, New Haven, CT USA. RP Stein, MB (reprint author), Univ Calif San Diego, Dept Psychiat, Mailcode 0855,9500 Gilman Dr, La Jolla, CA 92093 USA.; Stein, MB (reprint author), Univ Calif San Diego, Dept Family Med & Publ Hlth, Mailcode 0855,9500 Gilman Dr, La Jolla, CA 92093 USA. EM mstein@ucsd.edu FU Department of the Army [U01MH087981]; US Department of Health and Human Services; National Institutes of Health; National Institute of Mental Health (NIH/NIMH) FX Grant sponsor: Department of the Army; Grant number: U01MH087981; Grant sponsor: US Department of Health and Human Services; Grant sponsor: National Institutes of Health, National Institute of Mental Health (NIH/NIMH). NR 45 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR PY 2017 VL 174 IS 2 SI SI BP 120 EP 131 DI 10.1002/ajmg.b.32520 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA EL9RG UT WOS:000394957100002 PM 28224735 ER PT J AU Dunn, EC Sofer, T Gallo, LC Gogarten, SM Kerr, KF Chen, CY Stein, MB Ursano, RJ Guo, XQ Jia, YC Qi, QB Rotter, JI Argos, M Cai, JW Penedo, FJ Perreira, K Wassertheil-Smoller, S Smoller, JW AF Dunn, Erin C. Sofer, Tamar Gallo, Linda C. Gogarten, Stephanie M. Kerr, Kathleen F. Chen, Chia-Yen Stein, Murray B. Ursano, Robert J. Guo, Xiuqing Jia, Yucheng Qi, Qibin Rotter, Jerome I. Argos, Maria Cai, Jianwen Penedo, Frank J. Perreira, Krista Wassertheil-Smoller, Sylvia Smoller, Jordan W. TI Genome-Wide Association Study of Generalized Anxiety Symptoms in the Hispanic Community Health Study/Study of Latinos SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genetic association study; anxiety; Hispanics/Latinos ID COMORBIDITY SURVEY REPLICATION; POSTTRAUMATIC-STRESS-DISORDER; LIFETIME PREVALENCE RATES; DSM-IV DISORDERS; DEPRESSIVE SYMPTOMS; JAPANESE POPULATION; MENTAL-DISORDERS; QUALITY-CONTROL; PANIC DISORDER; ODDS RATIOS AB Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18-74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h(SNP)(2)) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; P=0.03), while the total trait anxiety score did not (4.97%; P=0.20). One genotyped SNP (rs78602344) intronic to thrombospondin 2 (THBS2) was nominally associated (P=5.28x10(-8)) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (P=4.18x10(-8)). However, meta-analysis of the replication samples did not support this association. Although we identified a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety. (C) 2016 Wiley Periodicals, Inc. C1 [Dunn, Erin C.; Chen, Chia-Yen; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Dunn, Erin C.; Chen, Chia-Yen; Smoller, Jordan W.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Dunn, Erin C.; Chen, Chia-Yen; Smoller, Jordan W.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Sofer, Tamar; Gogarten, Stephanie M.; Kerr, Kathleen F.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Gallo, Linda C.] San Diego State Univ, Dept Psychol, La Jolla, CA USA. [Chen, Chia-Yen] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. [Guo, Xiuqing; Jia, Yucheng; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90509 USA. [Qi, Qibin; Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Dept Med, Torrance, CA 90509 USA. [Argos, Maria] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Cai, Jianwen] Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC USA. [Penedo, Frank J.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Perreira, Krista] Univ North Carolina Chapel Hill, Coll & Arts & Sci, Chapel Hill, NC USA. RP Dunn, EC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, 185 Cambridge St,Simches Res Bldg 6th Floor, Boston, MA 02114 USA. EM edunn2@mgh.harvard.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01- HC65233, N01-HC65234, N01-HC65235, N01HC65236, N01-HC65237]; National Institute of Mental Health of the National Institutes of Health [K01MH102403]; NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation FX Grant sponsor: National Heart, Lung, and Blood Institute (NHLBI); Grant numbers: N01- HC65233, N01-HC65234, N01-HC65235, N01HC65236, N01-HC65237; Grant sponsor: National Institute of Mental Health of the National Institutes of Health; Grant number: K01MH102403; Grant sponsor: NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. NR 66 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR PY 2017 VL 174 IS 2 SI SI BP 132 EP 143 DI 10.1002/ajmg.b.32448 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA EL9RG UT WOS:000394957100003 PM 27159506 ER PT J AU Govetto, A Lalane, RA Sarraf, D Figueroa, MS Hubschman, JP AF Govetto, Andrea Lalane, Robert A., III Sarraf, David Figueroa, Marta S. Hubschman, Jean Pierre TI Insights Into Epiretinal Membranes: Presence of Ectopic Inner Foveal Layers and a New Optical Coherence Tomography. Staging Scheme SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OUTER SEGMENT TIPS; PROGNOSTIC-FACTOR; VITREOMACULAR TRACTION; VISUAL FUNCTION; SURGERY; METAMORPHOPSIA; ASSOCIATIONS; PREVALENCE; THICKNESS; EYES AB PURPOSE: To describe the presence of continuous ectopic inner foveal layers associated with epiretinal membranes (ERMs) and to present a new optical coherence tomography (OCT) staging system of ERMs. DESIGN: Retrospective multicenter observational case series. METHODS: Clinical charts and spectral-domain OCT images of 194 eyes of 172 consecutive patients diagnosed with ERMs were reviewed and analyzed. RESULTS: The presence of continuous ectopic inner foveal layers was identified in 63 out of 194 eyes (32.5%) and this morphology was significantly associated with lower visual acuity. ERMs were divided into 4 stages. Stage 1 (43 out of 194 eyes, 22.1%) ERMs were mild and thin and a fovea! depression was present. Stage 2 (88 out of 194 eyes, 45.4%) ERMs were associated with widening of the outer nuclear layer and loss of the foveal depression. Stage 3 (51 out of 194 eyes, 26.3%) ERMs were associated with continuous ectopic inner foveal layers crossing the entire foveal area. In stages 1, 2, and 3 all retinal layers were clearly defined on OCT. Stage 4 ERMs (12 out of 194 eyes, 6.2%) were thick and associated with continuous ectopic inner foveal layers. In addition, retinal layers were disrupted. Visual acuity progressively declined from stage 1 through stage 4 (P < .001). CONCLUSIONS: The presence of continuous ectopic inner foveal layers in ERMs is a newly described OCT finding associated with significant vision loss and is an essential element of a novel OCT-based grading scheme of ERMs that may influence visual prognosis. (C) 2016 Elsevier Inc. All rights reserved. C1 [Govetto, Andrea; Lalane, Robert A., III; Hubschman, Jean Pierre] Univ Calif Los Angeles, Stein Eye Inst, Retina Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. [Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Figueroa, Marta S.] Ramon y Cajal Univ Hosp, Dept Ophthalmol, Retina Div, Madrid, Spain. RP Govetto, A (reprint author), Univ Calif Los Angeles, Stein Eye Inst, Retina Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM a.govetto@gmail.com FU RESEARCH TO PRE vent Blindness (RPB), New York, New York, USA FX THIS WORK WAS SUPPORTED BY AN UNRESTRICTED INSTITUTIONAL GRANT FROM RESEARCH TO PRE vent Blindness (RPB), New York, New York, USA. NR 39 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 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2017 VL 175 BP 99 EP 113 DI 10.1016/j.ajo.2016.12.006 PG 15 WC Ophthalmology SC Ophthalmology GA EN4IK UT WOS:000395971000014 PM 27993592 ER PT J AU Jain, NB Luz, J Higgins, LD Dong, Y Warner, JJP Matzkin, E Katz, JN AF Jain, Nitin B. Luz, Jennifer Higgins, Laurence D. Dong, Yan Warner, Jon J. P. Matzkin, Elizabeth Katz, Jeffrey N. TI The Diagnostic Accuracy of Special Tests for Rotator Cuff Tear The ROW Cohort Study SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Physical Examination; Rotator Cuff Tear; Sensitivity; Special Tests ID PHYSICAL-EXAMINATION TESTS; SHOULDER PAIN; ULTRASONOGRAPHIC FINDINGS; CLINICAL EXAMINATION; INDIVIDUAL TESTS; BICEPS TENDON; PART I; RELIABILITY; SIGNS; METAANALYSIS AB Objective: The aim was to assess diagnostic accuracy of 15 shoulder special tests for rotator cuff tears. Design: From February 2011 to December 2012, 208 participants with shoulder pain were recruited in a cohort study. Results: Among tests for supraspinatus tears, Jobe test had a sensitivity of 88% (95% confidence interval [CI], 80%-96%), specificity of 62% (95% CI, 53%-71%), and likelihood ratio of 2.30 (95% CI, 1.79-2.95). The full can test had a sensitivity of 70% (95% CI, 59%-82%) and a specificity of 81% (95% CI, 74%-88%). Among tests for infraspinatus tears, external rotation lag signs at 0 degrees had a specificity of 98% (95% CI, 96%-100%) and a likelihood ratio of 6.06 (95% CI, 1.30-28.33), and the Hornblower sign had a specificity of 96% (95% CI, 93%-100%) and likelihood ratio of 4.81 (95% CI, 1.60-14.49). Conclusions: Jobe test and full can test had high sensitivity and specificity for supraspinatus tears, and Hornblower sign performed well for infraspinatus tears. In general, special tests described for subscapularis tears have high specificity but low sensitivity. These data can be used in clinical practice to diagnose rotator cuff tears and may reduce the reliance on expensive imaging. C1 [Jain, Nitin B.] Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil & Orthopaed, Nashville, TN 37212 USA. [Higgins, Laurence D.; Dong, Yan; Matzkin, Elizabeth; Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. [Higgins, Laurence D.; Dong, Yan; Warner, Jon J. P.; Matzkin, Elizabeth; Katz, Jeffrey N.] Harvard Med Sch, Boston, MA USA. [Luz, Jennifer] Spaulding Rehabil Hosp, Dept Phys Med, Charlestown, MA USA. [Luz, Jennifer] Spaulding Rehabil Hosp, Dept Rehabil, Charlestown, MA USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Warner, Jon J. P.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Jain, NB (reprint author), Vanderbilt Univ, Sch Med, Dept Phys Med & Rehabil & Orthopaed, Nashville, TN 37212 USA.; Jain, NB (reprint author), Vanderbilt Univ, Dept Phys Med & Rehabil, Med Ctr, 2201 Childrens Way,Suite 1318, Nashville, TN 37212 USA. FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [1K23AR059199]; Foundation for PMR; Biomedical Research Institute at Brigham; Women's Hospital; NIAMS [P60 AR 047782]; National Center for Research Resources [UL1RR024975-01]; National Center for Advancing Translational Sciences [UL1TR000445-06] FX NBJ is supported by funding from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 1K23AR059199, Foundation for PM&R, and Biomedical Research Institute at Brigham and Women's Hospital. JNK is in part supported by NIAMS P60 AR 047782. The project was supported by the National Center for Research Resources (grant UL1RR024975-01) and is now the National Center for Advancing Translational Sciences ( grant UL1TR000445-06). NR 53 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 MAR PY 2017 VL 96 IS 3 BP 176 EP 183 DI 10.1097/PHM.0000000000000566 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EM0JR UT WOS:000395005100012 PM 27386812 ER PT J AU Levy, DE Adams, IF Adamkiewicz, G AF Levy, Douglas E. Adams, Inez F. Adamkiewicz, Gary TI Delivering on the Promise of Smoke-Free Public Housing SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID FREE POLICY; EXPOSURE; INEQUALITIES C1 [Levy, Douglas E.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, Boston, MA 02114 USA. [Levy, Douglas E.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Levy, Douglas E.] Harvard Med Sch, Boston, MA USA. [Adams, Inez F.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Adamkiewicz, Gary] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. RP Levy, DE (reprint author), Mongan Inst Hlth Policy Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM dlevy3@mgh.harvard.edu FU National Institutes of Health [R01-HL112212, P50-CA148596]; Robert Wood Johnson Foundation FX We are grateful to the National Institutes of Health (grants R01-HL112212, P50-CA148596) and the Robert Wood Johnson Foundation (Health and Society Scholars Program seed grant) for support. NR 25 TC 0 Z9 0 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2017 VL 107 IS 3 BP 380 EP 383 DI 10.2105/AJPH.2016.303606 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO9YV UT WOS:000397044900017 PM 28103063 ER PT J AU Fiscella, K Beletsky, L Wakeman, SE AF Fiscella, Kevin Beletsky, Leo Wakeman, Sarah E. TI The Inmate Exception and Reform of Correctional Health Care SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Fiscella, Kevin] Univ Rochester, Sch Med & Dent, Dept Family Med, Rochester, NY USA. [Fiscella, Kevin] Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, Rochester, NY USA. [Beletsky, Leo] Northeastern Univ, Sch Law, Boston, MA 02115 USA. [Beletsky, Leo] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Beletsky, Leo] Univ Calif San Diego, Sch Med, Div Global Publ Hlth, San Diego, CA USA. [Wakeman, Sarah E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Fiscella, K (reprint author), Univ Rochester, Med Ctr, Dept Family Med, 1381 South Ave, Rochester, NY 14620 USA. EM kevin_fiscella@urmc.rochester.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2017 VL 107 IS 3 BP 384 EP 385 DI 10.2105/AJPH.2016.303626 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO9YV UT WOS:000397044900018 PM 28177816 ER PT J AU Hobai, IA AF Hobai, Ion A. TI Anesthetics, the Ryanodine Receptors, and the Heart SO ANESTHESIOLOGY LA English DT Editorial Material ID NONCARDIAC SURGERY; FAILURE; PHOSPHORYLATION; CONTRIBUTES; ARRHYTHMIAS; MYOCYTES C1 [Hobai, Ion A.] Massachusetts Gen Hosp, Dept Anesthesia, Crit Care & Pain Med, Boston, MA USA. [Hobai, Ion A.] Harvard Med Sch, Boston, MA USA. RP Hobai, IA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia, Crit Care & Pain Med, Boston, MA USA.; Hobai, IA (reprint author), Harvard Med Sch, Boston, MA USA. EM ihobai@partners.org NR 18 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 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2017 VL 126 IS 3 BP 373 EP 375 DI 10.1097/ALN.0000000000001520 PG 3 WC Anesthesiology SC Anesthesiology GA EO8DW UT WOS:000396920200005 PM 28079565 ER PT J AU Matioc, AA AF Matioc, Adrian A. TI An Anesthesiologist's Perspective on the History of Basic Airway Management The "Artisanal Anesthetic" Era: 1846 to 1904 SO ANESTHESIOLOGY LA English DT Article ID INTUBATION; MEDICINE; SURGERY AB This second installment of the history of basic airway management covers the early-artisanal-years of anesthesia from 1846 to 1904. Anesthesia was invented and practiced as a supporting specialty in the context of great surgical and medical advances. The current-day anesthesia provider tends to equate the history of airway management with the history of intubation, but for the first 58 yr after the introduction of ether anesthesia, airway management was provided by basic airway techniques with or without the use of a face mask. The jaw thrust and chin lift were described in the artisanal years and used primarily with inhalation anesthesia in the spontaneously breathing patient and less often with negative-pressure ventilation in the apneic victim. Positive-pressure ventilation and intubation stayed at the fringes of medical practice, and airway techniques and devices were developed by trial and error. At the beginning of the 20th century, airway management and anesthetic techniques lagged behind surgical requirements. C1 [Matioc, Adrian A.] Univ Wisconsin Sch Med & Publ Hlth, Dept Anesthesiol, Madison, WI USA. RP Matioc, AA (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace,Room,A8030, Madison, WI 53705 USA. EM aamatioc@wisc.edu FU Paul M. Wood Fellowship at the Wood Library-Museum of Anesthesiology, Schaumburg, Illinois FX Support was provided by departmental sources and by a 2013 Paul M. Wood Fellowship at the Wood Library-Museum of Anesthesiology, Schaumburg, Illinois, awarded in my name for this topic. NR 119 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 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2017 VL 126 IS 3 BP 394 EP 408 DI 10.1097/ALN.0000000000001508 PG 15 WC Anesthesiology SC Anesthesiology GA EO8DW UT WOS:000396920200007 PM 28079564 ER PT J AU Hashmi, JA Loggia, ML Khan, S Gao, L Kim, J Napadow, V Brown, EN Akeju, O AF Hashmi, Javeria A. Loggia, Marco L. Khan, Sheraz Gao, Lei Kim, Jieun Napadow, Vitaly Brown, Emery N. Akeju, Oluwaseun TI Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks SO ANESTHESIOLOGY LA English DT Article ID ANESTHESIA-INDUCED UNCONSCIOUSNESS; PROPOFOL-INDUCED UNCONSCIOUSNESS; ELECTROENCEPHALOGRAM SIGNATURES; AGONIST DEXMEDETOMIDINE; HYPNOTIC RESPONSE; DEFAULT NETWORK; LOCUS-CERULEUS; CONSCIOUSNESS; SLEEP; CONNECTIVITY AB Background: A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target. Methods: Dexmedetomidine was administered as a 1-mu g/kg bolus over 10 min, followed by a 0.7-mu g.kg(-1).h(-1) infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes. Results: Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine. Conclusions: Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain. C1 [Hashmi, Javeria A.] Dalhousie Univ, Pain Management & Perioperat Med, Halifax, NS, Canada. [Loggia, Marco L.; Kim, Jieun; Napadow, Vitaly] Massachusetts Gen Hosp, Harvard Med Sch, Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Khan, Sheraz] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, Charlestown, MA USA. [Gao, Lei; Brown, Emery N.; Akeju, Oluwaseun] Massachusetts Gen Hosp, Harvard Med Sch, Crit Care & Pain Med, Dept Anesthesia, Charlestown, MA USA. [Kim, Jieun] Korea Inst Oriental Med, Div Clin Res, Daejeon, South Korea. [Brown, Emery N.] MIT, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Hashmi, JA (reprint author), Dalhousie Univ, Pain Management Unit, 4th Floor Dickson Bldg,5820 Univ Ave, Halifax, NS B3H 1V7, Canada. EM javeria.hashmi@dal.ca OI Gao, Lei/0000-0003-1476-1460 FU National Institutes of Health (Bethesda, Maryland) [OT2 OD023867, P01 AT006663, R61 AT009306, R01 AR064367]; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; [R01 AG053582]; [TRO1 GM104948] FX Supported by grant no. R01 AG053582 (to Dr. Akeju); grant no. TRO1 GM104948 (to Dr. Brown); and grant nos. OT2 OD023867, P01 AT006663, R61 AT009306, R01 AR064367 (to Dr. Napadow) from the National Institutes of Health (Bethesda, Maryland) and by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 51 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 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2017 VL 126 IS 3 BP 419 EP 430 DI 10.1097/ALN.0000000000001509 PG 12 WC Anesthesiology SC Anesthesiology GA EO8DW UT WOS:000396920200009 PM 28092321 ER PT J AU Matulonis, UA Monk, BJ AF Matulonis, U. A. Monk, B. J. TI PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: does a development pathway forward exist? SO ANNALS OF ONCOLOGY LA English DT Editorial Material ID NEGATIVE BREAST-CANCER; BRCA MUTATION CARRIERS; POLY(ADP-RIBOSE) POLYMERASE; OVARIAN-CANCER; CERVICAL-CANCER; OLAPARIB; RUCAPARIB; PHASE-2; MULTICENTER; VELIPARIB C1 [Matulonis, U. A.] Dana Farber Canc Inst, Harvard Med Sch, Dept Med Oncol, Boston, MA USA. [Monk, B. J.] Univ Arizona, Arizona Oncol US Oncol Network, Tucson, AZ 85721 USA. [Monk, B. J.] Creighton Univ Phoenix, Phoenix, AZ USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, Harvard Med Sch, Dept Med Oncol, Boston, MA USA. EM ursula_matulonis@dfci.harvard.edu FU Ovarian Cancer Research Foundation; Breast Cancer Research Foundation FX UAM is supported by the Ovarian Cancer Research Foundation Program Project Grant (overall PI) and the Breast Cancer Research Foundation (overall PI of a grant). No grant number is applicable. NR 27 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 443 EP 447 PG 6 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100002 ER PT J AU Batth, IS Mitra, A Manier, S Ghobrial, IM Menter, D Kopetz, S Li, S AF Batth, I. S. Mitra, A. Manier, S. Ghobrial, I. M. Menter, D. Kopetz, S. Li, S. TI Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA for precision medicine SO ANNALS OF ONCOLOGY LA English DT Review DE circulating tumor cells; circulating tumor DNA; circulating tumor RNA; exosomes; cell free DNA; cell free RNA ID RESISTANT PROSTATE-CANCER; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; BREAST-CANCER; PROGNOSTIC-SIGNIFICANCE; DISEASE PROGRESSION; MICROFLUIDIC DEVICE; PERIPHERAL-BLOOD; PROGENITOR CELLS; LABEL-FREE AB Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study. C1 [Batth, I. S.; Mitra, A.; Li, S.] Univ Texas MD Anderson Canc Ctr, Dept Pediat Res, 7777 Knight Rd, Houston, TX 77054 USA. [Manier, S.; Ghobrial, I. M.] Dana Farber Canc Inst, Harvard Med Sch, Dept Med Oncol, Boston, MA USA. [Menter, D.; Kopetz, S.] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal GI Med Oncol, Houston, TX USA. RP Li, S (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Pediat Res, 7777 Knight Rd, Houston, TX 77054 USA. EM SLi4@mdanderson.org NR 112 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 468 EP 477 DI 10.1093/annonc/mdw619 PG 10 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100009 ER PT J AU Thaker, PH Salani, R Brady, WE Lankes, HA Cohn, DE Mutch, DG Mannel, RS Bell-McGuinn, KM Di Silvestro, PA Jelovac, D Carter, JS Duan, W Resnick, KE Dizon, DS Aghajanian, C Fracasso, PM AF Thaker, P. H. Salani, R. Brady, W. E. Lankes, H. A. Cohn, D. E. Mutch, D. G. Mannel, R. S. Bell-McGuinn, K. M. Di Silvestro, P. A. Jelovac, D. Carter, J. S. Duan, W. Resnick, K. E. Dizon, D. S. Aghajanian, C. Fracasso, P. M. TI A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852) SO ANNALS OF ONCOLOGY LA English DT Article DE cervical cancer; PARP inhibitors; novel therapeutics ID CONCURRENT CHEMOTHERAPY; PELVIC RADIATION; UTERINE CERVIX; STAGE IVB; III TRIAL; CANCER; TUMORS; RISK; CELL; TOPOTECAN AB Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3+3 phase I dose escalation with patients receiving paclitaxel 175mg/m(2) on day 1, cisplatin 50mg/m(2) on day 2, and escalating doses of veliparib ranging from 50 to 400mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting >= 3 weeks, and febrile neutropenia. At 400mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. C1 [Thaker, P. H.; Mutch, D. G.] Washington Univ Sch Med, Div Gynecol Oncol, Dept Obstet & Gynecol, Siteman Canc Ctr, 4911 Barnes Jewish Hosp Plaza,Campus Box 8064, St Louis, MO 63110 USA. [Salani, R.; Cohn, D. E.] Ohio State Univ Sch Med, Div Gynecol Oncol, Dept Obstet & Gynecol, Columbus, MS USA. [Brady, W. E.; Lankes, H. A.] Roswell Pk Canc Inst, NRG Gynecol Oncol Grp Stat & Data Ctr, Buffalo, NY USA. [Mannel, R. S.] Univ Oklahoma, Div Gynecol Oncol, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Bell-McGuinn, K. M.; Aghajanian, C.] Dept Med, Mem Sloan Kettering Canc Ctr, Gynecol Med Oncol Serv, New York, NY USA. [Di Silvestro, P. A.] Women Infants Hosp, Dept Obstet & Gynecol, Providence, RI USA. [Jelovac, D.] Div Med Oncol, Sidney Kimmel Comprehens Canc Ctr, Johns Hopkins, Baltimore, MD USA. [Carter, J. S.] Virginia Commonwealth Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Richmond, VA USA. [Duan, W.] Ohio State Univ Coll Med, Div Med Oncol, Dept Internal Med, Columbus, MS USA. [Resnick, K. E.] Case Western Reserve Univ Sch Med, Dept Obstet & Gynecol, Div Gynecol Oncol, Cleveland, OH USA. [Dizon, D. S.] Massachusetts Gen Hosp Canc Ctr, Div Med Gynecol Oncol, Boston, MA USA. [Fracasso, P. M.] Univ Virginia, Dept Med, Div Hematol Oncol, Charlottesville, VA USA. RP Thaker, PH (reprint author), Washington Univ Sch Med, Div Gynecol Oncol, Dept Obstet & Gynecol, Siteman Canc Ctr, 4911 Barnes Jewish Hosp Plaza,Campus Box 8064, St Louis, MO 63110 USA. EM thakerp@wudosis.wustl.edu FU National Cancer Institute [CA 27469]; Gynecologic Oncology Group Statistical Office [CA 37517]; NRG Oncology [1U10 CA180822]; NRG Operations [U10CA180868] FX This work was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical Office (CA 37517), NRG Oncology (1U10 CA180822), and NRG Operations (U10CA180868). NR 23 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 505 EP 511 DI 10.1093/annonc/mdw635 PG 7 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100013 ER PT J AU Matulonis, UA Wulf, GM Barry, WT Birrer, M Westin, SN Farooq, S Bell-McGuinn, KM Obermayer, E Whalen, C Spagnoletti, T Luo, W Liu, H Hok, RC Aghajanian, C Solit, DB Mills, GB Taylor, BS Won, H Berger, MF Palakurthi, S Liu, J Cantley, LC Winer, E AF Matulonis, U. A. Wulf, G. M. Barry, W. T. Birrer, M. Westin, S. N. Farooq, S. Bell-McGuinn, K. M. Obermayer, E. Whalen, C. Spagnoletti, T. Luo, W. Liu, H. Hok, R. C. Aghajanian, C. Solit, D. B. Mills, G. B. Taylor, B. S. Won, H. Berger, M. F. Palakurthi, S. Liu, J. Cantley, L. C. Winer, E. TI Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer SO ANNALS OF ONCOLOGY LA English DT Article DE BKM120; olaparib; ovarian cancer; breast cancer; PARP-inhibitors ID ADVANCED SOLID TUMORS; PI3K INHIBITOR; BUPARLISIB BKM120; MUTATION; CARCINOMA AB Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3+3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100mg b.i.d.). The MTD was determined to be BKM120 50mg q.d. and olaparib 300mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAmand gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone. C1 [Matulonis, U. A.; Barry, W. T.; Farooq, S.; Obermayer, E.; Whalen, C.; Spagnoletti, T.; Luo, W.; Palakurthi, S.; Liu, J.; Winer, E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wulf, G. M.; Liu, H.; Hok, R. C.] Div Hematol & Oncol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Birrer, M.] Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA USA. [Westin, S. N.] Dept Gynecol Oncol, MD Anderson Canc Ctr, Houston, TX USA. [Bell-McGuinn, K. M.] Eli Lilly, Indianapolis, IN USA. [Aghajanian, C.; Solit, D. B.; Taylor, B. S.; Won, H.; Berger, M. F.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Mills, G. B.] Univ Texas MD Anderson Canc Ctr, Div Basic Sci Res, Dept Syst Biol, Houston, TX USA. [Cantley, L. C.] Weill Cornell Med Coll, New York, NY USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ursula_matulonis@dfci.harvard.edu FU Ovarian Cancer Research Foundation; Breast Cancer Research Foundation; CJL Foundation; Adelson Medical Research Foundation; Stand Up to Cancer Dream Team Translational Research Grant; Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Mary Kay Ash Foundation; Men's Initiative of the Dana-Farber Harvard Cancer Center; Breast Cancer Alliance; National Institutes of Health [K12CA088084 K12]; Calabresi Scholar Award, National Institutes of Health [2P50CA083639]; [5 P50CA083639-13]; [R01-GM041890] FX Ursula Matulonis: Ovarian Cancer Research Foundation, Breast Cancer Research Foundation. William Barry: CJL Foundation. Gordon Mills: Adelson Medical Research Foundation and 5 P50CA083639-13. Gerburg Wulf: Stand Up to Cancer Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209), by the Breast Cancer Research Foundation, Mary Kay Ash Foundation, by the Men's Initiative of the Dana-Farber Harvard Cancer Center and the Breast Cancer Alliance. Lewis Cantley: R01-GM041890. Shannon Westin: National Institutes of Health K12CA088084 K12 Calabresi Scholar Award, National Institutes of Health 2P50CA083639 SPORE in Ovarian Cancer. Joyce Liu: Ovarian Cancer Research Foundation. NR 17 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 512 EP 518 DI 10.1093/annonc/mdw672 PG 7 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100014 ER PT J AU Wagner, AJ Kindler, H Gelderblom, H Schoffski, P Bauer, S Hohenberger, P Kopp, HG Lopez-Martin, JA Peeters, M Reichardt, P Qin, A Nippgen, J Ilaria, RL Rutkowski, P AF Wagner, A. J. Kindler, H. Gelderblom, H. Schoffski, P. Bauer, S. Hohenberger, P. Kopp, H. -G. Lopez-Martin, J. A. Peeters, M. Reichardt, P. Qin, A. Nippgen, J. Ilaria, R. L. Rutkowski, P. TI A phase II study of a human anti-PDGFR alpha monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors SO ANNALS OF ONCOLOGY LA English DT Article DE gastrointestinal stromal tumor; platelet-derived growth factor receptor alpha; IMC-3G3; mutation; monoclonal antibody ID GROWTH-FACTOR-RECEPTOR; MUTATIONS; MULTICENTER; IMATINIB; KIT AB Background: This study evaluated tumor response to olaratumab (an anti-PDGFR alpha monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFR alpha mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received >= 1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR+PR+SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade >= 3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFR alpha mutations, patients with PDGFR alpha-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. C1 [Wagner, A. J.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Kindler, H.] Univ Chicago, Sch Med, Chicago, IL USA. [Gelderblom, H.] Leids Univ Med Ctr, Leiden, Netherlands. [Schoffski, P.] Katholieke Univ Leuven, Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Bauer, S.] Univ Duisburg Essen, West German Canc Ctr, Essen, Germany. [Bauer, S.] German Canc Consortium, Heidelberg, Germany. [Hohenberger, P.] Heidelberg Univ, Med Fac Mannheim, Div Surg Oncol & Thorac Surg, Mannheim, Germany. [Kopp, H. -G.] Tuebingen Univ, Med Ctr, Dept Hematol & Oncol, Tubingen, Germany. [Peeters, M.] 12 Octubre Univ Hosp, Res Inst, Madrid, Spain. [Peeters, M.] Univ Ziekenhuis Antwerpen, Antwerp, Belgium. [Reichardt, P.] HELIOS Klinikum Berlin Buch, Berlin, Germany. [Qin, A.; Ilaria, R. L.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Nippgen, J.] Merck KGaA, Darmstadt, Germany. [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Rutkowski, P.] Inst Oncol, Warsaw, Poland. RP Wagner, AJ (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM andrew_wagner@dfci.harvard.edu FU Eli Lilly and Company FX This work was supported by Eli Lilly and Company. No grant numbers apply. NR 14 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 541 EP 546 DI 10.1093/annonc/mdw659 PG 6 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100018 ER PT J AU Myaskovsky, L Gao, SS Hausmann, LRM Bornemann, KR Burkitt, KH Switzer, GE Fine, MJ Phillips, SL Gater, D Spungen, AM Worobey, L Boninger, ML AF Myaskovsky, Larissa Gao, Shasha Hausmann, Leslie R. M. Bornemann, Kellee R. Burkitt, Kelly H. Switzer, Galen E. Fine, Michael J. Phillips, Samuel. L. Gater, David Spungen, Ann M. Worobey, Lynn Boninger, Michael. L. TI Quality and Equity in Wheelchairs Used by Veterans SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Healthcare disparities; Rehabilitation; Spinal cord injuries; Wheelchairs ID SPINAL-CORD-INJURY; HEALTH-CARE; PERCEIVED DISCRIMINATION; OF-LIFE; ASSISTIVE TECHNOLOGY; MANUAL WHEELCHAIRS; AFRICAN-AMERICAN; PARTICIPATION; ASSOCIATION; DISPARITIES AB Objectives: To assess in Veterans with spinal cord injury (SCI) or amputated limb (AL) the following: (1) patient demographics, medical factors, cultural and psychosocial characteristic by race; (2) wheelchair quality by race; and (3) the independent associations of patient race and the other factors with wheelchair quality. Design: Cross-sectional cohort study. Setting: Three Department of Veterans Affairs (VA) medical centers affiliated with academic medical centers. Participants: Eligible participants were Veterans with SCI or ALs (N=516); 482 of them completed the interview. Analyses were restricted to white and African American participants. Because there was no variation in wheelchair quality among AL patients (n=42), they were excluded from all but descriptive analyses, leading to a final sample size of 421. Interventions: Not applicable. Main Outcome Measure: Wheelchair quality as defined by the Medicare Healthcare Common Procedure Coding System. Results: We found race differences in many of our variables, but not in quality for manual (odds ratio [OR] = .67; 95% confidence interval [CI], .33-1.36) or power (OR=.82; 95% CI,.51-1.34) wheelchairs. Several factors including age (OR= .96; 95% CI, .93-.99) and income (OR=3.78; 95% CI, 1.43-9.97) were associated with wheelchair quality. There were no significant associations of cultural or psychosocial factors with wheelchair quality. Conclusions: Although there were no racial differences in wheelchair quality, we found a significant association of older age and lower income with poorer wheelchair quality among Veterans. Efforts are needed to raise awareness of such disparities among VA wheelchair providers and to take steps to eliminate these disparities in prescription practice across VA sites. Published by Elsevier Inc. on behalf of the American Congress of Rehabilitation Medicine C1 [Myaskovsky, Larissa; Gao, Shasha; Hausmann, Leslie R. M.; Bornemann, Kellee R.; Burkitt, Kelly H.; Switzer, Galen E.; Fine, Michael J.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. [Myaskovsky, Larissa; Hausmann, Leslie R. M.; Bornemann, Kellee R.; Switzer, Galen E.; Fine, Michael J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Phillips, Samuel. L.] James A Haley Vet Hosp, Tampa, FL 33612 USA. [Gater, David] Hunter Holmes McGuire Vet Affairs Med Ctr, Richmond, VA USA. [Gater, David] Penn State Univ, Med Ctr, Hershey, PA USA. [Spungen, Ann M.] James J Peters Vet Affairs Med Ctr, Natl Ctr Med Consequences Spinal Cord Injury, Bronx, NY USA. [Spungen, Ann M.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Spungen, Ann M.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Worobey, Lynn; Boninger, Michael. L.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Worobey, Lynn; Boninger, Michael. L.] Vet Affairs Pittsburgh Healthcare Syst, Human Engn & Res Labs, Pittsburgh, PA USA. RP Myaskovsky, L (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. EM larissa.myaskovsky@va.gov FU Rehabilitation Research and Development Department of the Veterans Affairs [871481] FX Supported by the Rehabilitation Research and Development Department of the Veterans Affairs (grant no. 871481). NR 69 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAR PY 2017 VL 98 IS 3 BP 442 EP 449 DI 10.1016/j.apmr.2016.09.116 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EN9CD UT WOS:000396297400004 PM 27713075 ER PT J AU Wahl, E Gross, A Chernitskiy, V Trupin, L Gensler, L Chaganti, K Michaud, K Katz, P Yazdany, J AF Wahl, Elizabeth Gross, Andrew Chernitskiy, Vladimir Trupin, Laura Gensler, Lianne Chaganti, Krishna Michaud, Kaleb Katz, Patricia Yazdany, Jinoos TI Validity and Responsiveness of a 10-Item Patient-Reported Measure of Physical Function in a Rheumatoid Arthritis Clinic Population SO ARTHRITIS CARE & RESEARCH LA English DT Article ID QUALITY-OF-LIFE; MINIMALLY IMPORTANT DIFFERENCE; ITEM RESPONSE THEORY; DISEASE-ACTIVITY; SHORT-FORM; FUNCTION SCALES; HEALTH-STATUS; RELIABILITY; OUTCOMES; VALIDATION AB Objective: We assessed implementation of the 10-item Patient-Reported Outcomes Measurement Information System (PROMIS) physical function form (PF-10a) in routine practice in a racially and ethnically diverse population with rheumatoid arthritis (RA). Objectives were to determine feasibility of implementing PF-10a in the electronic health record (EHR) and PF-10a validity and longitudinal responsiveness. Methods: Clinical and demographic data were abstracted from EHRs for all RA patients seen at a university-based rheumatology clinic between February 2013 and February 2015. We evaluated floor and ceiling (edge) effects and construct validity of PF-10a in a subgroup of patients with Health Assessment Questionnaire (HAQ) scores (n=189). We used linear mixed-effects models to assess responsiveness of PF-10a to longitudinal changes in the Clinical Disease Activity Index (CDAI) for patients in the entire clinical cohort, with both scores recorded on at least 2 encounters (n=326). Results: Half of the patients were nonwhite, and 15% were non-English speakers. Over a 2-year period, PF10a was successfully implemented; 97% of patients and 89% of encounters had at least 1 measurement performed. PF-10a had fewer ceiling (defined as best) effects than the HAQ (8% versus 22%), and convergent validity was high (r=-0.85). PF-10a was sensitive to expected differences (older versus younger patients, more versus less active disease). Longitudinal changes in PF-10a were highly associated with changes in the CDAI score (P<0.0001). Conclusion: PF-10a was feasible to implement in a diverse RA population. It strongly correlates with the HAQ but has fewer ceiling effects and is responsive to changes in RA disease activity, suggesting its validity for use in routine clinical practice. C1 [Wahl, Elizabeth] Div Rheumatol, Dept Inter nal Med, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Bldg 1,Room 219-D, Seattle, WA 98108 USA. RP Wahl, E (reprint author), Div Rheumatol, Dept Inter nal Med, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Bldg 1,Room 219-D, Seattle, WA 98108 USA. EM elizabeth.wahl@va.gov FU Veterans Affairs Quality Scholars Fellowship through the Veterans Affairs Office of Academic Affiliations; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [P60-AR-053308-01, K23-AR-060259]; Rheumatology Research Foundation Investigator Award; Innovative Research Grant; Russell/Engleman Rheumatology Research Center; Robert L. Kroc Endowed Chair in Rheumatic and Connective Tissue Diseases at the University of California, San Francisco FX Dr. Wahl's work was supported by a Veterans Affairs Quality Scholars Fellowship through the Veterans Affairs Office of Academic Affiliations. Ms Trupin's and Dr. Katz's work was supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant P60-AR-053308-01). Dr. Michaud's work was supported by a Rheumatology Research Foundation Investigator Award and Innovative Research Grant. Dr. Yazdany's work was supported by NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant K23-AR-060259), the Russell/Engleman Rheumatology Research Center, and the Robert L. Kroc Endowed Chair in Rheumatic and Connective Tissue Diseases at the University of California, San Francisco. NR 34 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2017 VL 69 IS 3 BP 338 EP 346 DI 10.1002/acr.22956 PG 9 WC Rheumatology SC Rheumatology GA EM0DK UT WOS:000394988800004 PM 27332620 ER PT J AU Sauer-Zavala, S Cassiello-Robbins, C Conklin, LR Bullis, JR Thompson-Hollands, J Kennedy, KA AF Sauer-Zavala, Shannon Cassiello-Robbins, Clair Conklin, Laren R. Bullis, Jacqueline R. Thompson-Hollands, Johanna Kennedy, Katherine A. TI Isolating the Unique Effects of the Unified Protocol Treatment Modules Using Single Case Experimental Design SO BEHAVIOR MODIFICATION LA English DT Article DE Unified Protocol; treatment personalization; treatment mechanisms ID BORDERLINE PERSONALITY-DISORDER; CLINICAL REPLICATION SERIES; COGNITIVE-BEHAVIOR THERAPY; TRANSDIAGNOSTIC TREATMENT; EMOTIONAL DISORDERS; CAPITALIZATION MODELS; PSYCHOTHERAPY; ANXIETY; DEPRESSION; COMPENSATION AB The Unified Protocol (UP) for the Transdiagnostic Treatment of Emotional Disorders is a cognitive-behavioral intervention designed to treat the range of anxiety, depressive, and related disorders. Thus far, the UP treatment modules have only been studied when they are delivered in their entirety and presented in a standard sequence. To personalize the presentation of the UP modules for a given patient's presentation (e.g., providing the modules in a varied order, dropping irrelevant modules), it is first necessary to establish that each module leads to change in the skill it is designed to promote, and that these changes can occur in the absence of the other modules. Using a multiple baseline design in accordance with the single-case reporting guidelines in behavioral interventions (SCRIBE), eight patients with heterogeneous emotional disorders were randomly assigned to a 1- or 3-week baseline assessment phase followed by four sessions of one of four UP modules (psychoeducation, emotional awareness, cognitive flexibility, and countering emotional behaviors). Results provide preliminary support for the notion that each UP module under study leads to change in its associated skill in the absence of the other modules (five of eight patients demonstrated reliable change in the module-specific skill). In addition, exploratory analyses suggest that the emotion awareness training and cognitive flexibility modules appeared to exhibit change specific to their associated skills, psychoeducation, and countering emotional behaviors demonstrated somewhat more broad-based change across skills. C1 [Sauer-Zavala, Shannon; Conklin, Laren R.; Bullis, Jacqueline R.; Thompson-Hollands, Johanna; Kennedy, Katherine A.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Cassiello-Robbins, Clair] Boston Univ, Clin Psychol, Boston, MA 02215 USA. [Thompson-Hollands, Johanna] Boston Univ, Sch Med, VA Boston Healthcare System, Boston, MA 02215 USA. [Kennedy, Katherine A.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Conklin, Laren R.] Chalmers P Wylie VA Ambulatory Care Ctr, Columbus, OH USA. [Bullis, Jacqueline R.] Harvard Med Sch, McLean Hosp, Div Depress & Anxiety Disorders, Boston, MA USA. [Thompson-Hollands, Johanna] VA Boston Healthcare Syst, Boston, MA USA. RP Sauer-Zavala, S (reprint author), Boston Univ, Ctr Anxiety & Related Disorders, 648 Beacon St,6th Floor, Boston, MA 02215 USA. EM shannonesauer@gmail.com NR 40 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 0145-4455 EI 1552-4167 J9 BEHAV MODIF JI Behav. Modificat. PD MAR PY 2017 VL 41 IS 2 BP 286 EP 307 DI 10.1177/0145445516673827 PG 22 WC Psychology, Clinical SC Psychology GA EL5MP UT WOS:000394665500005 PM 28198196 ER PT J AU Li, DJ Taniguchi, EV Cai, S Paschalis, EI Wang, HB Miller, JB Turalba, AV Greenstein, SH Brauner, S Pasquale, LR Shen, LQ AF Li, Dejiao Taniguchi, Elise V. Cai, Sophie Paschalis, Eleftherios I. Wang, Haobing Miller, John B. Turalba, Angela V. Greenstein, Scott H. Brauner, Stacey Pasquale, Louis R. Shen, Lucy Q. TI Comparison of swept-source and enhanced depth imaging spectral-domain optical coherence tomography in quantitative characterisation of the optic nerve head SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article DE Optic Nerve; Glaucoma; Imaging ID OPEN-ANGLE GLAUCOMA; LAMINA-CRIBROSA THICKNESS; SEGMENT AB Aims To compare swept-source optical coherence tomography (SS-OCT) and enhanced depth imaging spectral-domain OCT (EDI-OCT) in quantitative assessment of optic nerve head (ONH) parameters. Methods In a cross-sectional study, patients with primary open angle glaucoma (POAG) and age-matched control subjects underwent SS-OCT and EDI-OCT B-scans of the ONH in a single visit. Two masked readers independently measured the horizontal and vertical lamina cribrosa depth (LCDH and LCDV, respectively), as well as thinnest Bruch's membrane opening minimum rim width (BMO-MRW) from SS-OCT and EDI-OCT scans. We assessed agreement between SS-OCT and EDI-OCT measurements by linear regression models, Bland-Altman analysis and concordance correlation coefficients (CCC). Intrareader and inter-reader reproducibility was assessed using intraclass correlation coefficients (ICC). Results One eye from each of 40 patients with POAG and 20 controls were included. All three ONH measurements were higher on SS-OCT than on EDI-OCT, with significant differences in LCDH (mean difference=31.7 mu m, p<0.01) and thinnest BMO-MRW (mean difference=20.5 mu m, p<0.01). Linear regression models described the agreement between SS-OCT and EDI-OCT measurements with R-2>0.8 for LCDH among both patients with POAG and controls and for thinnest BMO-MRW among patients with POAG. The CCC was >0.8 overall for each parameter. Intrareader and inter-reader ICCs were 0.989 and 0.964, respectively, for all parameters. Conclusions LCDH, LCDV and thinnest BMO-MRW measurements are not interchangeable between SS-OCT and EDI-OCT, but show good intrareader and inter-reader reproducibility and interdevice agreement for quantitative characterisation of the ONH, particularly among patients with glaucoma. C1 [Li, Dejiao] China Japan Friendship Hosp, Dept Ophthalmol, Beijing, Peoples R China. [Li, Dejiao; Taniguchi, Elise V.; Cai, Sophie; Paschalis, Eleftherios I.; Wang, Haobing; Miller, John B.; Turalba, Angela V.; Greenstein, Scott H.; Brauner, Stacey; Pasquale, Louis R.; Shen, Lucy Q.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Paschalis, Eleftherios I.] Massachusetts Eye & Ear Infirm, Boston Keratoprosthesis Lab, Schepens Eye Res Inst, Boston, MA 02114 USA. [Pasquale, Louis R.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA. RP Shen, LQ (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM lucy_shen@meei.harvard.edu FU Harvard Glaucoma Center of Excellence; Miller Research Funds at the Massachusetts Eye and Ear Infirmary; Harvard Medical School Distinguished Scholar Award; Eleanor and Miles Shore Fellowship, Harvard Medical School FX This study was supported by the Harvard Glaucoma Center of Excellence and the Miller Research Funds at the Massachusetts Eye and Ear Infirmary. LRP is supported by a Harvard Medical School Distinguished Scholar Award. LQS is supported by the Eleanor and Miles Shore Fellowship, Harvard Medical School. 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 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD MAR PY 2017 VL 101 IS 3 BP 299 EP 304 DI 10.1136/bjophthalmol-2016-308586 PG 6 WC Ophthalmology SC Ophthalmology GA EM8BQ UT WOS:000395536600012 ER PT J AU Bruinvels, G Burden, RJ McGregor, AJ Ackerman, KE Dooley, M Richards, T Pedlar, C AF Bruinvels, G. Burden, R. J. McGregor, A. J. Ackerman, K. E. Dooley, M. Richards, T. Pedlar, C. TI Sport, exercise and the menstrual cycle: where is the research? SO BRITISH JOURNAL OF SPORTS MEDICINE LA English DT Editorial Material C1 [Bruinvels, G.; Richards, T.] UCL, London, England. [Bruinvels, G.; Burden, R. J.; Pedlar, C.] St Marys Univ, Twickenham, England. [Bruinvels, G.; Burden, R. J.] ORRECO Ltd, Inst Technol, Sligo, Ireland. [Burden, R. J.] English Inst Sport, Loughborough, Leics, England. [McGregor, A. J.] Brown Univ, Providence, RI 02912 USA. [Ackerman, K. E.; Pedlar, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dooley, M.] Poundbury Clin, Dorchester, Dorset, England. RP Bruinvels, G (reprint author), UCL, Div Surg & Intervent Sci, 21 Univ St, London WC1E 6AU, England. EM georgie.bruinvels@ucl.ac.uk NR 5 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 0306-3674 EI 1473-0480 J9 BRIT J SPORT MED JI Br. J. Sports Med. PD MAR PY 2017 VL 51 IS 6 BP 487 EP 488 DI 10.1136/bjsports-2016-096279 PG 2 WC Sport Sciences SC Sport Sciences GA EL3TR UT WOS:000394542700004 PM 27267895 ER PT J AU Gelfond, D Heltshe, S Ma, CX Rowe, SM Frederick, C Uluer, A Sicilian, L Konstan, M Tullis, E Roach, RNC Griffin, K Joseloff, E Borowitz, D AF Gelfond, Daniel Heltshe, Sonya Ma, Changxing Rowe, Steven M. Frederick, Carla Uluer, Ahmet Sicilian, Leonard Konstan, Michael Tullis, Elizabeth Roach, R. N. Christine Griffin, Katherine Joseloff, Elizabeth Borowitz, Drucy TI Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Article ID BICARBONATE SECRETION; MUCIN SECRETION; TRANSPORT; POTENTIATOR; CHILDREN; CHANNEL AB OBJECTIVES: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis ( CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel ( CFTR) potentiator. METHODS: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule ( n= 10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment. RESULTS: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying ( P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass ( P<0.05 for select 5 min intervals and all segments>30 min); mean weight gain was 1.1 kg ( P= 0.08). No difference in abdominal pain or regional transit times was seen. CONCLUSIONS: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement. C1 [Gelfond, Daniel] Univ Rochester, Med Ctr, WNY Pediat Gastroenterol, 166 Washington Ave, Batavia, NY 14020 USA. [Heltshe, Sonya] Univ Washington, Sch Med, CFF TDN, Seattle, WA USA. [Ma, Changxing; Frederick, Carla; Roach, R. N. Christine; Borowitz, Drucy] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA. [Rowe, Steven M.] Univ Alabama Birmingham, Birmingham, AL USA. [Uluer, Ahmet] Boston Childrens Hosp, Boston, MA USA. [Sicilian, Leonard] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Konstan, Michael] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Tullis, Elizabeth; Griffin, Katherine] St Michaels Hosp, Toronto, ON, Canada. [Joseloff, Elizabeth] Cyst Fibrosis Fdn Therapeut, Bethesda, MD USA. RP Gelfond, D (reprint author), Univ Rochester, Med Ctr, WNY Pediat Gastroenterol, 166 Washington Ave, Batavia, NY 14020 USA. EM dgelfond@wnypedgi.com FU CFFT [BOROWI03CS0, GOAL13K1]; NIH [DK072482, P30 DK089507/DK/NIDDK NIH HHS] FX This work was supported by grant support: CFFT BOROWI03CS0, GOAL13K1, NIH: DK072482, P30 DK089507/DK/NIDDK NIH HHS. NR 24 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2155-384X J9 CLIN TRANSL GASTROEN JI Clin. Transl. Gastroenterol. PD MAR PY 2017 VL 8 AR e81 DI 10.1038/ctg.2017.10 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP1AQ UT WOS:000397118200005 PM 28300821 ER PT J AU Jimenez-Torres, GJ Weinstein, BL Walker, CR Fowler, JC Ashford, P Borckardt, JJ Madan, A AF Jimenez-Torres, G. Janice Weinstein, Benjamin L. Walker, Cory R. Fowler, J. Christopher Ashford, Philippa Borckardt, Jeffrey J. Madan, Alok TI A study protocol for a single-blind, randomized controlled trial of adjunctive transcranial direct current stimulation (tDCS) for chronic pain among patients receiving specialized, inpatient multimodal pain management SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Chronic pain; Pain management; Transcranial direct current stimulation; Somatic symptoms; Serious mental illness ID DORSOLATERAL PREFRONTAL CORTEX; COGNITIVE-BEHAVIORAL THERAPY; COLD PRESSOR TASK; COMMITMENT THERAPY; CLINICAL-TRIAL; PRIMARY-CARE; EFFICACY; PERCEPTION; MINDFULNESS; ACCEPTANCE AB Background: Available treatments for chronic pain (CP) are modestly effective or associated with iatrogenic harm. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that may be an effective, adjunctive treatment to non-opioid therapies. In this randomized contrortrial (RCI), we compare adjunctive active versus sham tDCS among patients in a multimodal inpatient pain management program. The primary objectives of the RCT are to improve pain tolerance and subjective pain experience. Methods and design: Patients admitted to the Pain Management Program at The Menninger Clinic in Houston, Texas are eligible for this trial. Eighty-four participants will be randomized (1:1) into a single-blind, 2 x 12 (group x time) controlled trial. A battery-powered direct and constant current stimulator (Soterix Medical Inc. 2014) delivers anodal stimulation over the left dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation over the right DLPFC. Active tDCS is applied by supplying a 2 mA current for 20 min/session over 10 sessions. Participants complete self-report and performance-based assessments on a weekly basis just prior to brain stimulation. Self-report assessMents are collected via Chronic Pain Tracker version 3.6, an iPad interfaced application. The performance-based pain tolerance task is completed through the cold presser task. Discussion: Interventions with cross-symptomatic therapeutic potential are absolutely essential in the context of CP, in which psychiatric comorbidity is the norm. Modalities that can be used in tandem with evidence-based, non-opioid therapies have the potential to have a synergistic effect, resulting in increased effectiveness of what have been modestly effective treatments to date. (C) 2017 Elsevier Inc All rights reserved. C1 [Jimenez-Torres, G. Janice; Weinstein, Benjamin L.; Walker, Cory R.; Fowler, J. Christopher; Ashford, Philippa; Madan, Alok] Menninger Clin, Houston, TX USA. [Jimenez-Torres, G. Janice; Weinstein, Benjamin L.; Walker, Cory R.; Fowler, J. Christopher; Madan, Alok] Baylor Coll Med, Psychiat & Behav Sci, Houston, TX 77030 USA. [Borckardt, Jeffrey J.] Med Univ South Carolina, Anesthesia & Perioperat Med, Charleston, SC USA. [Borckardt, Jeffrey J.] Med Univ South Carolina, Psychiat & Behav Sci, Charleston, SC USA. [Borckardt, Jeffrey J.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Madan, A (reprint author), 12301 South Main St, Houston, TX 77035 USA. EM amadan@menninger.edu FU Menninger Clinic Foundation, McNair Medical Institute; William and Ella Owens Medical Research Foundation FX This research was partially supported by the Menninger Clinic Foundation, McNair Medical Institute, and the William and Ella Owens Medical Research Foundation. Dr. Madan is a McNair Scholar. The study follows the guidelines on good publication practices. The study sponsors were not involved in any aspect of the research activities. Thus, the authors were independent from study sponsors in the context of the research. The authors have no other potential conflicts of interest to disclose. NR 82 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2017 VL 54 BP 36 EP 47 DI 10.1016/j.cct.2016.12.024 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EL3YV UT WOS:000394557500005 ER PT J AU Mehta, M Wen, P Nishikawa, R Reardon, D Peters, K AF Mehta, M. Wen, P. Nishikawa, R. Reardon, D. Peters, K. TI Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review ID RANDOMIZED PHASE-III; PHYSICIANS CHOICE CHEMOTHERAPY; ALTERNATING ELECTRIC-FIELDS; NOVOTTF-100A(TM) SYSTEM; RECURRENT GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; OPEN-LABEL; TRIAL; RADIOTHERAPY; BEVACIZUMAB AB Since 2005, the standard of care for patients with newly diagnosed glioblastoma (GBM) has consisted of maximal resection followed by radiotherapy plus daily temozolomide (TMZ), followed by maintenance TMZ. In patients selected for clinical trials, median overall survival (OS) and progression-free survival (PFS) with this regimen is 15-17 months and 6-7 months, respectively. There have been various, largely unsuccessful attempts to improve on this standard of care. With the FDA approval of the tumor-treating fields (TTFields) device, Optune, for recurrent GBM (2011), and the more recent EF-14 interim trial results and approval for newly diagnosed GBM patients, several questions have arisen. A roundtable of experts was convened at the 2015 ASCO meeting to engage in an open conversation and debate of the EF-14 results presented at that meeting and their implications for neuro-oncology practice and clinical research. In October 2015, subsequent to the roundtable discussion, TTFields received FDA approval for newly diagnosed GBM. (C) 2017 The Authors. Published by Elsevier Ireland Ltd. C1 [Mehta, M.] Miami Canc Inst, Miami, FL 33176 USA. [Wen, P.] Harvard Univ, Ctr NeuroOncol, Dana Farber Canc Inst, Dept Neurol, Boston, MA 02115 USA. [Nishikawa, R.] Saitama Int Med Ctr, Dept Neurosurgery, Japanese Soc NeuroOncol, Saitama, Japan. [Reardon, D.] Harvard Med Sch, Ctr NeuroOncol, Boston, MA USA. [Peters, K.] Duke Univ, Med Ctr, Durham, NC USA. RP Mehta, M (reprint author), Miami Canc Inst, Miami, FL 33176 USA. EM mineshpmehta@gmail.com NR 30 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 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD MAR PY 2017 VL 111 BP 60 EP 65 DI 10.1016/j.critrevonc.2017.01.005 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA EO8RR UT WOS:000396958100007 PM 28259296 ER PT J AU Fan, Y Lee, K Wang, NS He, JC AF Fan, Ying Lee, Kyung Wang, Niansong He, John Cijiang TI The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy SO CURRENT DIABETES REPORTS LA English DT Review DE Diabetic nephropathy; Endoplasmic reticulum stress; Unfolded protein response. Apoptosis; Reticulon-1 (RTN-1) ID UNFOLDED PROTEIN RESPONSE; GLOMERULAR ENDOTHELIAL-CELLS; INDUCED PODOCYTE APOPTOSIS; TUBULAR EPITHELIAL-CELLS; ACID-BINDING PROTEIN; ER-STRESS; KIDNEY-DISEASE; MESENCHYMAL TRANSITION; PREMATURE SENESCENCE; ASTRAGALOSIDE IV AB Purpose of Review Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN. Recent Findings As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR. Summary These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN. C1 [Fan, Ying; Wang, Niansong] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai, Peoples R China. [Lee, Kyung; He, John Cijiang] Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. [He, John Cijiang] James J Peters VAMC, Renal Sect, Bronx, NY USA. RP He, JC (reprint author), Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA.; He, JC (reprint author), James J Peters VAMC, Renal Sect, Bronx, NY USA. EM cijiang.he@mssm.edu FU National Natural Science Foundation of China [81400735, 81270824, 81670657]; Chinese Medical Association Funding [15020140602]; NIH [P30 DK079307, 1R01DK098126, 1R01DK109683, 1R01DK078897, 1R01DK088541, P01-DK-56492] FX Y.F. is supported by National Natural Science Foundation of China (81400735) and Chinese Medical Association Funding (15020140602). K.L. is supported by NIH P30 DK079307 and 1R01DK098126. N.W. is supported by National Natural Science Foundation of China (81270824, 81670657). J.C.H. is supported by NIH 1R01DK109683, 1R01DK078897, 1R01DK088541, and P01-DK-56492. NR 69 TC 0 Z9 0 U1 1 U2 1 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD MAR PY 2017 VL 17 IS 3 AR 17 DI 10.1007/s11892-017-0842-y PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EO7KU UT WOS:000396870400004 PM 28271468 ER PT J AU Drain, PK Rousseau, C AF Drain, Paul K. Rousseau, Christine TI Point-of-care diagnostics: extending the laboratory network to reach the last mile SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE CD4(+) cell count; centralized laboratory; HIV self-testing; HIV viral load; HIV/AIDS; point-of-care test; resource-limited settings ID HIV-1 VIRAL LOAD; ASSAY; IMPLEMENTATION; PERFORMANCE; MOZAMBIQUE; SETTINGS; CD4 AB Purpose of reviewMore point-of-care (POC) diagnostic tests are becoming available for HIV diagnosis and treatment in resource-limited settings. These novel technologies have the potential to foster decentralized HIV care and treatment for the benefit of clinical laboratories, HIV clinics, and HIV-infected patients. There continue to be many business, technological, and operational challenges that limit product development and regulatory approval, which limits products available for the required operational and cost-effectiveness studies and delays policy adoption and implementation.Recent findingsAlthough the rapid HIV diagnostic test has been widely successful, the pathways for POC CD4(+) cell count and HIV viral load assay analyzers have been more challenging. We describe significant hurdles for product development, approval, and implementation, which include the business case, technical development, clinical impact, and integrating laboratory and clinical networks.SummaryThe objective of this review is to highlight the obstacles for developing and implementing appropriate strategies for POC HIV testing assays to improve the clinical services for HIV-infected patients in resource-limited settings. C1 [Drain, Paul K.; Rousseau, Christine] Univ Washington, Dept Global Hlth, 325 Ninth Ave,UW Box 359927, Seattle, WA 98104 USA. [Drain, Paul K.] Univ Washington, Dept Med, Seattle, WA USA. [Drain, Paul K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Drain, Paul K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Rousseau, Christine] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Drain, PK (reprint author), Univ Washington, Dept Global Hlth, 325 Ninth Ave,UW Box 359927, Seattle, WA 98104 USA. EM pkdrain@uw.edu FU National Institutes of Health [AI108293, AI124719, AI127200]; Infectious Disease Society of America; Bill and Melinda Gates Foundation FX P.K.D. receives research support from the National Institutes of Health (AI108293, AI124719, and AI127200), the Infectious Disease Society of America, and the Bill and Melinda Gates Foundation. NR 43 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 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2017 VL 12 IS 2 BP 175 EP 181 DI 10.1097/COH.0000000000000351 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EM7WB UT WOS:000395521900012 PM 28079591 ER PT J AU Kohler-Forsberg, O Sylvia, L Thase, M Calabrese, JR Deckersbach, T Tohen, M Bowden, CL McInnis, M Kocsis, JH Friedman, ES Ketter, TA McElroy, S Shelton, RC Nierenberg, AA AF Kohler-Forsberg, Ole Sylvia, Louisa Thase, Michael Calabrese, Joseph R. Deckersbach, Thilo Tohen, Mauricio Bowden, Charles L. McInnis, Melvin Kocsis, James H. Friedman, Edward S. Ketter, Terence A. McElroy, Susan Shelton, Richard C. Nierenberg, Andrew A. TI Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol do not affect 6-month mood-stabilizing treatment outcome among 482 patients with bipolar disorder SO DEPRESSION AND ANXIETY LA English DT Article DE bipolar disorder; nonsteroidal anti-inflammatory drugs (NSAIDs); lithium; polypharmacy; paracetamol; quetiapine ID MAJOR DEPRESSIVE DISORDER; CLINICAL-TRIALS; SYMPTOMS SCALE; DOUBLE-BLIND; ANTIDEPRESSANTS; CELECOXIB; INVENTORY; CHOICE AB BackgroundMany mood disorder patients need analgesics due to increased pain sensitivity. Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit antidepressant treatment, which requires replication before clinical recommendations. MethodsThe Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study randomized participants to 6 months lithium or quetiapine treatment. Use of NSAIDs and paracetamol was assessed throughout the study period and psychopathology measured with the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and Bipolar Inventory of Symptoms Scale (BISS). The effects of NSAIDs and paracetamol on treatment outcome were examined using mixed effects linear regression adjusted for age, gender, body mass index, smoking status, exercise, and somatic diseases. ResultsAmong 482 participants, 177 (36.7%) used NSAIDs and/or paracetamol during the study. NSAID and paracetamol users did not differ from nonusers with respect to treatment outcome with lithium or quetiapine at any time point during 6 months treatment on the overall CGI-BP ( = 0.001 (95% CI = -0.01 to -0.01), P = .87), the BISS ( = 0.01 (95% CI = -0.17 to 0.15), P = .91), nor the CGI-BP subscales for depression or mania. Users of NSAIDs only (n = 76), paracetamol only (n = 62), and users of both NSAIDs and paracetamol (n = 39) showed no statistical difference compared to nonusers (all P > .3). ConclusionsThis is the first trial to show that use of NSAIDs and paracetamol, alone or in combination, does not affect lithium- or quetiapine-based bipolar disorder mood-stabilizing treatment outcomes. Prior studies have suggested that NSAIDs may inhibit antidepressant treatment, whereas our results support findings indicating no detrimental effects of NSAIDs or paracetamol on affective disorder treatment. C1 [Kohler-Forsberg, Ole] Aarhus Univ Hosp, Psychosis Res Unit, Skovagervej 2, DK-8240 Risskov, Denmark. [Sylvia, Louisa; Deckersbach, Thilo; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sylvia, Louisa; Deckersbach, Thilo; Nierenberg, Andrew A.] Harvard Med Sch, Boston, MA USA. [Thase, Michael] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. [Tohen, Mauricio] Univ New Mexico, Dept Psychiat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [McInnis, Melvin] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Kocsis, James H.] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Friedman, Edward S.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Ketter, Terence A.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. [McElroy, Susan] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Cincinnati, OH USA. [McElroy, Susan] Lindner Ctr HOPE, Mason, OH USA. [Shelton, Richard C.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. RP Kohler-Forsberg, O (reprint author), Aarhus Univ Hosp, Psychosis Res Unit, Skovagervej 2, DK-8240 Risskov, Denmark. EM karkoe@rm.dk FU Agency for Healthcare Research and Quality (AHRQ) [1R01HS019371-01] FX Grant sponsor: Agency for Healthcare Research and Quality (AHRQ); Contract grant number: 1R01HS019371-01. NR 23 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2017 VL 34 IS 3 BP 281 EP 290 DI 10.1002/da.22601 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EM8IB UT WOS:000395553600009 PM 28135023 ER PT J AU Sosenko, JM Yu, L Skyler, JS Krischer, JP Gottlieb, PA Boulware, D Miao, D Palmer, JP Steck, AK AF Sosenko, Jay M. Yu, Liping Skyler, Jay S. Krischer, Jeffrey P. Gottlieb, Peter A. Boulware, David Miao, Dongmei Palmer, Jerry P. Steck, Andrea K. TI The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article DE Type 1 diabetes; Autoantibodies; Hyperglycemia; Pediatrics ID GLUTAMIC-ACID DECARBOXYLASE; IDENTIFY HIGH-RISK; RELATIVES; INSULIN; CHILDREN AB Background: Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. Subjects and Methods: TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL+) were compared with those ECL negative (ECL-) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. Results: The progression to multiple autoantibodies was significantly higher for those GADA/ECL+ (n = 107) than those GADA/ECL-(n = 78) (P = 0.001) and for those mIAA/ECL+ (n = 24) than those mIAA/ECL-(n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL+ and mIAA/ECL+ participants had significantly higher PS6M values than their ECL-counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL+, 14% progressed to T1D; of those mIAA/ECL+, 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL-progressed to T1D (median follow-up: 5 years). Conclusion: ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL+ are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL-are at very low risk. C1 [Sosenko, Jay M.; Skyler, Jay S.] Univ Miami, Miller Sch Med, Div Endocrinol, POB 016960 D1110, Miami, FL 33101 USA. [Yu, Liping; Gottlieb, Peter A.; Miao, Dongmei; Steck, Andrea K.] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Sch Med, Aurora, CO USA. [Krischer, Jeffrey P.; Boulware, David] Univ S Florida, Div Informat & Biostat, Tampa, FL USA. Univ Washington, VA Puget Sound Hlth Care Syst, Div Endocrinol Metab & Nutr, Seattle, WA USA. RP Sosenko, JM (reprint author), Univ Miami, Miller Sch Med, Div Endocrinol, POB 016960 D1110, Miami, FL 33101 USA. EM jsosenko@med.miami.edu FU Type 1 Diabetes TrialNet Pathway to Prevention Study Group; National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01DK085453, U01DK085461, U01DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01DK085509, U01 DK103180, U01-DK103153, U01-DK085476, U01-DK103266]; Juvenile Diabetes Research Foundation International (JDRF) FX The sponsor of the study was the Type 1 Diabetes TrialNet Pathway to Prevention Study Group. Type 1 Diabetes TrialNet Pathway to Prevention Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development through the cooperative agreements. TrialNet is funded by NIH grants U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01DK085453, U01DK085461, U01DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01DK085509, U01 DK103180, U01-DK103153, U01-DK085476, U01-DK103266, and the Juvenile Diabetes Research Foundation International (JDRF). NR 14 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 1520-9156 EI 1557-8593 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD MAR PY 2017 VL 19 IS 3 BP 183 EP 187 DI 10.1089/dia.2016.0243 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EN8AP UT WOS:000396223600008 PM 28177779 ER PT J AU Moyers, TB Houck, J Glynn, LH Hallgren, KA Manuel, JK AF Moyers, Theresa B. Houck, Jon Glynn, Lisa H. Hallgren, Kevin A. Manuel, Jennifer K. TI A randomized controlled trial to influence client language in substance use disorder treatment SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Motivational interviewing; Counselor training; Client language; Randomized controlled trial; Active mechanism; Technical component ID BRIEF MOTIVATIONAL INTERVENTION; COMMITMENT LANGUAGE; DRINKING OUTCOMES; SELF-PERSUASION; CHANGE TALK; METAANALYSIS; DISSONANCE; STRENGTH; ALCOHOL; MATTERS AB Background: Client language is hypothesized to be a mechanism of action in motivational interviewing (MI). Despite the association of change and sustain talk with substance treatment outcomes, it not known whether providers can intentionally influence this language as hypothesized. Objective: This is a randomized controlled trial to investigate whether substance use providers can be trained to influence client language. Methods: Treatment providers specializing in substance use disorders (n = 190) were randomly assigned to standard training in MI (MI-AU) or training emphasizing an influence of client language (MI-LEAF). Treatment sessions with actual clients were evaluated 3, 6 and 12 months after training by masked raters. Frequencies of client change and sustain talk were the outcome variables. Results: Sustain talk, but not change talk, was significantly lower in clients whose providers had received the specialized training (b = -0.175, SE = 0.087, p=0.046, CI[-0.348 to 0.0021, d = -0.325). Mediation analyses supported a causal chain between a) training, b) providers' attempts to minimize sustain talk in treatment sessions via directive reflective listening and c) client sustain talk in the treatment session (kappa(2) = 0.0833, bootstrap SE = 0.0394, 95% CI [0.0148, 0.1691]). Conclusions: With specialized training, providers can reduce the amount of opposition language their clients offer when considering a change in their substance use. Demonstrating that client language is under partial control of the provider supports the feasibility of clinical trials to investigate the impact of shaping client language on treatment outcomes. (C) 2017 Elsevier B.V. All rights reserved. C1 [Moyers, Theresa B.; Houck, Jon] Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, MSC11 6280 1, Albuquerque, NM 87131 USA. [Glynn, Lisa H.] VA Puget Sound Hlth Care Syst, Dept Anesthesiol, 1660 S Columbian Way, Seattle, WA 98108 USA. [Hallgren, Kevin A.] Univ Washington, Dept Psychiat & Behav Sci, 1959 NE Pacific St, Seattle, WA 98195 USA. [Manuel, Jennifer K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Manuel, Jennifer K.] Univ Calif San Francisco, San Francisco, CA USA. RP Moyers, TB (reprint author), Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Dept Psychol, Albuquerque, NM 87106 USA. EM tmoyers@unm.edu; jhouck@unm.edu; Lisa.glynn2@va.gov; khallgre@uw.edu; jennifer.manuel@va.gov FU National Institute on Drug Abuse [R01 DA 021227-01] FX This research was funded by grant R01 DA 021227-01 from the National Institute on Drug Abuse. No other contributions were made to this project. NR 34 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 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2017 VL 172 BP 43 EP 50 DI 10.1016/j.drugalcdep.2016.11.036 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EM3LV UT WOS:000395217500006 PM 28122270 ER PT J AU Riley, ED Hsue, PY Vittinghoff, E Wu, AHB Coffin, PO Moore, PK Lynch, KL AF Riley, Elise D. Hsue, Priscilla Y. Vittinghoff, Eric Wu, Alan H. B. Coffin, Phillip O. Moore, Peter K. Lynch, Kara L. TI Higher prevalence of detectable troponin I among cocaine-users without known cardiovascular disease SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Benzoylecgonine; Cardiac injury; Troponin; cTnI ID ACUTE MYOCARDIAL-INFARCTION; MORGAM BIOMARKER PROJECT; CRACK-COCAINE; GENERAL-POPULATION; CORONARY-ARTERIES; RISK PREDICTION; HUMAN PLATELETS; UNITED-STATES; SUBSTANCE USE; MORTALITY AB Background: While cocaine use is an established risk factor for acute cardiovascular complications, associations between cocaine use and markers of cardiac injury outside of acute hospital presentation remain poorly characterized. We leveraged advances in cardiac troponin (cTnI) testing to assess low but clinically meaningful levels of cardiac injury among cocaine users and non-users. Methods: We conducted a case control study comparing cTnI levels by the presence of cocaine among patients presenting for non-cardiac care in an urban safety net hospital. Samples were chosen sequentially among those for which urine drug screens were ordered by providers hospital-wide. Results: During 2015, 14% of all hospital drug screens ordered were cocaine-positive. Among unique persons providing cocaine-positive (N = 100) and cocaine-negative (N = 100) samples, 37% were female, 45% were African-American and the median age was 51. Detectable cTnI (> 0.02 ng/mL) was observed in 21 samples (11%). It was more common in subjects using cocaine (Adjusted OR = 2.81; 95% CI = 1.03-7.65), but not other drugs. Moreover, there was a significant correlation between concentrations of cTnI and the cocaine metabolite, benzoylecgonine (Spearman Correlation = 0.34, p < 0.01). Conclusions: Among urban safety net hospital patients, 11% had detectable cTnI, and cTnI concentration was significantly correlated with benzoylecgonine concentration. While these preliminary results require additional confirmation, they suggest the potential utility of considering cocaine use as more than just an episodic exposure leading to acute cardiac events. The consideration of cocaine use as an ongoing chronic exposure leading to subclinical cardiac injury may improve risk-stratification and patient outcomes in populations where cocaine use is high. (C) 2017 Elsevier B.V. All rights reserved. C1 [Riley, Elise D.; Coffin, Phillip O.] Univ Calif San Francisco, Infect Dis & Global Hlth, Dept Med, Div HIV, San Francisco, CA 94143 USA. [Hsue, Priscilla Y.] Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA. [Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostatist, San Francisco, CA 94143 USA. [Wu, Alan H. B.; Lynch, Kara L.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Lab Med, San Francisco, CA 94143 USA. [Coffin, Phillip O.] San Francisco Dept Publ Hlth, San Francisco, CA 94143 USA. [Moore, Peter K.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Moore, Peter K.] San Francisco VA Med Ctr, Dept Med, Div Hosp Med, San Francisco, CA USA. RP Riley, ED (reprint author), 1001 Potrero Ave,UCSF Mailbox 0874, San Francisco, CA 94143 USA. EM elise.riley@ucsf.edu FU National Institutes of Health [R01 DA037012, K24 DA039780] FX This study was funded by the National Institutes of Health (R01 DA037012 and K24 DA039780). The National Institutes of Health and the National Institute on Drug Abuse had no role in the design or conduct of the study; the collection, management, analysis or interpretation of the data; or the preparation, review or approval of the manuscript. NR 56 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 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2017 VL 172 BP 88 EP 93 DI 10.1016/j.drugalcdep.2016.11.039 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EM3LV UT WOS:000395217500012 PM 28157591 ER PT J AU Gottschalk, MG Leussis, MP Ruland, T Gjeluci, K Petryshen, TL Bahn, S AF Gottschalk, Michael G. Leussis, Melanie P. Ruland, Tillmann Gjeluci, Klaudio Petryshen, Tracey L. Bahn, Sabine TI Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar disorder; Translational model; Proteomics; Protein interaction networks; Mass spectrometry ID GENOME-WIDE ASSOCIATION; CHANNEL BETA-SUBUNITS; ANKYRIN-G; INITIAL SEGMENT; MOOD STABILIZERS; KINESIN; BRAIN; METAANALYSIS; LOCALIZATION; MICROTUBULES AB Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSE or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSE followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior. (C) 2017 Elsevier B.V. and ECNP. All rights reserved. C1 [Gottschalk, Michael G.; Ruland, Tillmann; Bahn, Sabine] Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge Ctr Neuropsychiat Res, Cambridge, England. [Leussis, Melanie P.; Gjeluci, Klaudio; Petryshen, Tracey L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA. [Leussis, Melanie P.; Gjeluci, Klaudio; Petryshen, Tracey L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Leussis, Melanie P.; Gjeluci, Klaudio; Petryshen, Tracey L.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Leussis, Melanie P.] Emmanuel Coll, Dept Psychol, Boston, MA USA. [Ruland, Tillmann] Univ Munster, Dept Psychiat & Psychotherapy, Mood & Anxiety Disorders Res Unit, Munster, Germany. [Petryshen, Tracey L.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Petryshen, TL (reprint author), Ctr Genom Med, Psychiat & Neurodev Genet Unit, 185 Cambridge St, Boston, MA 02114 USA.; Bahn, S (reprint author), Univ Cambridge, Dept Chem Engn & Biotechnol, Tennis Court Rd, Cambridge CB2 1QT, England. EM tpetryshen@mgh.harvard.edu; sb209@cam.ac.uk OI Gottschalk, Michael/0000-0002-2386-3701 FU Stanley Medical Research Institute (SMRI) FX Funding for this study was provided by the Stanley Medical Research Institute (SMRI); the SMRI had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 68 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2017 VL 27 IS 3 BP 274 EP 288 DI 10.1016/j.euroneuro.2017.01.001 PG 15 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EO8WL UT WOS:000396971100007 PM 28109561 ER PT J AU Aggarwal, S Yamaguchi, T Dana, R Hamrah, P AF Aggarwal, Shruti Yamaguchi, Takefumi Dana, Reza Hamrah, Pedram TI Exophiala phaeomuriformis Fungal Keratitis: Case Report and In Vivo Confocal Microscopy Findings SO EYE & CONTACT LENS-SCIENCE AND CLINICAL PRACTICE LA English DT Article DE Keratomycosis; Exophiala phaeomuriformis; Penetrating keratoplasty; In vivo confocal microscopy ID BLACK YEASTS; SOUTH-INDIA; DERMATITIDIS; PATHOGENS AB Purpose:Corneal infections, particularly fungal keratitis due to rare fungal species, pose a diagnostic and therapeutic challenge because of difficulty in identification and varying susceptibility profiles. In this study, we report the first case of fungal keratitis because of Exophiala phaeomuriformis.Methods:We report the clinical findings and microbial identification techniques of a case of fungal keratitis due to E. phaeomuriformis. An 84-year-old woman presented with redness, pain, and itching in the left eye for 2 weeks. Slit-lamp biomicroscopy revealed one broken suture from previous penetrating keratoplasty (PKP), black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Microbial identification was based cultures on Sabouraud dextrose agar and DNA sequencing and correlations to laser in vivo confocal microscopy (IVCM; Heidelberg Retinal Tomograph 3/Rostock Cornea Module, Heidelberg Engineering) and multiphoton microscopy (Ultima Microscope; Prairie Technologies) images.Results:Slit-lamp biomicroscopy revealed one broken suture from previous PKP, black infiltrates at the 4-o'clock position, without an overlying epithelial defect and hypopyon. Based on a clinical suspicion of fungal keratitis, antifungals and fortified antibiotics were started. However, the patient did not respond to therapy and required urgent PKP. After surgery, the patient was maintained on topical and systemic voriconazole and also topical 2% cyclosporine for 5 months because of possibility of scleral involvement noticed during surgery. At the end of the treatment period, her vision improved from hand motion to 20/40, with no recurrence observed in a follow-up period of 1 year. Results of diagnostic tests were supported by fungal elements in stroma on IVCM. Culture from the infiltrate grew black yeast. DNA sequencing led to the diagnosis of E. phaeomuriformis keratitis. Antifungal susceptibility testing revealed sensitivity to voriconazole.Conclusion:This is, to our knowledge, the first reported case of E. phaeomuriformis fungal keratitis. Diagnostic testing included slit-lamp biomicroscopy, which revealed pigmented infiltrates, culture plates grew black yeast, microscopy showed branched fungal hyphae with budding conidia, and physiological features showed tolerance to high temperatures, nitrate assimilation, and ribosomal DNA sequencing. Collectively, these tests demonstrate unique features seen for this microorganism. High suspicion should be kept with pigmented infiltrates and with dark yeast on culture plates. Prompt and aggressive medical management with voriconazole or therapeutic PKP in nonresponsive cases is essential to prevent irreversible loss of vision. C1 [Aggarwal, Shruti; Hamrah, Pedram] Harvard Med Sch, Dept Ophthalmol, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Aggarwal, Shruti; Yamaguchi, Takefumi; Dana, Reza; Hamrah, Pedram] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cornea & Refract Surg Serv, Boston, MA USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, New England Eye Ctr,Boston Image Reading Ctr, 800 Washington St, Boston, MA 02111 USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, New England Eye Ctr,Cornea Serv, 800 Washington St, Boston, MA 02111 USA. RP Hamrah, P (reprint author), Tufts Univ, Sch Med, Tufts Med Ctr, New England Eye Ctr,Boston Image Reading Ctr, 800 Washington St, Boston, MA 02111 USA.; Hamrah, P (reprint author), Tufts Univ, Sch Med, Tufts Med Ctr, New England Eye Ctr,Cornea Serv, 800 Washington St, Boston, MA 02111 USA. EM phamrah@tuftsmedicalcenter.org FU NIH [K08-EY020575]; Falk Medical Research Foundation; Research to Prevent Blindness Career Development Award; MEEI Foundation FX Supported by NIH K08-EY020575 (P.H.), Falk Medical Research Foundation (P.H.), Research to Prevent Blindness Career Development Award (P.H.), and MEEI Foundation (P.H.). NR 16 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 1542-2321 EI 1542-233X J9 EYE CONTACT LENS JI Eye Contact Lens-Sci. Clin. Pra. PD MAR PY 2017 VL 43 IS 2 BP e4 EP e6 DI 10.1097/ICL.0000000000000193 PG 3 WC Ophthalmology SC Ophthalmology GA EM8WY UT WOS:000395593000012 PM 26513718 ER PT J AU Machida, H Nathenson, MJ Takiuchi, T Adams, CL Garcia-Sayre, J Matsuo, K AF Machida, Hiroko Nathenson, Michael J. Takiuchi, Tsuyoshi Adams, Crystal L. Garcia-Sayre, Jocelyn Matsuo, Koji TI Significance of lymph node metastasis on survival of women with uterine adenosarcoma SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Uterine adenosarcoma; Lymph node metastasis; Endometrial stromal sarcoma; Leiomyosarcoma ID CLINICOPATHOLOGICAL ANALYSIS; MULLERIAN ADENOSARCOMA; SARCOMATOUS OVERGROWTH; UTERUS; EPIDEMIOLOGY; MANAGEMENT AB Objective. Uterine adenosarcoma (UAS) is a rare gynecologic malignancy and the significance of lymph node metastasis on survival has not been well studied. Methods. A retrospective study was performed utilizing the Surveillance, Epidemiology, End Results Program to examine UAS (n = 994), endometrial stromal sarcoma (ESS, n = 2910), and uterine leiomyosarcoma (LMS, n = 5506) diagnosed between 1973 and 2013. The impact of lymph node metastasis on cause-specific survival (CSS) was cross-compared by multivariable analysis. Systematic literature review was conducted to examine the impact of nodal metastasis on progression-free survival (PFS) in UAS. Results. UAS had the lowest incidence of lymph node metastasis among the sarcoma subtypes examined (UAS 2.9%, LMS 3.4%, and ESS 6.6%, P < 0.001). Lymph node metastasis was independently associated with decreased CSS in all three tumor types (all, P < 0.01); however, magnitudes of statistical significance of lymph node metastasis for CSS were similar across the three tumor types: adjusted-hazard ratio (aHR) for UAS 2.34, ESS 2.43, and LMS 2.10. Systematic literature review identified 230 unique cases of surgically treated UAS. On multivariable analysis, lymph node metastasis (aHR 4.72) had the greatest degree of significance for PFS compared to other tumor factors including sarcomatous overgrowth (aHR 2.88), heterologous elements (aHR 2.08), and deep myometrial invasion (aHR 151). Large tumor, deep myometrial invasion, and sarcomatous overgrowth were associated with increased risk of lymph node metastasis (all, P < 0.05). Conclusion. While uterine adenosarcoma had a low incidence of lymph node metastasis, the impact of lymph node metastasis on survival was comparable to ESS or LMS. (C) 2017 Elsevier Inc. All rights reserved. C1 [Machida, Hiroko; Takiuchi, Tsuyoshi; Adams, Crystal L.; Garcia-Sayre, Jocelyn; Matsuo, Koji] Univ Southern Calif, Div Gynecol Oncol, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Matsuo, Koji] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Nathenson, Michael J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Matsuo, K (reprint author), Univ Southern Calif, Norris Comprehens Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, 2020 Zonal Ave IRD 520, Los Angeles, CA 90089 USA. EM koji.matsuo@med.usc.edu FU Ensign Endowment for Gynecologic Cancer Research FX Ensign Endowment for Gynecologic Cancer Research (K.M.) NR 24 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2017 VL 144 IS 3 BP 524 EP 530 DI 10.1016/j.ygyno.2017.01.012 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EN2PJ UT WOS:000395852100013 PM 28109626 ER PT J AU Goldstone, RN Hasan, SR Drury, S Darragh, TM van Zante, A Goldstone, SE AF Goldstone, Robert N. Hasan, Shirin R. Drury, Steven Darragh, Teresa M. van Zante, Annemieke Goldstone, Stephen E. TI A trial of radiofrequency ablation for anal intraepithelial neoplasia SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Anal cancer; High-grade squamous intraepithelial lesion; Radiofrequency ablation ID HIGH-RESOLUTION ANOSCOPY; SQUAMOUS-CELL CARCINOMA; HIGH-GRADE DYSPLASIA; HIV-POSITIVE MEN; BARRETTS-ESOPHAGUS; MOLECULAR-BIOLOGY; FOLLOW-UP; THERAPY; LESIONS; SEX AB Radiofrequency ablation (RFA) effectively treats esophageal high-grade dysplasia, but its efficacy in treating anal canal high-grade squamous intraepithelial lesions (HSILs) is unsubstantiated. This prospective study assessed the safety and efficacy of applying hemi-circumferential RFA to anal canal HSIL. Twenty-one HIV-negative participants with HSIL occupying ae half the anal canal circumference were treated with hemi-circumferential anal canal RFA. Participants were assessed every 3 months for 12 months with high-resolution anoscopy; recurrence in the treatment zone was re-treated with focal RFA. Twenty-one participants with a mean of 1.7 lesions (range 1-4) enrolled and completed the trial. Six (29 %) participants had recurrent HSIL within the treated hemi-circumference within 1 year. Four participants (19 %) had persistence of an index lesion at 3 months. One (2.9 %) index HSIL persisted again at 12 months. No participants had more than two RFA treatments. KM curve-predicted HSIL-free survival within the treatment zone at 1 year was 76 % (95 % CI 52-89 %). Comparing the first 7 and last 14 participants, the predicted 1-year HSIL-free survivals are 43 % (95 % CI 10-73 %) and 93 % (95 % CI 59-99 %), respectively (p = 0.008), suggesting a learning curve with the treating physician. Multivariable analysis showed decreased recurrence in the last 14 participants (HR 0.02; 95 % CI 0.001-0.63) while increasing BMI increased recurrence (HR 1.43, 95 % CI 1.01-2.01). No participants had device or procedure-related serious adverse events, anal stricture, or heavy bleeding. Hemi-circumferential RFA yielded a high rate of anal HSIL eradication in HIV-negative patients at 1 year with minimal adverse events. Lesion persistence was probably related to incomplete initial ablation. C1 [Goldstone, Robert N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hasan, Shirin R.] Medtronic, Sunnyvale, CA USA. [Drury, Steven] Medtronic, New Haven, CT USA. [Darragh, Teresa M.; van Zante, Annemieke] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Darragh, Teresa M.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Goldstone, Stephen E.] Icahn Sch Med, 420 West 23rd St, New York, NY 10011 USA. RP Goldstone, SE (reprint author), Icahn Sch Med, 420 West 23rd St, New York, NY 10011 USA. EM goldstone.stephen@gmail.com FU Medtronic (Sunnyvale, CA); Medtronic FX The study was sponsored and funded by Medtronic (Sunnyvale, CA). Medtronic provided medical writing assistance and statistical analysis support. SEG and TMD (or their institutions) received research support from Medtronic to conduct this trial. TMD has received supplies from Hologic. SRH and SD are employees and stockholders of Medtronic. SEG received consulting fees from Medtronic. NR 34 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 EI 1432-1262 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD MAR PY 2017 VL 32 IS 3 BP 357 EP 365 DI 10.1007/s00384-016-2679-2 PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA EM0DE UT WOS:000394988200008 ER PT J AU Park, SH Chung, YJ Song, JY Il Kim, S Pepin, D Maclaughlin, DT Donahoe, PK Kim, JH AF Park, Sang Ho Chung, Youn Jee Song, Jae Yen Il Kim, Sang Pepin, David Maclaughlin, David T. Donahoe, Patricia K. Kim, Jang Heub TI Mullerian inhibiting substance inhibits an ovarian cancer cell line via beta-catenin interacting protein deregulation of the Wnt signal pathway SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Mullerian inhibiting substance; anti-Mullerian; hormone; ovarian cancer; Wnt signal pathway; ICAT; CTNNBIP1 protein (beta-catenin interacting protein) ID II RECEPTOR; GROWTH; ENDOMETRIAL; AUTOPHAGY; EXPRESSION; APOPTOSIS; HORMONE; TARGET; GENES; ICAT AB Mfillerian inhibiting substance/anti-Mullerian hormone (MIS/AMH) has been suggested as a biotherapeutic agent in gynecological cancers that highly express the MIS/ AMH type II receptors (MISRII/AMHRII) but the anticancer mechanisms by which MIS/AMH acts are not fully understood. Our experiments show that MIS/AMH inhibits ovarian cancer by deregulating the Wnt signal pathway via the beta-catenin interacting protein (ICAT). MIS/AMH inhibition of ICAT by small interfering RNAs (siRNA) decreased ICAT driven ovarian cancer cell viability as measured by the methylthiazoltetrazolium assay, reversed cell cycle arrest and Annexin V expression and diminished migration by scratch wound assay. Changes in expression of regulatory proteins were shown by western blotting. We determined that MIS/AMH upregulated ICAT in ovarian cancer cell line which caused decreased cell viability, cell cycle arrest and apoptosis. This effect, however, was blocked when ICAT was downregulated by siRNA. The present study demonstrates role for ICAT in MIS/AMH mediated inhibition of the Wnt signaling pathway in ovarian cancer. C1 [Park, Sang Ho; Chung, Youn Jee; Song, Jae Yen; Il Kim, Sang; Pepin, David; Kim, Jang Heub] Catholic Univ Korea, Coll Med, Dept Obstet & Gynecol, Seoul 137140, South Korea. [Maclaughlin, David T.; Donahoe, Patricia K.] Harvard Med Sch, Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. RP Kim, JH (reprint author), Catholic Univ Korea, Dept Obstet & Gynecol, Seoul St Marys Hosp, Coll Med, 505 Banpo Dong, Seoul 137140, South Korea. EM janghkim@catholic.ac.kr NR 34 TC 0 Z9 0 U1 2 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD MAR PY 2017 VL 50 IS 3 BP 1022 EP 1028 DI 10.3892/ijo.2017.3874 PG 7 WC Oncology SC Oncology GA EN7MH UT WOS:000396186400029 PM 28197641 ER PT J AU Boehmer, JP Hariharan, R Devecchi, FG Smith, AL Molon, G Capucci, A An, Q Averina, V Stolen, CM Thakur, PH Thompson, JA Wariar, R Zhang, Y Singh, JP AF Boehmer, John P. Hariharan, Ramesh Devecchi, Fausto G. Smith, Andrew L. Molon, Giulio Capucci, Alessandro An, Qi Averina, Viktoria Stolen, Craig M. Thakur, Pramodsingh H. Thompson, Julie A. Wariar, Ramesh Zhang, Yi Singh, Jagmeet P. TI A Multisensor Algorithm Predicts Heart Failure Events in Patients With Implanted Devices Results From the MultiSENSE Study SO JACC-HEART FAILURE LA English DT Article DE cardiac devices; cardiac resynchronization therapy; decompensation; diagnostics; heart failure; remote monitoring; sensors ID RANDOMIZED CONTROLLED-TRIAL; FLUID STATUS; HOSPITALIZATIONS; ASSOCIATION; ALERTS; RISK AB OBJECTIVES The aim of this study was to develop and validate a device-based diagnostic algorithrh to predict heart failure (HF) events. BACKGROUND HF involves costly hospitalizations with adverse impact on patient outcomes. The authors hypothesized that an algorithm combining a diverse set of implanted device-based sensors chosen to target HF pathophysiology could detect worsening HF. METHODS The MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) study enrolled patients with investigational chronic ambulatory data collection via implanted cardiac resynchronization therapy defibrillators. HF events (HFEs), defined as HF admissions or unscheduled visits with intravenous treatment, were independently adjudicated. The development cohort of patients was used to construct a composite index and alert algorithm (HeartLogic) combining heart sounds, respiration, thoracic impedance, heart rate, and activity; the test cohort was sequestered for independent validation. The 2 coprimary endpoints were sensitivity to detect HFE >40% and unexplained alert rate <2 alerts per patient-year. RESULTS Overall, 900 patients (development cohort, n = 500; test cohort, n = 400) were followed for up to 1 year. Coprimary endpoints were evaluated using 320 patient-years of follow-up data and 50 HFEs in the test cohort (72% men; mean age 66.8 +/- 10.3 years; New York Heart Association functional class at enrollment: 69% in class II, 25% in class III; mean left ventricular ejection fraction 30.0 +/- 11.4%). Both endpoints were significantly exceeded, with sensitivity of 70% (95% confidence interval [CI]: 55.4% to 82.1%) and an unexplained alert rate of 1.47 per patient-year (95% CI: 1.32 to 1.65). The median lead time before HFE was 34.0 days (interquartile range: 19.0 to 66.3 days). CONCLUSIONS The HeartLogic multisensor index and alert algorithm provides a sensitive and timely predictor of impending HF decompensation, (Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices [MultiSENSE]; NCT01128166) (J Am Coll Cardiol HF 2017;5:216-25) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Boehmer, John P.] Penn State Hershey Med Ctr, Hershey, PA USA. [Hariharan, Ramesh] Univ Texas Phys, EP Heart, Houston, TX USA. [Devecchi, Fausto G.] Lutheran Hlth Network, Cardiac Arrhythmia Serv, Ft Wayne, IN USA. [Smith, Andrew L.] Emory Univ, Atlanta, GA 30322 USA. [Molon, Giulio] Sacro Cuore Hosp, Dept Cardiol, Negrar, Italy. [Capucci, Alessandro] Univ Politecn March, Ancona, Italy. [An, Qi; Averina, Viktoria; Stolen, Craig M.; Thakur, Pramodsingh H.; Thompson, Julie A.; Wariar, Ramesh; Zhang, Yi] Boston Sci, St Paul, MN USA. [Singh, Jagmeet P.] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. RP Boehmer, JP (reprint author), Penn State Univ, Heart Failure Program, Coll Med, Penn State Hershey Med Ctr, 500 Univ Dr,H047, Hershey, PA 17033 USA. EM jboehmer@psu.edu FU Boston Scientific; Biotronik; Medtronic; St. Jude Medical FX This study was funded by Boston Scientific. Dr. Boehmer is a consultant for Boston Scientific. Dr. Hariharan has received consultation fees from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical. Dr. Molon is a consultant for Boston Scientific, Medtronic, Sorin, and St. Jude Medical. Dr. Capucci has received honoraria from Abbott, Bayer, Boehringer Ingelheim, Boston Scientific, Pfizer, and Sorin Italia. Drs. An, Averina, Stolen, Thakur, Thompson, Wariar, and Zhang are employees of Boston Scientific. Dr. Singh is a consultant for BackBeat, Biotronik, Boston Scientific, Impulse Dynamics, Livallova, Medtronic, Respicardia, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 18 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD MAR PY 2017 VL 5 IS 3 BP 216 EP 225 DI 10.1016/3.3chf.2016.12.011 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN4IV UT WOS:000395972100011 PM 28254128 ER PT J AU Mounessa, JS Caravaglio, JV Dellavalle, RP AF Mounessa, Jessica S. Caravaglio, Joseph Vincent Dellavalle, Robert P. TI Comparison of Regional and State Differences in Melanoma Rates in the United States: 2003 vs 2013 SO JAMA DERMATOLOGY LA English DT Letter C1 [Mounessa, Jessica S.; Dellavalle, Robert P.] Denver Vet Affairs Med Ctr, Dermatol Serv, 1055 Clermont St,POB 165, Denver, CO 80220 USA. [Mounessa, Jessica S.; Dellavalle, Robert P.] Univ Colorado, Sch Med, Dept Dermatol, Aurora, CO USA. [Caravaglio, Joseph Vincent] Univ Cent Florida, Coll Med, Dept Dermatol, Orlando, FL 32816 USA. RP Dellavalle, RP (reprint author), Denver Vet Affairs Med Ctr, Dermatol Serv, 1055 Clermont St,POB 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD MAR 1 PY 2017 VL 153 IS 3 BP 345 EP 347 DI 10.1001/jamadermatol.2016.4625 PG 4 WC Dermatology SC Dermatology GA EN8JQ UT WOS:000396247100029 PM 28030665 ER PT J AU Romine, PE Kiely, DK Holt, N Percac-Lima, S Leveille, S Bean, JF AF Romine, Perrin E. Kiely, Dan K. Holt, Nicole Percac-Lima, Sanja Leveille, Suzanne Bean, Jonathan F. TI Task-Specific Fatigue Among Older Primary Care Patients SO JOURNAL OF AGING AND HEALTH LA English DT Article DE fatigue; mobility; aged; task performance ID FUNCTIONAL ABILITY; MEANINGFUL CHANGE; ADULTS; TIREDNESS; DISABILITY; MOBILITY; PEOPLE; HEALTH; WOMEN; SCALE AB Objective: Fatigue is a common condition contributing to disability among older patients. We studied self-reported task-specific fatigue and its relation with mobility task performance among community-dwelling primary care patients. Method: Cross-sectional analysis of baseline demographic and health data from a prospective cohort study of 430 primary care patients aged 65 years or older. Fatigue was measured using the Avlund Mobility-Tiredness Scale. Performance tasks included rising from a chair, walking 4 m, and climbing two flights of stairs. Results: Among demographic and health factors, pain was the only attribute consistently predictive of fatigue status. Self-reported chair rise fatigue and walking fatigue were associated with specific task performance. Stair climb fatigue was not associated with stair climb time. Discussion: Pain is strongly associated with fatigue while rising from a chair, walking indoors, and climbing stairs. This study supports the validity of self-reported chair rise fatigue and walking fatigue as individual test items. C1 [Romine, Perrin E.; Leveille, Suzanne; Bean, Jonathan F.] Harvard Med Sch, Brookline, MA USA. [Kiely, Dan K.; Bean, Jonathan F.] Spaulding Rehabil Hosp, Cambridge, MA USA. [Holt, Nicole; Percac-Lima, Sanja] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Leveille, Suzanne] Univ Massachusetts, Boston, MA 02125 USA. [Leveille, Suzanne] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bean, Jonathan F.] New England Geriatr Res Educ & Clin Ctr, Jamaica Plain, MA USA. RP Romine, PE (reprint author), Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. EM Perrin_Romine@hms.harvard.edu RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 FU National Institute on Aging [5 R01 AG032052-03]; National Center for Research Resources, Harvard Clinical and Translational Science Center [1 UL1 RR025758-01]; Center for Primary Care at Harvard Medical School; Harvard Medical School's Scholars in Medicine Office FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Boston RISE is funded by the National Institute on Aging (Grant 5 R01 AG032052-03). This study is also supported by the National Center for Research Resources, Harvard Clinical and Translational Science Center (Grant 1 UL1 RR025758-01). Perrin E. Romine receives funding from the Center for Primary Care at Harvard Medical School as well as Harvard Medical School's Scholars in Medicine Office. NR 33 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 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD MAR PY 2017 VL 29 IS 2 BP 310 EP 323 DI 10.1177/0898264316635567 PG 14 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA EL5QC UT WOS:000394674800007 ER PT J AU Gros, DF Szafranski, DD Shead, SD AF Gros, Daniel F. Szafranski, Derek D. Shead, Sarah D. TI A real world dissemination and implementation of Transdiagnostic Behavior Therapy (TBT) for veterans with affective disorders SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Transdiagnostic Behavior Therapy; TBT; Dissemination; Implementation; Veterans; Veterans Affairs Medical Center ID SOMATIC ANXIETY STICSA; STATE-TRAIT INVENTORY; PRIMARY-CARE; PREVALENCE; FEATURES; TRIAL AB Dissemination and implementation of evidence-based psychotherapies is challenging in real world clinical settings. Transdiagnostic Behavior Therapy (TBT) for affective disorders was developed with dissemination and implementation in clinical settings in mind. The present study investigated a voluntary local dissemination and implementation effort, involving 28 providers participating in a four-hour training on TBT. Providers completed immediate (n = 22) and six-month follow-up (n = 12) training assessments and were encouraged to collect data on their TBT patients (delivery fidelity was not investigated). Findings demonstrated that providers endorsed learning of and interest in using TBT after the training. At six-months, 50% of providers reported using TBT with their patients and their perceived effectiveness of TBT to be very good to excellent. Submitted patient outcome data evidenced medium to large effect sizes. Together, these findings provide preliminary support for the effectiveness of a real world dissemination and implementation of TBT. Published by Elsevier Ltd. C1 [Gros, Daniel F.; Szafranski, Derek D.; Shead, Sarah D.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv, Charleston, SC USA. [Gros, Daniel F.; Szafranski, Derek D.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. RP Gros, DF (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu FU Department of Veteran Affairs Clinical Sciences Research and Development [CX000845] FX This study is supported by Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award CX000845 (PI: Gros). 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 or the United States government. There are no conflicts of interest to disclose. I would like to thank the providers within the Ralph H. Johnson Veterans Affairs Medical Center for their participation in this project. NR 26 TC 2 Z9 2 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD MAR PY 2017 VL 46 BP 72 EP 77 DI 10.1016/j.janxdis.2016.04.010 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EO8VE UT WOS:000396967800009 PM 27158076 ER PT J AU Gillentine, MA Berry, LN Goin-Kochel, RP Ali, MA Ge, J Guffey, D Rosenfeld, JA Hannig, V Bader, P Proud, M Shinawi, M Graham, BH Lin, A Lalani, SR Reynolds, J Chen, M Grebe, T Minard, CG Stankiewicz, P Beaudet, AL Schaaf, CP AF Gillentine, M. A. Berry, L. N. Goin-Kochel, R. P. Ali, M. A. Ge, J. Guffey, D. Rosenfeld, J. A. Hannig, V. Bader, P. Proud, M. Shinawi, M. Graham, B. H. Lin, A. Lalani, S. R. Reynolds, J. Chen, M. Grebe, T. Minard, C. G. Stankiewicz, P. Beaudet, A. L. Schaaf, C. P. TI The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE 15q13.3 microduplication; CHRNA7; Neurodevelopment; Behavior; Autism spectrum disorder ID IDIOPATHIC GENERALIZED EPILEPSY; COPY-NUMBER; GENOMIC DISORDERS; DELETION; 15Q13.3; ASSOCIATION AB Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals. C1 [Gillentine, M. A.; Ali, M. A.; Ge, J.; Rosenfeld, J. A.; Graham, B. H.; Lalani, S. R.; Stankiewicz, P.; Beaudet, A. L.; Schaaf, C. P.] Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA. [Gillentine, M. A.; Ali, M. A.; Schaaf, C. P.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Moursund St,Ste 1325, Houston, TX 77030 USA. [Berry, L. N.; Goin-Kochel, R. P.] Texas Childrens Hosp, Autism Ctr, Houston, TX 77030 USA. [Berry, L. N.; Goin-Kochel, R. P.; Proud, M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Guffey, D.; Minard, C. G.] Baylor Coll Med, Dan L Duncan Inst Clin & Translat Res, Houston, TX 77030 USA. [Hannig, V.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Bader, P.] Northeast Indiana Genet, Ft Wayne, IN USA. [Proud, M.] Texas Childrens Hosp, Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Shinawi, M.] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA. [Lin, A.] Harvard Med Sch, MassGen Hosp Children, Med Genet, Boston, MA USA. [Reynolds, J.] Shodair Childrens Hosp, Med Genet, Helena, MT USA. [Chen, M.] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat Diabet & Endocrinol, Houston, TX 77030 USA. [Grebe, T.] Univ Arizona, Coll Med, Dept Child Hlth, Div Genet & Metab,Phoenix Childrens Hosp, Phoenix, AZ USA. RP Schaaf, CP (reprint author), Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA.; Schaaf, CP (reprint author), Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Moursund St,Ste 1325, Houston, TX 77030 USA. EM schaaf@bcm.edu FU Doris Duke Charitable Foundation [2011034]; IDDRC from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [1U54 HD083092]; National Institute of General Medical Sciences [T32GM008307] FX This work was generously supported by the Doris Duke Charitable Foundation Grant #2011034. The project was supported in part by IDDRC Grant Number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Cores: Tissue culture core, translational core. Miss Gillentine was supported by Grant Number T32GM008307 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. Dr. Schaaf was generously supported by the Joan and Stanford Alexander Family. NR 19 TC 1 Z9 1 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 MAR PY 2017 VL 47 IS 3 BP 549 EP 562 DI 10.1007/s10803-016-2961-8 PG 14 WC Psychology, Developmental SC Psychology GA EO6PQ UT WOS:000396815400003 PM 27853923 ER PT J AU Gillentine, MA Berry, LN Goin-Kochel, RP Ali, MA Ge, J Guffey, D Rosenfeld, JA Hannig, V Bader, P Proud, M Shinawi, M Graham, BH Lin, A Lalani, SR Reynolds, J Chen, M Grebe, T Minard, CG Stankiewicz, P Beaudet, AL Schaaf, CP AF Gillentine, M. A. Berry, L. N. Goin-Kochel, R. P. Ali, M. A. Ge, J. Guffey, D. Rosenfeld, J. A. Hannig, V. Bader, P. Proud, M. Shinawi, M. Graham, B. H. Lin, A. Lalani, S. R. Reynolds, J. Chen, M. Grebe, T. Minard, C. G. Stankiewicz, P. Beaudet, A. L. Schaaf, C. P. TI The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications (vol 47, pg 549, 2017) SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Correction C1 [Gillentine, M. A.; Ge, J.; Rosenfeld, J. A.; Graham, B. H.; Lalani, S. R.; Stankiewicz, P.; Beaudet, A. L.; Schaaf, C. P.] Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA. [Gillentine, M. A.; Ali, M. A.; Schaaf, C. P.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Moursund St,Ste 1325, Houston, TX 77030 USA. [Berry, L. N.; Goin-Kochel, R. P.] Texas Childrens Hosp, Autism Ctr, Houston, TX 77030 USA. [Berry, L. N.; Goin-Kochel, R. P.; Proud, M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Guffey, D.; Minard, C. G.] Baylor Coll Med, Dan L Duncan Inst Clin & Translat Res, Houston, TX 77030 USA. [Hannig, V.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Bader, P.] Northeast Indiana Genet, Ft Wayne, IN USA. [Proud, M.] Texas Childrens Hosp, Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Shinawi, M.] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA. [Lin, A.] Harvard Med Sch, MassGen Hosp Children, Med Genet, Boston, MA USA. [Reynolds, J.] Shodair Childrens Hosp, Med Genet, Helena, MT USA. [Chen, M.] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat Diabet & Endocrinol, Houston, TX 77030 USA. [Grebe, T.] Univ Arizona, Dept Child Hlth, Coll Med, Div Genet & Metab,Phoenix Childrens Hosp, Phoenix, AZ USA. RP Schaaf, CP (reprint author), Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA.; Schaaf, CP (reprint author), Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Moursund St,Ste 1325, Houston, TX 77030 USA. EM schaaf@bcm.edu NR 1 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 MAR PY 2017 VL 47 IS 3 BP 563 EP 563 DI 10.1007/s10803-017-3047-y PG 1 WC Psychology, Developmental SC Psychology GA EO6PQ UT WOS:000396815400004 PM 28168676 ER PT J AU Li, Z Kitanishi, K Twahir, UT Cracan, V Chapman, D Warncke, K Banerjee, R AF Li, Zhu Kitanishi, Kenichi Twahir, Umar T. Cracan, Valentin Chapman, Derrell Warncke, Kurt Banerjee, Ruma TI Cofactor Editing by the G-protein Metallochaperone Domain Regulates the Radical B-12 Enzyme IcmF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METHYLMALONYL-COA MUTASE; CORRINOID-ADENOSYLTRANSFERASE PDUO; COENZYME B-12; LACTOBACILLUS-REUTERI; SALMONELLA-ENTERICA; SUBSTRATE-SPECIFICITY; COMPLEMENTATION GROUP; MECHANISM; CHAPERONE; ATP AB IcmF is a 5 '-deoxyadenosylcobalamin (AdoCbl)-dependent enzyme that catalyzes the carbon skeleton rearrangement of isobutyryl-CoA to butyryl-CoA. It is a bifunctional protein resulting from the fusion of a G-protein chaperone with GTPase activity and the cofactor-and substrate-binding mutase domains with isomerase activity. IcmF is prone to inactivation during catalytic turnover, thus setting up its dependence on a cofactor repair system. Herein, we demonstrate that the GTPase activity of IcmF powers the ejection of the inactive cob(II) alamin cofactor and requires the presence of an acceptor protein, adenosyltransferase, for receiving it. Adenosyltransferase in turn converts cob(II) alamin to AdoCbl in the presence of ATP and a reductant. The repaired cofactor is then reloaded onto IcmF in a GTPase-gated step. The mechanistic details of cofactor loading and offloading from the AdoCbl-dependent IcmF are distinct from those of the better characterized and homologous methylmalonyl-CoA mutase/ G-protein chaperone system. C1 [Li, Zhu; Kitanishi, Kenichi; Cracan, Valentin; Chapman, Derrell; Banerjee, Ruma] Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA. [Twahir, Umar T.; Warncke, Kurt] Emory Univ, Dept Phys, Atlanta, GA 30322 USA. [Kitanishi, Kenichi] Ibaraki Univ, Grad Sch Sci & Engn, Hitachi, Ibaraki 3168511, Japan. [Cracan, Valentin] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Banerjee, R (reprint author), Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA. EM rbanerje@umich.edu FU National Institutes of Health Grant [DK45776] FX This work was supported in part by National Institutes of Health Grant DK45776. 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 41 TC 0 Z9 0 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 MAR PY 2017 VL 292 IS 10 BP 3977 EP 3987 DI 10.1074/jbc.M117.775957 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100003 PM 28130442 ER PT J AU Bonvin, P Gueneau, F Buatois, V Charreton-Galby, M Lasch, S Messmer, M Christen, U Luster, AD Johnson, Z Ferlin, W Kosco-Vilbois, M Proudfoot, A Fischer, N AF Bonvin, Pauline Gueneau, Franck Buatois, Vanessa Charreton-Galby, Maud Lasch, Stanley Messmer, Marie Christen, Urs Luster, Andrew D. Johnson, Zoe Ferlin, Walter Kosco-Vilbois, Marie Proudfoot, Amanda Fischer, Nicolas TI Antibody Neutralization of CXCL10 in Vivo Is Dependent on Binding to Free and Not Endothelial-bound Chemokine IMPLICATIONS FOR THE DESIGN OF A NEW GENERATION OF ANTI-CHEMOKINE THERAPEUTIC ANTIBODIES SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; CARLUMAB CNTO 888; ESCHERICHIA-COLI; HEPARAN-SULFATE; LIGAND 2; T-CELLS; TRAFFICKING; RECEPTORS; OLIGOMERIZATION; INTERLEUKIN-8 AB To improve our understanding of properties that confer successful inhibition of chemokines in vivo, we analyzed antimurine CXCL10 monoclonal antibodies (mAb) having different characteristics. 1B6 displayed potent inhibition of cell recruitment in vitro with an IC50 of 0.5 nM but demonstrated little efficacy in various animal models of human disease. On the contrary, 1P11 showed efficacy in several models of inflammation yet was less potent at inhibiting chemotaxis in vitro with an IC50 of 21 nM. Furthermore, we observed that 1B6 displayed a rapid dosedependent clearance (t1/ 2 1060 h) in contrast to 1F11, which presented a dose-proportional pharmacokinetic profile and a half-life of 12 days. Moreover, 1B6 recognized glycosaminoglycan (GAG)bound CXCL10, resulting in target-mediated clearance, which was corroborated using CXCL10-deficient mice. In contrast to 1B6, 1F11 inhibited the interaction of CXCL10 with GAGs, did not recognize GAG-bound CXCL10, and did not display target-mediated drug disposition. Confirming previous animal studies, 1B6 was poor at reversing glycemia in a model of type 1 diabetes, whereas 1F11 induced early and prolonged control of diabetes. Furthermore, when using 1A4, a subsequently generated anti-mCXCL10 mAb that shares the property with 1F11 of being unable to recognize CXCL10 immobilized on GAG, we observed a similar superior control of diabetes as compared with 1B6. We therefore concluded that targeting chemokines with antibodies such as 1B6 that recognize the more abundant GAG-bound form of the chemokine may not be the optimal strategy to achieve disease control. C1 [Bonvin, Pauline; Gueneau, Franck; Buatois, Vanessa; Charreton-Galby, Maud; Johnson, Zoe; Ferlin, Walter; Kosco-Vilbois, Marie; Proudfoot, Amanda; Fischer, Nicolas] Novimmune SA, Chemin Aulx 14, CH-1228 Geneva, Switzerland. [Lasch, Stanley; Messmer, Marie; Christen, Urs] ZAFES Goethe Univ Hosp Frankfurt, Pharmazentrum Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. [Luster, Andrew D.] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Fischer, N (reprint author), Novimmune SA, Chemin Aulx 14, CH-1228 Geneva, Switzerland. EM nfischer@novimmune.com FU European Union [HEALTH-F4-2011-281608] FX This was supported by Grant HEALTH-F4-2011-281608 (TIMER) from the European Union Seventh Framework Programme (FP7-2007-2013). P. B., F. G., V. B., M. C.-G., Z. J., W. F., M. K.-V., A. P., and N. F. are current or former employees of Novimmune SA. NR 51 TC 0 Z9 0 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 MAR PY 2017 VL 292 IS 10 BP 4185 EP 4197 DI 10.1074/jbc.M116.745877 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100017 PM 28154179 ER PT J AU Lee, AF Ryan, CM Schneider, JC Kazis, LE Li, NC Rose, M Liang, MH Wang, C Palmieri, T Meyer, WJ Pidcock, FS Reilly, D Sheridan, RL Tompkins, RG AF Lee, Austin F. Ryan, Colleen M. Schneider, Jeffrey C. Kazis, Lewis E. Li, Nien Chen Rose, Mary Liang, Matthew H. Wang, Chao Palmieri, Tina Meyer, Walter J., III Pidcock, Frank S. Reilly, Debra Sheridan, Robert L. Tompkins, Ronald G. TI Quantifying Risk Factors for Long-Term Sleep Problems After Burn Injury in Young Adults SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; QUALITY-OF-LIFE; DEPRESSIVE SYMPTOMS; DISTURBANCE; INTENSITY; HEALTH; PAIN; REHABILITATION; CONTRACTURES; ARCHITECTURE AB Restorative sleep is an important component of quality of life. Disturbances in sleep after burn injury were reported but all based on uncontrolled or nonstandardized data. The occurrence and the effect of long-term sleep problems in young adult burn survivors have not been well defined. This 5-year (2003-2008) prospective multicenter longitudinal study included adults with burn injuries ages 19 to 30 years who completed the Young Adult Burn Outcome Questionnaire (YABOQ) up to 36 months after injury. The items measured 15 patient-reported outcomes including physical, psychological, and social statuses and symptoms such as itch and pain. Scores of these 15 YABOQ outcome domains were standardized to a mean of 50 and a SD of 10 based on an age-matched nonburned reference group of young adults. Sleep quality was assessed using the item "How satisfied are you now with your sleep,"rated by a 5-point Likert scale. Patients responding with very and somewhat dissatisfied were classified as having sleep dissatisfaction and the remaining as less or not dissatisfied. The associations between sleep dissatisfaction (yes/no) and YABOQ outcome domains were analyzed longitudinally using mixed-effect generalized linear models, adjusted for %TBSA burned, age, gender, and race. Generalized estimating equations were used to take into account correlated error resulting from repeated surveys on each patient over time. One hundred and fifty-two burn survivors participated in the YABOQ survey at baseline and during the follow-up who had at least one survey with a response to the sleep item. Among them, sleep dissatisfaction was twice as prevalent (76/152, 50%) when compared with the nonburned reference group (29/112, 26%). The likelihood of a burn survivor being dissatisfied with sleep was reduced over time after the burn injury. Sleep dissatisfaction following burns was significantly associated, in a dose-dependent manner, with increasing burn size (P =.001). C1 [Lee, Austin F.] Xian Univ Finance & Econ, Sch Stat, Res Ctr Stat & Actuarial Sci Med, Xian, Peoples R China. [Lee, Austin F.] Univ Int Business & Econ, Sch Insurance & Econ, Beijing, Peoples R China. [Lee, Austin F.; Ryan, Colleen M.; Rose, Mary; Sheridan, Robert L.; Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Lee, Austin F.; Ryan, Colleen M.; Schneider, Jeffrey C.; Liang, Matthew H.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Palmieri, Tina] Bentley Univ, Dept Math Sci, Waltham, MA USA. [Ryan, Colleen M.; Schneider, Jeffrey C.; Palmieri, Tina; Sheridan, Robert L.] Harvard Med Sch, Boston, MA USA. [Ryan, Colleen M.; Meyer, Walter J., III] Shriners Hosp Children Boston, Boston, MA USA. [Schneider, Jeffrey C.] Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Kazis, Lewis E.; Li, Nien Chen; Wang, Chao] Boston Univ Sch Publ Hlth, CAPP, Dept Hlth Policy & Management, Boston, MA USA. [Rose, Mary] Baylor Coll Med, Michael E DeBakey VA Med Ctr, Dept Med Pulmonary Crit Care & Sleep Med, Sleep Disorders Res Ctr, Houston, TX USA. [Liang, Matthew H.] Brigham & Womens Hosp, Harvard Med Sch, Dept Med Rheumatol & Immunol, Boston, MA USA. [Palmieri, Tina] Univ Calif, Dept Surg, Davis, CA USA. [Palmieri, Tina] Shriners Hosp Children Northern Calif, Sacramento, CA USA. [Meyer, Walter J., III] Univ Texas Med Branch, Dept Psychiat, Galveston, TX USA. [Meyer, Walter J., III] Shriners Hosp Children Galveston, Galveston, TX USA. [Pidcock, Frank S.] Johns Hopkins Sch Med, Dept Phys Med & Rehabil, Baltimore, MD USA. [Reilly, Debra] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA. RP Ryan, CM (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA USA.; Ryan, CM (reprint author), Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA.; Ryan, CM (reprint author), Harvard Med Sch, Boston, MA USA.; Ryan, CM (reprint author), Shriners Hosp Children Boston, Boston, MA USA.; Ryan, CM (reprint author), Massachusetts Gen Hosp, Bigelow 1302,55 Fruit St, Boston, MA 02114 USA. EM cryan@mgh.harvard.edu FU Fraser Family Fund of the Massachusetts General Hospital; National Institute on Disability, Independent Living, and Rehabilitation Research [H133A130023, H133A120034]; NIDILRR grant [90DP0055, 90DP0035] FX This work is partially funded by the Fraser Family Fund of the Massachusetts General Hospital and grants from the National Institute on Disability, Independent Living, and Rehabilitation Research (H133A130023 and H133A120034), NIDILRR grant number 90DP0055 and 90DP0035. NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). The contents of this article do not necessarily represent the policy of NIDILRR, ACL, HHS, and the reader should not assume endorsement by the Federal Government. NR 40 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 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD MAR-APR PY 2017 VL 38 IS 2 BP E510 EP E520 DI 10.1097/BCR.0000000000000315 PG 11 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA EN1TS UT WOS:000395793700002 PM 27003738 ER PT J AU Young, AW Graves, C Kowalske, KJ Daphne, AP Md, CMR Sheridan, RL Valenta, A Conlon, KM Jeng, JC Palmieri, T AF Young, Alan W. Graves, Caran Kowalske, Karen J. Daphne, A. Perry Ryan, Colleen M. Sheridan, Robert L. Valenta, Andrea Conlon, Kathe M. Jeng, James C. Palmieri, Tina TI Guideline for Burn Care Under Austere Conditions: Special Care Topics SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID MASS CASUALTY EVENTS; PAIN MANAGEMENT; DEVELOPING-COUNTRIES; SCARCE RESOURCES; PALLIATIVE CARE; CRITICALLY-ILL; PATIENT-CARE; DISASTER; INJURY; MORTALITY C1 [Young, Alan W.] US Army Inst Surg Res, Ft Sam Houston, TX USA. [Graves, Caran; Daphne, A. Perry] Univ Utah, Burn Ctr, Salt Lake City, UT USA. [Kowalske, Karen J.] UT Southwestern Med Ctr, Dallas, TX USA. [Ryan, Colleen M.; Sheridan, Robert L.] Massachusetts Gen Hosp, Boston, MA USA. [Valenta, Andrea] MedStar Washington Hosp Ctr, Washington, DC USA. [Conlon, Kathe M.] St Barnabas Hosp, Livingston, NJ USA. [Jeng, James C.] Mt Sinai Hlth Care Syst, New York, NY USA. [Palmieri, Tina] Univ Calif Davis, Reg Burn Ctr, Sacramento, CA 95817 USA. [Palmieri, Tina] Shriners Hosp Children, Sacramento, CA 95817 USA. RP Palmieri, T (reprint author), Univ Calif Davis, Reg Burn Ctr, Sacramento, CA 95817 USA.; Palmieri, T (reprint author), Shriners Hosp Children, Sacramento, CA 95817 USA. EM palmieri@ucdmc.ucdavis.edu NR 67 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 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD MAR-APR PY 2017 VL 38 IS 2 BP E497 EP E509 DI 10.1097/BCR.0000000000000369 PG 13 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA EN1TS UT WOS:000395793700001 PM 27355657 ER PT J AU Badour, CL Flanagan, JC Gros, DF Killeen, T Pericot-Valverde, I Korte, KJ Allan, NP Back, SE AF Badour, Christal L. Flanagan, Julianne C. Gros, Daniel F. Killeen, Therese Pericot-Valverde, Irene Korte, Kristina J. Allan, Nicholas P. Back, Sudie E. TI Habituation of Distress and Craving During Treatment as Predictors of Change in PTSD Symptoms and Substance Use Severity SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE PTSD; posttraumatic stress disorder; substance use disorders; veterans; prolonged exposure ID POSTTRAUMATIC-STRESS-DISORDER; EXPOSURE THERAPY; ALCOHOL DEPENDENCE; PROLONGED EXPOSURE; LONGITUDINAL DATA; CONTROLLED-TRIAL; INDIVIDUALS; INTERVIEW; EFFICACY AB Objective: Increasing evidence supports the efficacy of trauma-focused exposure therapy in the treatment of posttraumatic stress disorder (PTSD) and co-occurring substance use disorders. Little is known, however, about the mechanisms of change in treatment for patients with PTSD and co-occurring substance use disorders. The aim of the present study was to examine whether within-and between-session habituation of distress and substance craving during imaginal exposure relates to treatment outcomes among U.S. military veterans with PTSD and a co-occurring substance use disorder (N = 54). Method: Veterans received Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure, a manualized integrated treatment combining prolonged exposure with cognitive-behavioral therapy for substance use disorders as part of a larger randomized clinical trial. Self-reported distress and craving ratings were collected during each imaginal exposure session. Results: Data were analyzed using a series of random intercept and slope multilevel linear and generalized linear models. Results revealed that between-session habituation of distress and craving was associated with greater improvement in PTSD symptoms during treatment. Between-session habituation of craving was also associated with a marginally greater reduction in frequency of substance use among participants still reporting use during treatment. Within-session habituation of distress was unrelated to treatment outcome. Conclusion: Together, these findings indicate that habituation in both distress and craving may be important in maximizing treatment outcome for patients with PTSD and comorbid substance use disorders. C1 [Badour, Christal L.] Univ Kentucky, Dept Psychol, 106b Kastle Hall, Lexington, KY 40506 USA. [Flanagan, Julianne C.; Gros, Daniel F.; Killeen, Therese; Back, Sudie E.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Gros, Daniel F.; Back, Sudie E.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv Line, Charleston, SC USA. [Pericot-Valverde, Irene; Allan, Nicholas P.] Univ Oviedo, Dept Psychol, Oviedo, Spain. [Korte, Kristina J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Korte, Kristina J.] Harvard Med Sch, Boston, MA USA. RP Badour, CL (reprint author), Univ Kentucky, Dept Psychol, 106b Kastle Hall, Lexington, KY 40506 USA. EM christal.badour@uky.edu FU National Institute on Drug Abuse (NIDA) [DA030143]; U.S. Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award [CX000845] FX The authors would like to acknowledge support from the National Institute on Drug Abuse (NIDA), Grant DA030143 (to Sudie E. Back), the U.S. Department of Veteran Affairs Clinical Sciences Research and Development Career Development Award CX000845 (principal investigator, Daniel F. Gros), and resources at the Ralph H. Johnson Veterans Affairs Medical Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of NIDA, the U.S. Department of Veterans Affairs, or the U.S. government. NR 27 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD MAR PY 2017 VL 85 IS 3 BP 274 EP 281 DI 10.1037/ccp0000180 PG 8 WC Psychology, Clinical SC Psychology GA EN0SO UT WOS:000395720100009 PM 28221062 ER PT J AU Marcum, ZA Gellad, WF AF Marcum, Zachary A. Gellad, Walid F. TI Improving Medication Adherence: Keep Your Eyes on the Prize SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Marcum, Zachary A.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Gellad, Walid F.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA USA. [Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Univ Dr 151C, Pittsburgh, PA 15240 USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr 151C, Pittsburgh, PA 15240 USA. EM Walid.gellad@pitt.edu FU Agency for Healthcare Research and Quality (AHRQ) [K12HS022982] FX Dr. Marcum is supported by funding from the Agency for Healthcare Research and Quality (AHRQ; K12HS022982). NR 10 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 236 EP 237 DI 10.1007/s11606-016-3927-4 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300003 PM 27848188 ER PT J AU Rollman, BL Belnap, BH Mazumdar, S Abebe, KZ Karp, JF Lenze, EJ Schulberg, HC AF Rollman, Bruce L. Belnap, Bea Herbeck Mazumdar, Sati Abebe, Kaleab Z. Karp, Jordan F. Lenze, Eric J. Schulberg, Herbert C. TI Telephone-Delivered Stepped Collaborative Care for Treating Anxiety in Primary Care: A Randomized Controlled Trial SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; clinical trial; collaborative care; anxiety; depression; mental health ID COGNITIVE-BEHAVIORAL THERAPY; DISORDER SEVERITY SCALE; QUALITY-OF-CARE; PANIC DISORDER; DEPRESSION; HEALTH; MANAGEMENT; VALIDITY; PROTOCOL; IMPROVE AB Collaborative care for depression is more effective in improving treatment outcomes than primary care physicians' (PCPs) usual care (UC). However, few trials of collaborative care have targeted anxiety. To examine the impact and 12-month durability of a centralized, telephone-delivered, stepped collaborative care intervention (CC) for treating anxiety disorders across a network of primary care practices. Randomized controlled trial with blinded outcome assessments. A total of 329 patients aged 18-64 referred by their PCPs in response to an electronic medical record (EMR) prompt. They include 250 highly anxious patients randomized to either CC or to UC, and 79 moderately anxious patients who were triaged to a watchful waiting (WW) cohort and later randomized if their conditions clinically deteriorated. Twelve months of telephone-delivered CC involving non-mental health professionals who provided patients with basic psycho-education, assessed preferences for guideline-based pharmacotherapy, monitored treatment responses, and informed PCPs of their patients' care preferences and progress via the EMR. Mental health-related quality of life ([HRQoL]; SF-36 MCS); secondary outcomes: anxiety (Hamilton Anxiety Rating Scale [SIGH-A], Panic Disorder Severity Scale) and mood (PHQ-9). At 12-month follow-up, highly anxious patients randomized to CC reported improved mental HRQoL (effect size [ES]: 0.38 [95 % CI: 0.13-0.63]; P = 0.003), anxiety (SIGH-A ES: 0.30 [0.05-0.55]; P = 0.02), and mood (ES: 0.45 [0.19-0.71] P = 0.001) versus UC. These improvements were sustained for 12 months among African-Americans (ES: 0.70-1.14) and men (ES: 0.43-0.93). Of the 79 WW patients, 29 % met severity criteria for randomization, and regardless of treatment assignment, WW patients reported fewer anxiety and mood symptoms and better mental HRQoL over the full 24-month follow-up period than highly anxious patients who were randomized at baseline. Telephone-delivered, centralized, stepped CC improves mental HRQoL, anxiety and mood symptoms. These improvements were durable and particularly evident among those most anxious at baseline, and among African-Americans and men. C1 [Rollman, Bruce L.; Belnap, Bea Herbeck; Abebe, Kaleab Z.] Univ Pittsburgh, Sch Med, Ctr Behav Hlth & Smart Technol, Div Gen Internal Med, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. [Mazumdar, Sati] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. [Karp, Jordan F.] Univ Pittsburgh, Sch Med, Dept Psychiat, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. [Karp, Jordan F.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Lenze, Eric J.] Washington Univ, Sch Med, Dept Psychiat, Hlth Mind Lab, St Louis, MO 63110 USA. [Schulberg, Herbert C.] Weill Cornell Med Coll, Dept Psychiat, White Plains, NY USA. RP Rollman, BL (reprint author), Univ Pittsburgh, Sch Med, Ctr Behav Hlth & Smart Technol, Div Gen Internal Med, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. EM rollmanbl@upmc.edu FU National Institute of Mental Health [R01 MH09421, R01 MH093501] FX All work described herein was supported by grants from the National Institute of Mental Health (R01 MH09421 and R01 MH093501). The funding source had no role in the design, conduct, or reporting of our study, or in the preparation, review, or decision to submit this manuscript for publication. NR 41 TC 2 Z9 2 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 245 EP 255 DI 10.1007/s11606-016-3873-1 PG 11 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300008 PM 27714649 ER PT J AU Reddy, A Huseman, TL Canamucio, A Marcus, SC Asch, DA Volpp, K Long, JA AF Reddy, Ashok Huseman, Tiffany L. Canamucio, Anne Marcus, Steven C. Asch, David A. Volpp, Kevin Long, Judith A. TI Patient and Partner Feedback Reports to Improve Statin Medication Adherence: A Randomized Control Trial SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medication adherence; social force; social support; statins ID MYOCARDIAL-INFARCTION; FINANCIAL INCENTIVES; THERAPY; MORTALITY; HEALTH AB Simple nudges such as reminders and feedback reports to either a patient or a partner may facilitate improved medication adherence. To test the impact of a pill bottle used to monitor adherence, deliver a daily alarm, and generate weekly medication adherence feedback reports on statin adherence. Three-month, three-arm randomized clinical trial (ClinicalTrials.gov identifier: NCT02480530). One hundred and twenty-six veterans with known coronary artery disease and poor adherence (medication possession ratio < 80 %). Patients were randomized to one of three groups: (1) a control group (n = 36) that received a pill-monitoring device with no alarms or feedback; (2) an individual feedback group (n = 36) that received a daily alarm and a weekly medication adherence feedback report; and (3) a partner feedback group (n = 54) that received an alarm and a weekly feedback report that was shared with a friend, family member, or a peer. The intervention continued for 3 months, and participants were followed for an additional 3 months after the intervention period. Adherence as measured by pill bottle. Secondary outcomes included change in LDL (mg/dl), patient activation, and social support. During the 3-month intervention period, medication adherence was higher in both feedback arms than in the control arm (individual feedback group 89 %, partner feedback group 86 %, control group 67 %; p < 0.001 and = 0.001). At 6 months, there was no difference in medication adherence between either of the feedback groups and the control (individual feedback 60 %, partner feedback 52 %, control group 54 %; p = 0.75 and 0.97). Daily alarms combined with individual or partner feedback reports improved statin medication adherence. While neither an individual feedback nor partner feedback strategy created a sustainable medication adherence habit, the intervention itself is relatively easy to implement and low cost. C1 [Reddy, Ashok] Univ Washington, Sch Med, Div Gen Internal Med, 1959 NE Pacific St,Suite BB1240,Box 356526, Seattle, WA 98195 USA. [Reddy, Ashok] UW Med Ctr Scholarship Patient Care Qual & Safety, Seattle, WA USA. [Reddy, Ashok] Univ Washington, Sch Med, Dept Med, 1959 NE Pacific St,Suite BB1240,Box 356526, Seattle, WA 98195 USA. [Huseman, Tiffany L.; Canamucio, Anne; Asch, David A.; Volpp, Kevin; Long, Judith A.] Philadelphia VA Med Ctr, VISN Ctr Evaluat PACT 4, Philadelphia, PA USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin; Long, Judith A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asch, David A.; Volpp, Kevin; Long, Judith A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Reddy, A (reprint author), Univ Washington, Sch Med, Dept Med, 1959 NE Pacific St,Suite BB1240,Box 356526, Seattle, WA 98195 USA. EM reddya@uw.edu FU Center for the Evaluation of Patient Aligned Care Teams at the Philadelphia VA FX This work was supported by a grant from the Center for the Evaluation of Patient Aligned Care Teams at the Philadelphia VA. 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 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2017 VL 32 IS 3 BP 256 EP 261 DI 10.1007/s11606-016-3858-0 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300009 PM 27612487 ER PT J AU Hwang, AS Atlas, SJ Hong, J Ashburner, JM Zai, AH Grant, RW Hong, CS AF Hwang, Andrew S. Atlas, Steven J. Hong, Johan Ashburner, Jeffrey M. Zai, Adrian H. Grant, Richard W. Hong, Clemens S. TI Defining Team Effort Involved in Patient Care from the Primary Care Physician's Perspective SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care redesign; psychosocial; health services research; resource allocation; risk adjustment ID CHRONIC NONCANCER PAIN; MANAGEMENT PROGRAM; COMPLEXITY; PAYMENT; MODEL; COMORBIDITY; SPECIALTY; WORKLOAD; OUTCOMES; BURDEN AB A better understanding of the attributes of patients who require more effort to manage may improve risk adjustment approaches and lead to more efficient resource allocation, improved patient care and health outcomes, and reduced burnout in primary care clinicians. To identify and characterize high-effort patients from the physician's perspective. Cohort study. Ninety-nine primary care physicians in an academic primary care network. From a list of 100 randomly selected patients in their panels, PCPs identified patients who required a high level of team-based effort and patients they considered complex. For high-effort patients, PCPs indicated which factors influenced their decision: medical/care coordination, behavioral health, and/or socioeconomic factors. We examined differences in patient characteristics based on PCP-defined effort and complexity. Among 9594 eligible patients, PCPs classified 2277 (23.7 %) as high-effort and 2676 (27.9 %) as complex. Behavioral health issues were the major driver of effort in younger patients, while medical/care coordination issues predominated in older patients. Compared to low-effort patients, high-effort patients were significantly (P < 0.01 for all) more likely to have higher rates of medical (e.g. 23.2 % vs. 6.3 % for diabetes) and behavioral health problems (e.g. 9.8 % vs. 2.9 % for substance use disorder), more frequent primary care visits (10.9 vs. 6.0 visits), and higher acute care utilization rates (25.8 % vs. 7.7 % for emergency department [ED] visits and 15.0 % vs. 3.9 % for hospitalization). Almost one in five (18 %) patients who were considered high-effort were not deemed complex by the same PCPs. Patients defined as high-effort by their primary care physicians, not all of whom were medically complex, appear to have a high burden of psychosocial issues that may not be accounted for in current chronic disease-focused risk adjustment approaches. C1 [Hwang, Andrew S.; Atlas, Steven J.; Ashburner, Jeffrey M.] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Gray Bigelow 730,55 Fruit St, Boston, MA 02114 USA. [Hong, Johan] Stanford Univ, Sch Med, Stanford, CA USA. [Zai, Adrian H.] Massachusetts Gen Hosp, Comp Sci Lab, Gray Bigelow 730,55 Fruit St, Boston, MA 02114 USA. [Grant, Richard W.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Hong, Clemens S.] Los Angeles Cty Dept Hlth Serv, Los Angeles, CA USA. RP Hwang, AS (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Gray Bigelow 730,55 Fruit St, Boston, MA 02114 USA. EM ahwang1@partners.org FU Partners Community Healthcare, Inc.; MGH Primary Care Operations Improvement Program; KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources); KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [KL2 TR001100] FX This study was funded by Partners Community Healthcare, Inc., and by the MGH Primary Care Operations Improvement Program. Dr. Hong was supported by a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100). The funding sources had no involvement in the collection, analysis, or interpretation of the data, or in the decision to submit the manuscript for publication. NR 47 TC 1 Z9 1 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 269 EP 276 DI 10.1007/s11606-016-3897-6 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300011 PM 27770385 ER PT J AU Jasuja, GK Bhasin, S Reisman, JI Hanlon, JT Miller, DR Morreale, AP Pogach, LM Cunningham, FE Park, A Berlowitz, DR Rose, AJ AF Jasuja, Guneet K. Bhasin, Shalender Reisman, Joel I. Hanlon, Joseph T. Miller, Donald R. Morreale, Anthony P. Pogach, Leonard M. Cunningham, Francesca E. Park, Angela Berlowitz, Dan R. Rose, Adam J. TI Who Gets Testosterone? Patient Characteristics Associated with Testosterone Prescribing in the Veteran Affairs System: a Cross-Sectional Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE testosterone; prescribing; patient; predictors ID CARDIOVASCULAR-DISEASE; SEXUAL DYSFUNCTION; OLDER MEN; THERAPY; DEFICIENCY; METAANALYSIS; MORBIDITY; MORTALITY; OBESITY; STROKE AB There has been concern about the growing off-label use of testosterone. Understanding the context within which testosterone is prescribed may contribute to interventions to improve prescribing. To evaluate patient characteristics associated with receipt of testosterone. Cross-sectional. A national cohort of male patients, who had received at least one outpatient prescription within the Veterans Affairs (VA) system during Fiscal Year 2008- Fiscal Year 2012. The study sample consisted of 682,915 non-HIV male patients, of whom 132,764 had received testosterone and a random 10% sample, 550,151, had not. Conditions and medications associated with testosterone prescription. Only 6.3% of men who received testosterone from the VA during the study period had a disorder of the testis, pituitary or hypothalamus associated with male hypogonadism. Among patients without a diagnosed disorder of hypogonadism, the use of opioids and obesity were the strongest predictors of testosterone prescription. Patients receiving > 100 mg/equivalents of oral morphine daily (adjusted odds ratio = 5.75, p < 0.001) and those with body mass index (BMI) > 40 kg/m(2) (adjusted odds ratio = 3.01, p < 0.001) were more likely to receive testosterone than non-opioid users and men with BMI < 25 kg/m(2). Certain demographics (age 40-54, White race), comorbid conditions (sleep apnea, depression, and diabetes), and medications (antidepressants, systemic corticosteroids) also predicted a higher likelihood of testosterone receipt, all with an adjusted odds ratio less than 2 (p < 0.001). In the VA, 93.7% of men receiving testosterone did not have a diagnosed condition of the testes, pituitary, or hypothalamus. The strongest predictors of testosterone receipt (e.g., obesity, receipt of opioids), which though are associated with unapproved, off-label use, may be valid reasons for therapy. Interventions should aim to increase the proportion of testosterone recipients who have a valid indication. C1 [Jasuja, Guneet K.; Reisman, Joel I.; Miller, Donald R.; Berlowitz, Dan R.; Rose, Adam J.] Bedford VA Med Ctr, Ctr Healthcare Org & Implementat Res CHOIR, ENRM VAMC, 200 Springs Rd, Bedford, MA 01730 USA. [Jasuja, Guneet K.; Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Bhasin, Shalender] Harvard Med Sch, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, Boston, MA USA. [Bhasin, Shalender] Harvard Med Sch, Brigham & Womens Hosp, Boston Claude D Pepper Older Amer Independence Ct, Boston, MA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Morreale, Anthony P.] VA Pharm Benefits Management Serv VACO, Clin Pharm Serv, Washington, DC USA. [Morreale, Anthony P.] VA Pharm Benefits Management Serv VACO, Healthcare Serv Res, Washington, DC USA. [Pogach, Leonard M.] New Jersey Healthcare Syst, Ctr Healthcare Knowledge Management, Dept Vet Affairs, E Orange, NJ USA. [Pogach, Leonard M.] Univ Med & Dent New Jersey, New Jersey Med Sch, 185 S Orange Ave, Newark, NJ 07103 USA. [Cunningham, Francesca E.] VA Pharm Benefits Management Serv, Hines, IL USA. [Park, Angela] VA Boston Healthcare Syst, New England Vet Engn Resource Ctr, Boston, MA USA. [Rose, Adam J.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Jasuja, GK (reprint author), Bedford VA Med Ctr, Ctr Healthcare Org & Implementat Res CHOIR, ENRM VAMC, 200 Springs Rd, Bedford, MA 01730 USA. EM guneet.jasuja@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (VA HSRD) Service; VA HSRD [CDA 13-265] FX The research reported/outlined here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development (VA HSR&D) Service. Dr. Jasuja is a VA HSR&D Career Development awardee at the Bedford VA (CDA 13-265). The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs. NR 37 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 304 EP 311 DI 10.1007/s11606-016-3940-7 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300016 PM 27995426 ER PT J AU Payne, B Brzezinski, WA Clark, AV Estrada, CA Kraemer, RR AF Payne, Brittany Brzezinski, Walter A. Clark, Amanda V. Estrada, Carlos A. Kraemer, Ryan R. TI Lessons Learned from a Middle-Aged Man with Testicular Pain: Exercises in Clinical Reasoning SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE clinical reasoning; cognitive error; testicular pain; self-reflection ID POLYARTERITIS-NODOSA; DIAGNOSTIC ERRORS; STRATEGIES C1 [Payne, Brittany; Kraemer, Ryan R.] Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, Birmingham, AL USA. [Brzezinski, Walter A.] Med Univ South Carolina, Charleston, SC USA. [Clark, Amanda V.] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. [Clark, Amanda V.] Case Western Reserve Sch Med, Cleveland, OH USA. [Estrada, Carlos A.; Kraemer, Ryan R.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.; Kraemer, Ryan R.] Univ Alabama Birmingham, 734 Fac Off Tower,510 20th St South, Birmingham, AL 35294 USA. RP Kraemer, RR (reprint author), Univ Alabama Birmingham, 734 Fac Off Tower,510 20th St South, Birmingham, AL 35294 USA. EM rkraemer@uabmc.edu NR 15 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 355 EP 359 DI 10.1007/s11606-016-3882-0 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300024 PM 27778213 ER PT J AU Hunt, SC AF Hunt, Stephen C. TI The Patient on the Long Journey Home SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Hunt, Stephen C.] Univ Washington, Dept Med, VA Puget Sound Hlth Care Syst, OEM Program, 1660 Columbian Way S, Seattle, WA 98108 USA. RP Hunt, SC (reprint author), Univ Washington, Dept Med, VA Puget Sound Hlth Care Syst, OEM Program, 1660 Columbian Way S, Seattle, WA 98108 USA. EM stephen.hunt@va.gov NR 3 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 32 IS 3 BP 366 EP 367 DI 10.1007/s11606-016-3908-7 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300029 PM 27844259 ER PT J AU Frydman, GH Le, A Ellett, F Jorgensen, J Fox, JG Tompkins, RG Irimia, D AF Frydman, Galit H. Le, Anna Ellett, Felix Jorgensen, Julianne Fox, James G. Tompkins, Ronald G. Irimia, Daniel TI Technical Advance: Changes in neutrophil migration patterns upon contact with platelets in a microfluidic assay SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE chemotaxis; platelet-leukocyte aggregate; innate immune system ID TUMOR-NECROSIS-FACTOR; ORGAN DYSFUNCTION; INNATE IMMUNITY; DISSE SPACES; P-SELECTIN; INTERLEUKIN-1; LIPOPOLYSACCHARIDES; TRANSLOCATION; ACCUMULATION; INFLAMMATION AB Neutrophils are traditionally regarded as the "first responders" of the immune system. However, recent observations revealed that platelets often respond earlier to recruit and activate neutrophils within sites of injury and inflammation. Currently, platelet-neutrophil interactions are studied by intravital microscopy. Although such studies provide exceptional, physiologic in vivo data, they are also laborious and have low throughput. To accelerate platelet-neutrophil interaction studies, we have developed and optimized an ex vivo microfluidic platform with which the interactions between platelets and moving neutrophils are measured at single-cell level in precise conditions and with high throughput. With the use of this new assay, we have evaluated changes in neutrophil motility upon direct contact with platelets. Motility changes include longer distances traveled, frequent changes in direction, and faster neutrophil velocities compared with a standard motility response to chemoattractant fMLP. We also found that the neutrophil-platelet direct interactions are transient and mediated by CD62P-CD162 interactions, localized predominantly at the uropod of moving neutrophils. This "crawling," oscillatory neutrophil behavior upon platelet contact is consistent with previous in vivo studies and validates the use of this new test for the exploration of this interactive relationship. C1 [Frydman, Galit H.; Le, Anna; Ellett, Felix; Jorgensen, Julianne; Tompkins, Ronald G.; Irimia, Daniel] Massachusetts Gen Hosp, Dept Surg, BioMEMS Resource Ctr, Ctr Surg Innovat & Bioengn, Boston, MA 02114 USA. [Frydman, Galit H.; Fox, James G.] MIT, Dept Biol Engn, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ellett, Felix; Irimia, Daniel] Shriners Hosp Children, Boston, MA USA. RP Irimia, D (reprint author), Massachusetts Gen Hosp, Dept Surg, BioMEMS Resource Ctr, Ctr Surg Innovat & Bioengn, Boston, MA 02114 USA. EM dirimia@mgh.harvard.edu FU U.S. National Institutes of Health [T32-0D019078-27, P30-ES002109, GM092804, AI113937] FX Financial support was provided by The U.S. National Institutes of Health through grants T32-0D019078-27 and P30-ES002109 (to J.G.F.) and GM092804 and AI113937 (to D.I.). All microfabrication procedures were performed at the BioMEMS Resource Center (EB002503). The authors acknowledge Alyssa Terestre for the final review and editing of this manuscript. NR 32 TC 0 Z9 0 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2017 VL 101 IS 3 BP 797 EP 806 DI 10.1189/jlb.1TA1115-517RR PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA EM7UP UT WOS:000395518100020 PM 27630219 ER PT J AU Diver, E Hinchcliff, E Gockley, A Melamed, A Contrino, L Feldman, S Growdon, W AF Diver, Elisabeth Hinchcliff, Emily Gockley, Allison Melamed, Alexander Contrino, Leah Feldman, Sarah Growdon, Whitfield TI Minimally Invasive Radical Hysterectomy for Cervical Cancer Is Associated With Reduced Morbidity and Similar Survival Outcomes Compared With Laparotomy SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Article DE Cervical cancer; Laparoscopy; Radical hysterectomy; Robotic surgery ID GYNECOLOGIC-ONCOLOGY; SURGERY; LAPAROSCOPY; EXPERIENCE AB Study Objective: To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. Design: Retrospective cohort study (Canadian Task Force classification II-1). Setting: Two academic medical institutions in the United States. Patients: Women undergoing upfront RH for cervical cancer between 2000 and 2013. Intervention: Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL, Measurements and Main Results: A total of 383 women met the eligibility requirements. Of these, 101 underwent an MIS (i.e., traditional laparoscopy, laparoendoscopic single site, or robotic) approach, and 282 underwent an XL approach. Overall survival (median not reached; p =.29) was not different between the 2 groups. Recurrence was rare and equivalent in the 2 groups, affecting 5.0% of patients in the MIS group and 6.4% of those in the XL group (p = .86). Pelvic lymph nodes were dissected in 98% of patients in the MIS group and 97% of those in the XL group (p > .99) and were found to be positive in 10.9% and 8.5% of those patients, respectively (p =.55). The mean number of pelvic lymph nodes retrieved was higher in the MIS group (19.4 vs 16.0; p < .001). There was no between -group difference in the rate of postoperative chemotherapy (p = .32) or radiation therapy (p = .28). Surgical margins were positive in 5.0% of specimens in the MIS group and in 4.6% of specimens in the XL group (p = .54). Although there was no difference in the overall rate of complications (15.1% and 17.2%, respectively; p = .87), laparotomy was associated with a higher median estimated blood loss (EBL) (50 cm(3) vs 500 cm(3)) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 clays; p <.001). Conclusion: MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay. (C) 2016 AAGL. All rights reserved. C1 [Diver, Elisabeth; Melamed, Alexander; Growdon, Whitfield] Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA USA. [Hinchcliff, Emily; Gockley, Allison] Massachusetts Gen Hosp, Brigham & Womens Hosp, Integrated Residency Program Obstet & Gynecol, Boston, MA USA. [Contrino, Leah; Feldman, Sarah] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Contrino, Leah; Feldman, Sarah] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Growdon, W (reprint author), Massachusetts Gen Hosp, Dept Obster & Gynecol, Div Gynecol Oncol, 55 Fruit St,Yawkey Ctr Outpatient Care 9E, Boston, MA 02114 USA. EM wgrowdon@partners.org NR 20 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 1553-4650 EI 1553-4669 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD MAR-APR PY 2017 VL 24 IS 3 BP 402 EP 406 DI 10.1016/j.jmig.2016.12.005 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO6MR UT WOS:000396807700010 PM 28011096 ER PT J AU Lih, CJ Harrington, RD Sims, DJ Harper, KN Bouk, CH Datta, V Yau, J Singh, RR Routbort, MJ Luthra, R Patel, KP Mantha, GS Krishnamurthy, S Ronski, K Walther, Z Finberg, KE Canosa, S Robinson, H Raymond, A Le, LP Mcshane, LM Polley, EC Conley, BA Doroshow, JH Iafrate, AJ Sklar, JL Hamilton, SR Williams, PM AF Lih, Chih-Jian Harrington, Robin D. Sims, David J. Harper, Kneshay N. Bouk, Courtney H. Datta, Vivekananda Yau, Jonathan Singh, Rajesh R. Routbort, Mark J. Luthra, Rajyalakshmi Patel, Keyur P. Mantha, Geeta S. Krishnamurthy, Savitri Ronski, Karyn Walther, Zenta Finberg, Karin E. Canosa, Sandra Robinson, Hayley Raymond, Amelia Le, Long P. Mcshane, Lisa M. Polley, Eric C. Conley, Barbara A. Doroshow, James H. Iafrate, A. John Sklar, Jeffrey L. Hamilton, Stanley R. Williams, P. Mickey TI Analytical Validation of the Next-Generation Sequencing Assay for a Nationwide Signal-Finding Clinical Trial Molecular Analysis for Therapy Choice Clinical Trial SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CHALLENGES; IMPACT AB The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial is a national signal-finding precision medicine study that relies on genomic assays to screen and enroll patients with relapsed or refractory cancer after standard treatments. We report the analytical validation processes for the next-generation sequencing (NGS) assay that was tailored for regulatory compliant use in the trial. The Oncomine Cancer Panel assay and the Personal Genome Machine were used in four networked laboratories accredited for the Clinical Laboratory Improvement Amendments. Using formaLin-fixed paraffin-embedded clinical specimens and cell lines, we found that the assay achieved overall sensitivity of 96.98% for 265 known mutations and 99.99% specificity. High reproducibility in detecting all reportable variants was observed, with a 99.99% mean interoperator pairwise concordance across the four laboratories. The limit of detection for each variant type was 2.8% for single-nucleotide variants, 10.5% for insertion/deletions, 6.8% for large insertion/deletions (gap >= 4 bp), and four copies for gene amplification. The assay system from biopsy collection through reporting was tested and found to be fully fit for purpose. Our results indicate that the NCI-MATCH NGS assay met the criteria for the intended clinical use and that high reproducibility of a complex NGS assay is achievable across multiple clinical laboratories. Our validation approaches can serve as a template for development and validation of other NGS assays for precision medicine. C1 [Lih, Chih-Jian; Harrington, Robin D.; Sims, David J.; Harper, Kneshay N.; Bouk, Courtney H.; Datta, Vivekananda; Williams, P. Mickey] Frederick Natl Lab Canc Res, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Yau, Jonathan; Singh, Rajesh R.; Routbort, Mark J.; Luthra, Rajyalakshmi; Patel, Keyur P.; Mantha, Geeta S.; Krishnamurthy, Savitri; Finberg, Karin E.; Canosa, Sandra; Hamilton, Stanley R.] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX USA. [Ronski, Karyn; Walther, Zenta; Sklar, Jeffrey L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT USA. [Robinson, Hayley; Raymond, Amelia; Le, Long P.; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Mcshane, Lisa M.; Polley, Eric C.; Conley, Barbara A.; Doroshow, James H.] Natl Canc Inst, Div Canc Treatment & Diagnosis, Bethesda, MD USA. RP Williams, PM (reprint author), Frederick Natl Lab Canc Res, Bldg 320,Room 2,1050 Boyles St, Frederick, MD 21702 USA. EM mickey.williams@nih.gov FU NIH grants [HHSN261200800001E, NO1-CO-2008-00001]; Eastern Cooperative Oncology Group-American College of Radiology [1U24CA196172]; ECOG-ACRIN Medical Research Foundation; Frederick F. Becker Distinguished University Chair in Cancer Research from The University of Texas FX Supported by NIH grants HHSN261200800001E and NO1-CO-2008-00001, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group Central Biorepository and Pathology Facility in the Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center grant 1U24CA196172, and the ECOG-ACRIN Medical Research Foundation. S.R.H. is supported by the Frederick F. Becker Distinguished University Chair in Cancer Research from The University of Texas. NR 18 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 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2017 VL 19 IS 2 BP 313 EP 327 DI 10.1016/j.jmoldx.2016.10.007 PG 15 WC Pathology SC Pathology GA EL9DS UT WOS:000394920200013 PM 28188106 ER PT J AU Sylvia, LG Salcedo, S Peters, AT Magalhaes, PVD Frank, E Miklowitz, DJ Otto, MW Berk, M Nierenberg, AA Deckersbach, T AF Sylvia, Louisa G. Salcedo, Stephanie Peters, Amy T. da Silva Magalhaes, Pedro Vieira Frank, Ellen Miklowitz, David J. Otto, Michael W. Berk, Michael Nierenberg, Andrew A. Deckersbach, Thilo TI Do Sleep Disturbances Predict or Moderate the Response to Psychotherapy in Bipolar Disorder? SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Sleep disturbance; insomnia; hypersomnia ID TREATMENT ENHANCEMENT PROGRAM; SOCIAL RHYTHM THERAPY; STEP-BD; INSOMNIA; DEPRESSION; PHARMACOTHERAPY; INDIVIDUALS; MANAGEMENT; ADULTS; TREAT AB This study examined whether sleep disturbance predicted or moderated responses to psychotherapy in participants who participated in STEP-BD, a national, multisite study that examined the effectiveness of different treatment combinations for bipolar disorder. Participants received either a brief psychosocial intervention called collaborative care (CC; n = 130) or intensive psychotherapy (IP; n = 163), with study-based pharmacotherapy. Participants (N = 243) were defined as current (past week) short sleepers (<6 hours/night), normal sleepers (6.5-8.5 hours/night), and long sleepers (>= 9 hours/night), according to reported average nightly sleep duration the week before randomization. Sleep disturbances did not predict the likelihood of recovery nor time until recovery from a depressive episode. There was no difference in recovery rates between IP versus CC for normal sleepers, and medium effect sizes were observed for differences in short and long sleepers. In this study, sleep did not play a major role in predicting or moderating response to psychotherapy in bipolar disorder. C1 [Sylvia, Louisa G.; Nierenberg, Andrew A.; Deckersbach, Thilo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sylvia, Louisa G.; Nierenberg, Andrew A.; Deckersbach, Thilo] Harvard Med Sch, Boston, MA USA. [Salcedo, Stephanie] Univ North Carolina Chapel Hill, Dept Psychol & Neurosci, Chapel Hill, NC USA. [Peters, Amy T.] Univ Illinois, Dept Psychol, Chicago, IL 60680 USA. [da Silva Magalhaes, Pedro Vieira] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Natl Inst Translat Med, Porto Alegre, RS, Brazil. [Frank, Ellen] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Miklowitz, David J.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Otto, Michael W.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Berk, Michael] Deakin Univ, Dept Psychiat, Geelong, Vic, Australia. [Berk, Michael] Univ Melbourne, Dept Psychiat, Melbourne, Vic, Australia. RP Deckersbach, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM tdeckersbach@mgh.harvard.edu FU National Institute of Mental Health [N01MH80001, MH29618, MH43931, MH55101]; National Alliance for Research on Schizophrenia and Depression FX STEP-BD was funded in part by contract N01MH80001 from the National Institute of Mental Health (Gary Sachs). Support for the development of the psychosocial treatments was provided by grants MH29618 (E.F.), MH43931 (D.J.M.), and MH55101 (D.J.M.) from the National Institute of Mental Health and by the National Alliance for Research on Schizophrenia and Depression (D.J.M.). NR 35 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 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAR PY 2017 VL 205 IS 3 BP 196 EP 202 DI 10.1097/NMD.0000000000000579 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EM9WY UT WOS:000395663400007 PM 27660995 ER PT J AU McTaggart, RA Ansari, SA Goyal, M Abruzzo, TA Albani, B Arthur, AJ Alexander, MJ Albuquerque, FC Baxter, B Bulsara, KR Chen, M Almandoz, JED Fraser, JF Frei, D Gandhi, CD Heck, DV Hetts, SW Hussain, MS Kelly, M Klucznik, R Lee, SK Leslie-Mawzi, T Meyers, PM Prestigiacomo, CJ Pride, GL Patsalides, A Starke, RM Sunenshine, P Rasmussen, PA Jayaraman, MV AF McTaggart, Ryan A. Ansari, Sameer A. Goyal, Mayank Abruzzo, Todd A. Albani, Barb Arthur, Adam J. Alexander, Michael J. Albuquerque, Felipe C. Baxter, Blaise Bulsara, Ketan R. Chen, Michael Almandoz, Josser E. Delgado Fraser, Justin F. Frei, Donald Gandhi, Chirag D. Heck, Don V. Hetts, Steven W. Hussain, M. Shazam Kelly, Michael Klucznik, Richard Lee, Seon-Kyu Leslie-Mawzi, Thabele Meyers, Philip M. Prestigiacomo, Charles J. Pride, G. Lee Patsalides, Athos Starke, Robert M. Sunenshine, Peter Rasmussen, Peter A. Jayaraman, Mahesh V. CA Stand Guidelines Comm Soc NeuroInterventional Surg SNIS TI Initial hospital management of patients with emergent large vessel occlusion ( ELVO): report of the standards and guidelines committee of the Society of NeuroInterventional Surgery SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID ACUTE ISCHEMIC-STROKE; RANDOMIZED CONTROLLED-TRIAL; CEREBRAL-ARTERY OCCLUSION; COOPERATIVE ACUTE STROKE; INTRAVENOUS T-PA; COMPUTED-TOMOGRAPHY; ENDOVASCULAR THERAPY; INFARCT VOLUME; CT ANGIOGRAPHY; SYMPTOM ONSET AB Objective To summarize the current literature regarding the initial hospital management of patients with acute ischemic stroke (AIS) secondary to emergent large vessel occlusion (ELVO), and to offer recommendations designed to decrease the time to endovascular treatment (EVT) for appropriately selected patients with stroke. Methods Using guidelines for evidenced-based medicine proposed by the Stroke Council of the American Heart Association, a critical review of all available medical literature supporting best initial medical management of patients with AIS secondary to ELVO was performed. The purpose was to identify processes of care that most expeditiously determine the eligibility of a patient with an acute stroke for interventions including intravenous fibrinolysis with recombinant tissue plasminogen activator (IV tPA) and EVT using mechanical embolectomy. Results This review identifies four elements that are required to achieve timely revascularization in ELVO. (1) In addition to non-contrast CT (NCCT) brain scan, CT angiography should be performed in all patients who meet an institutional threshold for clinical stroke severity. The use of any advanced imaging beyond NCCT should not delay the administration of IV tPA in eligible patients. (2) Activation of the neurointerventional team should occur as soon as possible, based on either confirmation of large vessel occlusion or a prespecified clinical severity threshold. (3) Additional imaging techniques, particularly those intended to physiologically select patients for EVT (CT perfusion and diffusionperfusion mismatch imaging), may provide additional value, but should not delay EVT. (4) Routine use of general anesthesia during EVT procedures, should be avoided if possible. These workflow recommendations apply to both primary and comprehensive stroke centers and should be tailored to meet the needs of individual institutions. Conclusions Patients with ELVO are at risk for severe neurologic morbidity and mortality. To achieve the best possible clinical outcomes stroke centers must optimize their triage strategies. Strategies that provide patients with ELVO with the fastest access to reperfusion depend upon detail-oriented process improvement. C1 [McTaggart, Ryan A.; Jayaraman, Mahesh V.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA. [Ansari, Sameer A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Goyal, Mayank] Univ Calgary, Dept Neurosurg, Calgary, AB, Canada. [Abruzzo, Todd A.] Univ Cincinnati, Dept Neurosurg, Cincinnati, OH USA. [Albani, Barb] Christiana Care Hlth Syst, Dept Neurointervent Surg, Newark, DC USA. [Arthur, Adam J.] Semmes Murphey Clin, Dept Neurosurg, Memphis, TN USA. [Alexander, Michael J.] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA. [Albuquerque, Felipe C.] Barrow Neurol Inst, Dept Neurol Surg, Phoenix, AZ USA. [Baxter, Blaise] Erlanger Med Ctr, Dept Radiol, Chattanooga, TN USA. [Bulsara, Ketan R.] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Chen, Michael] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Almandoz, Josser E. Delgado] Abbott NW Hosp, Dept Intervent Neuroradiol, Minneapolis, MN USA. [Fraser, Justin F.] Univ Kentucky, Dept Neurol Surg, Lexington, KY USA. [Frei, Donald] Radiol Imaging Associates Intervent Neuroradiol, Englewood, CO USA. [Gandhi, Chirag D.] Univ Med & Dent New Jersey, Sch Med, Rutgers Univ New Jersey, Dept Neurol Surg, Newark, NJ USA. [Heck, Don V.] Forsyth Med Ctr, Dept Radiol, Winston Salem, NC USA. [Hetts, Steven W.] UCSF, Dept Radiol, San Francisco, CA USA. [Hussain, M. Shazam] Cleveland Clin, Cerebrovasc Ctr, Cleveland, OH 44106 USA. [Kelly, Michael] Univ Saskatchewan, Royal Univ Hosp, Dept Neurosurg, Saskatoon, SK, Canada. [Klucznik, Richard] Houston Methodist Hosp, Houston Methodist Neurol Inst, Dept Intervent Neuroradiol, Houston, TX USA. [Lee, Seon-Kyu] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Leslie-Mawzi, Thabele] Massachusetts Gen Hosp, Dept Neurointervent Surg, Boston, MA 02114 USA. [Meyers, Philip M.] Columbia Presbyterian Med Ctr, Dept Neurointervent Surg, New York, NY USA. [Pride, G. Lee] UT SouthWestern, Dept Neuroradiol, Dallas, TX USA. [Patsalides, Athos] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Neurol Surg, New York, NY USA. [Starke, Robert M.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA. [Sunenshine, Peter] Banner Good Samaritan Med Ctr, Dept Radiol, Phoenix, AZ USA. RP McTaggart, RA (reprint author), Brown Univ, Warren Alpert Med Sch, Providence, RI 02903 USA. EM ryan.mctaggart@lifespan.org NR 76 TC 5 Z9 5 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAR PY 2017 VL 9 IS 3 BP 316 EP U115 DI 10.1136/neurintsurg-2015-011984 PG 9 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA EL4VF UT WOS:000394618300019 PM 26323793 ER PT J AU Bruner, JM Louis, DN McLendon, R Rosenblum, MK Archambault, WT Most, S Tihan, T AF Bruner, Janet M. Louis, David N. McLendon, Roger Rosenblum, Marc K. Archambault, W. Tad Most, Susan Tihan, Tarik TI The Utility of Expert Diagnosis in Surgical Neuropathology: Analysis of Consultations Reviewed at 5 National Comprehensive Cancer Network Institutions SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Brain tumor; Diagnosis tic accuracy; Diagnostic discrepancies; Expert diagnoses; Neuropathology; Pathology consultation ID HEALTH-ORGANIZATION CLASSIFICATION; 2ND OPINION; CLINICAL IMPACT; PATHOLOGY; DISCREPANCIES; 2ND-OPINION; ISSUES AB The aim of this study was to characterize the type and degree of discrepancies between non-expert and expert diagnoses of CNS tumors to identify the value of consultations in surgical neuropathology. Neuropathology experts from 5 National Comprehensive Cancer Network (NCCN) member institutions participated in the review of 1281 consultations selected based on inclusion criteria. The consultation cases were re-reviewed at the NCCN headquarters to determine concordance with the original diagnoses. Among all consultations, 249 (19.4%) were submitted for expert diagnoses without final diagnoses from the submitting institution. Within the remaining 1032 patients, the serious/ major discrepancy rate was 4.8%, and less serious and minor discrepancies were seen in 19.4% of the cases. The discrepancy rate was higher among patients who were referred to NCCN institutions for consultation compared to those who were referred for treatment only. The discrepancy rates, patient demographics, type of consultations and submitting institutions varied among participating NCCN institutions. Expert consultations identified a subset of cases with significant diagnostic discrepancies, and constituted the initial diagnoses in some cases. These data indicate that expert consultations in glial tumors and all types of pediatric CNS tumors can improve accurate diagnosis and enable appropriate management. C1 [Bruner, Janet M.] MD Anderson Canc Ctr, Houston, TX USA. [Louis, David N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McLendon, Roger] Duke Univ, Med Ctr, Durham, NC USA. [Rosenblum, Marc K.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Archambault, W. Tad] Virtu Stat Ltd, N Wales, PA USA. [Most, Susan] NCCN, Ft Washington, MD USA. [Tihan, Tarik] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Tihan, T (reprint author), UCSF Dept Pathol, Div Neuropathol, Room M551,505 Parnassus Ave, San Francisco, CA 94143 USA. EM tarik.tihan@ucsf.edu NR 17 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 0022-3069 EI 1554-6578 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAR PY 2017 VL 76 IS 3 BP 189 EP 194 DI 10.1093/jnen/nlw122 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EP1NM UT WOS:000397151600003 ER PT J AU Vasudeva, VS Ropper, AE Rodriguez, S Wu, KC Chi, JH AF Vasudeva, Viren S. Ropper, Alexander E. Rodriguez, Samuel Wu, Kyle C. Chi, John H. TI Contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection: a technique for oncological resection of posterolateral spinal tumors SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE spinal tumor; en bloc resection; spinal osteotomy; COPPER; oncology; surgical technique ID QUALITY-OF-LIFE; SURGICAL TECHNIQUE; VERTEBRAL TUMORS; SPONDYLECTOMY; EXPERIENCE; SURGERY; CHONDROSARCOMAS; CHORDOMA; OUTCOMES AB En bloc resection of tumors involving the spinal column is technically challenging and is associated with high morbidity to the patient due to the proximity of critical neurological and vascular structures and the destabilizing nature of this surgery. Nevertheless, evidence has shown improved progression-free survival with en bloc resection for certain low-grade malignant and aggressive benign musculoskeletal tumors. To avoid the morbidity of en bloc spondylectomy in patients with tumors localized to the lateral and posterolateral spinal column, the authors have found that the goals of surgery can be accomplished through a contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection (COPPER). They reviewed their series of 5 patients who underwent successful tumor removal through a COPPER approach. These patients were all found to harbor spinal column tumors involving the posterolateral elements that, based on pathology, would benefit from en bloc resection. Tumor pathology included chondrosarcoma, leiomyosarcoma, osteoblastoma, and liposarcoma. Resections were performed by completing ipsilateral facetectomies above and below the lesion and ipsilateral pedicle osteotomies from a contralateral approach following hemilaminectomy. By disarticulating the posterolateral elements while carefully protecting the thecal sac, the tumors were removed en bloc along with the affected lamina, pedicles, pars interarticularis, and spinous processes, allowing tumor-free margins. This technical report suggests that the COPPER approach is safe and effective for en bloc resection of tumors involving the posterolateral aspect of the spinal column with tumor-free margins and that it eliminates the need for anterior column reconstruction. C1 [Vasudeva, Viren S.; Wu, Kyle C.; Chi, John H.] Brigham & Womens Hosp, Harvard Med Sch, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Ropper, Alexander E.] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA. [Rodriguez, Samuel] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. [Chi, John H.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Chi, JH (reprint author), Brigham & Womens Hosp, Harvard Med Sch, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. EM jchi@partners.org NR 24 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 26 IS 3 BP 275 EP 281 DI 10.3171/2016.8.SPINE16398 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EL9FQ UT WOS:000394925900001 PM 27791830 ER PT J AU Liu, N Wood, KB AF Liu, Ning Wood, Kirkham B. TI Multiple-hook fixation in revision spinal deformity surgery for patients with a previous multilevel fusion mass: technical note and preliminary outcomes SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE multiple-hook fixation; spinal deformity; revision surgery ID ADOLESCENT IDIOPATHIC SCOLIOSIS; FLAT BACK; INSTRUMENTATION; OSTEOTOMY AB OBJECTIVE A previous multilevel fusion mass encountered during revision spinal deformity surgery may obscure anatomical landmarks, making instrumentation unworkable or incurring substantial blood loss and operative time. This study introduced a surgical technique of multiple-hook fixation for fixating previous multilevel fusion masses in revision spinal deformity surgeries and then evaluated its outcomes. METHODS Patients with a previous multilevel fusion mass who underwent revision corrective surgery down to the lumbosacral junction were retrospectively studied. Multiple hooks were used to fixate the fusion mass and linked to distal pedicle screws in the lumbosacral-pelvic complex. Radiological and clinical outcomes were evaluated. RESULTS The charts of 8 consecutive patients with spinal deformity were retrospectively reviewed (7 women, 1 man; mean age 56 years). The primary diagnoses included flat-back deformity (6 cases), thoracolumbar kyphoscoliosis (1 case), and lumbar spondylosis secondary to a previous scoliosis fusion (1 case). The mean follow-up duration was 30.1 months. Operations were performed at T3/4 ilium (4 cases), T7 ilium (1 case), T6 S1 (1 case), T12 S1 (1 case), and T9 L5 (1 case). Of 8 patients, 7 had sagittal imbalance preoperatively, and their mean C-7 plumb line improved from 10.8 2.9 cm preoperatively to 5.3 3.6 cm at final follow-up (p = 0.003). The mean lumbar lordosis of these patients at final follow-up was significantly greater than that preoperatively (35.2 degrees +/- 12.6 degrees vs 16.8 degrees +/- 11.8 degrees, respectively; p = 0.005). Two perioperative complications included osteotomy-related leg weakness in 1 patient and a stitch abscess in another. CONCLUSIONS The multiple-hook technique provides a viable alternative option for fixating a previous multilevel fusion mass in revision spinal deformity surgery. C1 [Liu, Ning; Wood, Kirkham B.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Spine Serv, Boston, MA 02114 USA. [Wood, Kirkham B.] Stanford Univ, Med Ctr, Dept Orthopaed Surg, 450 Broadway St,MC 6342,Pavilion C,4th Fl, Redwood City, CA 94063 USA. [Liu, Ning] Washington Univ, Brown Sch, St Louis, MO USA. RP Wood, KB (reprint author), Stanford Univ, Med Ctr, Dept Orthopaed Surg, 450 Broadway St,MC 6342,Pavilion C,4th Fl, Redwood City, CA 94063 USA. EM kbwood@stanford.edu NR 10 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 26 IS 3 BP 368 EP 373 DI 10.3171/2016.8.SPINE16432 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EL9FQ UT WOS:000394925900014 PM 27935449 ER PT J AU Kwan, T Floyd, CL Kim, S King, PH AF Kwan, Thaddaeus Floyd, Candace L. Kim, Soojin King, Peter H. TI RNA Binding Protein Human Antigen R Is Translocated in Astrocytes following Spinal Cord Injury and Promotes the Inflammatory Response SO JOURNAL OF NEUROTRAUMA LA English DT Article DE glial cell response to injury; inflammation; molecular biological approaches; spinal cord injury ID FACTOR-KAPPA-B; AMYOTROPHIC-LATERAL-SCLEROSIS; TRAUMATIC BRAIN-INJURY; MESSENGER-RNA; HUR; EXPRESSION; CELLS; REGENERATION; MACROPHAGES; ACTIVATION AB Inflammation plays a prominent role in the events following traumatic injury to the central nervous system (CNS). The initial inflammatory response is driven by mediators such as tumor necrosis factor a and interleukin 1 beta, which are produced by activated astrocytes and microglia at the site of injury. These factors are regulated post-transcriptionally by RNA binding proteins (RBP) that interact with adenylate and uridylate-rich elements (ARE) in the 3'-untranslated region of the messenger RNA (mRNA). Human antigen R (HuR) is one of these RBPs and generally functions as a positive regulator of ARE-containing mRNAs. Here, we hypothesized that HuR plays an important role in the induction of cytokine and chemokines in astrocytes following traumatic injury. Using a mouse model of spinal cord injury, we found HuR to be extensively translocated to the cytoplasm in astrocytes at the level of injury, consistent with its activation. In an in vitro stretch injury model of CNS trauma, we observed a similar cytoplasmic shift of HuR in astrocytes and an attenuation of cytokine induction with HuR knockdown. RNA kinetics and luciferase assays suggested that the effect was more related to transcription than RNA destabilization. A small molecule inhibitor of HuR suppressed cytokine induction of injured astrocytes and reduced chemoattraction for neutrophils and microglia. In summary, HuR is activated in astrocytes in the early stages of CNS trauma and positively regulates the molecular response of key inflammatory mediators in astrocytes. Our findings suggest that HuR may be a therapeutic target in acute CNS trauma for blunting secondary tissue injury triggered by the inflammatory response. C1 [Kwan, Thaddaeus; Kim, Soojin; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35487 USA. [Floyd, Candace L.] Univ Alabama Birmingham, Dept Phys Med & Rehabil, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Cell & Integrat Biol, Dept Dev & Integrat Biol, Birmingham, AL 35487 USA. [King, Peter H.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35487 USA. RP King, PH (reprint author), Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35487 USA.; King, PH (reprint author), Univ Alabama Birmingham, Dept Cell & Integrat Biol, Dept Dev & Integrat Biol, Birmingham, AL 35487 USA.; King, PH (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35487 USA. EM phking@uabmc.edu FU UAB Comprehensive Neuroscience Center FX We wish to thank Terry Lewis, PhD, and the UAB Neuroscience Molecular Detection Core Facility (P30 NS47466) for assistance with immunohistochemistry, and Marion Spell and the UAB Center for AIDS Research flow cytometry core for their assistance with FACS analysis. This work was supported by a pilot grant from the UAB Comprehensive Neuroscience Center. NR 58 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2017 VL 34 IS 6 BP 1249 EP 1259 DI 10.1089/neu.2016.4757 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EN7ZR UT WOS:000396221200012 PM 27852147 ER PT J AU Alexander, M Courtois, F AF Alexander, Marcalee Courtois, Frederique TI Blood Pressure during Sexual Activity after Spinal Cord Injury Inaccurately Portrayed SO JOURNAL OF NEUROTRAUMA LA English DT Letter ID AUTONOMIC DYSREFLEXIA; CARDIOVASCULAR-RESPONSES; SPERM RETRIEVAL; MEN; STIMULATION; EJACULATION C1 [Alexander, Marcalee] Birmingham VA Med Ctr, Dept Rehabilitat Med, Birmingham, AL USA. [Alexander, Marcalee] Univ Alabama Birmingham, Med Sch Birmingham, Dept Phys Med & Rehabil, Birmingham, AL USA. [Alexander, Marcalee] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Courtois, Frederique] Univ Quebec Montreal, Fac Sci Humaines, Dept Sexol, CP 8888,Succ,Ctr Ville, Montreal, PQ, Canada. [Courtois, Frederique] Univ Quebec Montreal, Fac Sci Humaines, Dept Psychol, Montreal, PQ, Canada. RP Courtois, F (reprint author), Univ Quebec Montreal, Fac Sci Humaines, Dept Sexol, CP 8888,Succ,Ctr Ville, Montreal, PQ, Canada. EM courtois.frederique@uqam.ca NR 11 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 34 IS 6 BP 1289 EP 1290 DI 10.1089/neu.2016.4810 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EN7ZR UT WOS:000396221200017 PM 27796188 ER PT J AU Rohan, JM Fukuda, T Alderfer, MA Donewar, CW Ewing, L Katz, ER Muriel, AC Vinks, AA Drotar, D AF Rohan, Jennifer M. Fukuda, Tsuyoshi Alderfer, Melissa A. Donewar, Crista Wetherington Ewing, Linda Katz, Ernest R. Muriel, Anna C. Vinks, Alexander A. Drotar, Dennis TI Measuring Medication Adherence in Pediatric Cancer: An Approach to Validation SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE adherence; cancer; metabolites; pediatrics; pharmacology; metabolites ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MERCAPTOPURINE METABOLISM; CHILDREN; NONCOMPLIANCE; NONADHERENCE; RELAPSE; RISK AB Objective This study described the prospective relationship between pharmacological and behavioral measures of 6- mercaptopurine (6MP) medication adherence in amultisite cohort of pediatric patients diagnosed with cancer (N = 139). Methods Pharmacological measures (i.e., metabolite concentrations) assessed 6MP intake. Behavioral measures (e. g., electronic monitoring) described adherence patterns over time. Results Three metabolite profiles were identified across 15 months: one group demonstrated low levels of both metabolites (40.8%) consistent with nonadherence and/or suboptimal therapy; two other groups demonstrated metabolite clusters indicative of adequate adherence (59.2%). Those patients whose metabolite profile demonstrated low levels of both metabolites had consistently lower behavioral adherence rates. Conclusions To our knowledge, thiswas the first study to prospectively validate a pharmacological measure of medication adherence with a behavioral adherence measure in a relatively large sample of pediatric patients with cancer. Using multiple methods of adherencemeasurement could informclinical care and target patients in need of intervention. C1 [Rohan, Jennifer M.; Drotar, Dennis] Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. [Rohan, Jennifer M.; Drotar, Dennis] Cincinnati Childrens Hosp Med Ctr, Ctr Adherence & Self Management, Cincinnati, OH 45229 USA. [Fukuda, Tsuyoshi; Vinks, Alexander A.; Drotar, Dennis] Univ Cincinnati, Sch Med, Dept Pediat, Cincinnati, OH 45221 USA. [Fukuda, Tsuyoshi; Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Alderfer, Melissa A.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA. [Alderfer, Melissa A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Donewar, Crista Wetherington] Childrens Med Ctr Dallas, Ctr Pediat Psychiat, Dallas, TX USA. [Donewar, Crista Wetherington] UT Southwestern Med Ctr, Dallas, TX USA. [Ewing, Linda] Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. [Katz, Ernest R.] Childrens Hosp Los Angeles, Div Gen Pediat, Los Angeles, CA 90027 USA. [Katz, Ernest R.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Muriel, Anna C.] Dana Farber Canc Inst, Div Psychosocial Oncol, Boston, MA 02115 USA. [Muriel, Anna C.] Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Rohan, Jennifer M.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Rohan, Jennifer M.] Harvard Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. [Alderfer, Melissa A.] Nemours Childrens Hlth Syst, Ctr Healthcare Delivery Sci, Delaware, NJ USA. [Alderfer, Melissa A.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Pediat, Philadelphia, PA 19107 USA. RP Rohan, JM (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA.; Rohan, JM (reprint author), Boston Childrens Hosp, Dept Psychiat, Boston, MA USA.; Rohan, JM (reprint author), Harvard Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. EM Jennifer.Rohan@childrens.harvard.edu FU National Cancer Institute at the National Institutes of Health [1F31CA168307, 1R01CA119162]; National Center for Research Resources [UL1RR024134]; National Center for Advancing Translational Sciences [UL1TR000003] FX The work reported in this article was funded by the National Cancer Institute at the National Institutes of Health (grant numbers 1F31CA168307 to J.M.R., 1R01CA119162 to D.D.). This work was also supported by the National Center for Research Resources (grant number UL1RR024134 to M.A.) and the National Center for Advancing Translational Sciences (grant number UL1TR000003 to M.A.). NR 22 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 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD MAR PY 2017 VL 42 IS 2 BP 232 EP 244 DI 10.1093/jpepsy/jsw039 PG 13 WC Psychology, Developmental SC Psychology GA EP2CM UT WOS:000397190600010 ER PT J AU Edersheim, J Murray, ED Padmanabhan, JL Price, BH AF Edersheim, Judith Murray, Evan D. Padmanabhan, Jaya L. Price, Bruce H. TI Protecting the Health and Finances of the Elderly With Early Cognitive Impairment SO JOURNAL OF THE AMERICAN ACADEMY OF PSYCHIATRY AND THE LAW LA English DT Editorial Material ID DECISION-MAKING CAPACITY; ALZHEIMERS ASSOCIATION WORKGROUPS; NURSING-HOME PLACEMENT; NEUROPSYCHIATRIC SYMPTOMS; OLDER-ADULTS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; MEMORY DEFICIT; DISEASE; DEMENTIA AB The projected expansion of the nation's elderly population necessitates the revision of health care and policy strategies for safeguarding the health and assets of this community. The elderly are at greatly increased risk for developing mild cognitive impairment and Alzheimer's disease. These conditions are associated with diminished complex decision-making abilities that adversely affect patients, their families, and society, even during early stages of Alzheimer's disease. We present three composite patient histories that demonstrate problems routinely encountered by families, health care providers, and legal professionals during the course of early AD and MCI. We review the prevalence of cognitive and behavioral symptoms associated with MCI and early AD. Obstacles to early detection of cognitive decline, limitations of current testing modalities and benefits of earlier detection are discussed. Central themes common to medical and judicial approaches toward capacity assessment are discussed. We argue that an emphasis on earlier detection will result in benefits for patient health and result in financial savings to patients and the country as a whole. Finally, we recommend national guidelines for the evaluation of task-specific decision-making capacities to reduce the variability of outcome and improve quality of evaluations found among medical professionals, forensic evaluators, and legal actors. C1 [Edersheim, Judith] Massachusetts Gen Hosp, Ctr Law Brain & Behav, 55 Fruit St, Boston, MA 02114 USA. [Edersheim, Judith] Harvard Med Sch, Psychiat, Boston, MA USA. [Murray, Evan D.] Harvard Med Sch, Traumat Brain Injury Ctr, Manchester VA Med Ctr, Boston, MA USA. [Murray, Evan D.; Price, Bruce H.] Harvard Med Sch, Neurol, Boston, MA USA. [Padmanabhan, Jaya L.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Padmanabhan, Jaya L.] Harvard Med Sch, Boston, MA USA. [Price, Bruce H.] McLean Hosp, Dept Neurol, Boston, MA USA. RP Edersheim, J (reprint author), Massachusetts Gen Hosp, Ctr Law Brain & Behav, 55 Fruit St, Boston, MA 02114 USA. NR 86 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PSYCHIATRY & LAW PI BLOOMFIELD PA ONE REGENCY DR, PO BOX 30, BLOOMFIELD, CT 06002 USA SN 1093-6793 EI 1943-3662 J9 J AM ACAD PSYCHIATRY JI J. Am. Acad. Psychiatry Law PD MAR 1 PY 2017 VL 45 IS 1 BP 81 EP 91 PG 11 WC Law; Psychiatry SC Government & Law; Psychiatry GA EO0KK UT WOS:000396386500012 PM 28270466 ER PT J AU Brink, JA AF Brink, James A. TI Supporting Policy With Evidence SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID PHYSICIANS C1 [Brink, James A.] Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. EM jabrink@partners.org 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2017 VL 14 IS 3 BP 303 EP 304 DI 10.1016/j.jacr.2017.01.005 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EO4BS UT WOS:000396639900001 PM 28259323 ER PT J AU Rehani, B Zhang, YC Gao, KT Giordani, GS Lau, L Rehani, MM Dillon, WP AF Rehani, Bhavya Zhang, Yi C. Gao, Kenneth T. Giordani, Gloria Soto Lau, Lawrence Rehani, Madan M. Dillon, William P. TI Radiology Education in Latin America SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID SIMILARITIES; RESIDENTS C1 [Rehani, Bhavya; Zhang, Yi C.; Gao, Kenneth T.; Dillon, William P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Giordani, Gloria Soto] Clin Alemana Santiago, Dept Radiol, Santiago, Chile. [Rehani, Madan M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Rehani, B (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM Bhavya.rehani@ucsf.edu NR 7 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2017 VL 14 IS 3 BP 397 EP 403 DI 10.1016/j.jacr.2016.10.005 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EO4BS UT WOS:000396639900019 PM 28011158 ER PT J AU Wagholikar, KB Mandel, JC Klann, JG Wattanasin, N Mendis, M Chute, CG Mandl, KD Murphy, SN AF Wagholikar, Kavishwar B. Mandel, Joshua C. Klann, Jeffery G. Wattanasin, Nich Mendis, Michael Chute, Christopher G. Mandl, Kenneth D. Murphy, Shawn N. TI SMART-on-FHIR implemented over i2b2 SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE Database management systems; information storage and retrieval; medical informatics; systems integration; clinical decision support; user-computer interface ID INTEGRATING BIOLOGY; INFORMATION ECONOMY; INFRASTRUCTURE; BEDSIDE AB We have developed an interface to serve patient data from Informatics for Integrating Biology and the Bedside (i2b2) repositories in the Fast Healthcare Interoperability Resources (FHIR) format, referred to as a SMART-on FHIR cell. The cell serves FHIR resources on a per-patient basis, and supports the "substitutable" modular thirdparty applications (SMART) OAuth2 specification for authorization of client applications. It is implemented as an i2b2 server plug-in, consisting of 6 modules: authentication, REST, i2b2-to-FHIR converter, resource enrichment, query engine, and cache. The source code is freely available as open source. We tested the cell by accessing resources from a test i2b2 installation, demonstrating that a SMART app can be launched from the cell that accesses patient data stored in i2b2. We successfully retrieved demographics, medications, labs, and diagnoses for test patients. The SMART-on-FHIR cell will enable i2b2 sites to provide simplified but secure data access in FHIR format, and will spur innovation and interoperability. Further, it transforms i2b2 into an apps platform. C1 [Wagholikar, Kavishwar B.; Klann, Jeffery G.] Massachusetts Gen Hosp, Dept Med, 50 Staniford St,Suite 750, Boston, MA 02114 USA. [Mandel, Joshua C.; Mandl, Kenneth D.] Harvard Med Sch, Dept Biomed Informat, Cambridge, MA USA. [Mandel, Joshua C.; Mandl, Kenneth D.] Boston Childrens Hosp, Computat Hlth Informat Program, Boston, MA USA. [Klann, Jeffery G.] Dept Med, Comp Sci Lab, Boston, MA USA. [Wattanasin, Nich; Mendis, Michael] Partners HealthCare, Res Informat Serv & Comp, Boston, MA USA. [Chute, Christopher G.] Johns Hopkins Univ, Baltimore, MD USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Wagholikar, KB (reprint author), Massachusetts Gen Hosp, Dept Med, 50 Staniford St,Suite 750, Boston, MA 02114 USA. EM kwagholikar@mgh.harvard.edu FU National Library of Medicine [K99LM011575, R00LM011575]; National Institute of General Medical Sciences [R01GM104303] FX This work was supported by National Library of Medicine grant numbers K99LM011575 and R00LM011575, and National Institute of General Medical Sciences grant number R01GM104303. NR 20 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2017 VL 24 IS 2 BP 398 EP 402 DI 10.1093/jamia/ocw079 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA EO9ST UT WOS:000397029100023 ER PT J AU Tabari, A Lo Gullo, R Murugan, V Otrakji, A Digumarthy, S Kalra, M AF Tabari, Azadeh Lo Gullo, Roberto Murugan, Venkatesh Otrakji, Alexi Digumarthy, Subba Kalra, Mannudeep TI Recent Advances in Computed Tomographic Technology: Cardiopulmonary Imaging Applications SO JOURNAL OF THORACIC IMAGING LA English DT Review DE chest computed tomography; cardiopulmonary; advances ID DUAL-ENERGY CT; CORONARY-ARTERY STENOSIS; FILTERED BACK-PROJECTION; RADIATION-DOSE REDUCTION; FRACTIONAL FLOW RESERVE; TOTAL INJECTION VOLUME; LOW TUBE VOLTAGE; ITERATIVE RECONSTRUCTION; CONTRAST MATERIAL; DIAGNOSTIC PERFORMANCE AB Cardiothoracic diseases result in substantial morbidity and mortality. Chest computed tomography (CT) has been an imaging modality of choice for assessing a host of chest diseases, and technologic advances have enabled the emergence of coronary CT angiography as a robust noninvasive test for cardiac imaging. Technologic developments in CT have also enabled the application of dual-energy CT scanning for assessing pulmonary vascular and neoplastic processes. Concerns over increasing radiation dose from CT scanning are being addressed with introduction of more dose-efficient wide-area detector arrays and iterative reconstruction techniques. This review article discusses the technologic innovations in CT and their effect on cardiothoracic applications. C1 [Tabari, Azadeh; Lo Gullo, Roberto; Murugan, Venkatesh; Otrakji, Alexi; Digumarthy, Subba; Kalra, Mannudeep] Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. [Tabari, Azadeh; Lo Gullo, Roberto; Murugan, Venkatesh; Otrakji, Alexi; Digumarthy, Subba; Kalra, Mannudeep] Harvard Med Sch, Boston, MA USA. RP Tabari, A (reprint author), Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. EM atabari@mgh.harvard.edu NR 87 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 0883-5993 EI 1536-0237 J9 J THORAC IMAG JI J. Thorac. Imaging PD MAR PY 2017 VL 32 IS 2 BP 89 EP 100 DI 10.1097/RTI.0000000000000258 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM8BA UT WOS:000395535000003 PM 28221262 ER PT J AU Pacheco, B Alsahafi, N Debbeche, O Prevost, J Ding, SL Chapleau, JP Herschhorn, A Madani, N Princiotto, A Melillo, B Gu, C Zeng, X Mao, YD Smith, AB Sodroski, J Finzi, A AF Pacheco, Beatriz Alsahafi, Nirmin Debbeche, Olfa Prevost, Jeremie Ding, Shilei Chapleau, Jean-Philippe Herschhorn, Alon Madani, Navid Princiotto, Amy Melillo, Bruno Gu, Christopher Zeng, Xin Mao, Youdong Smith, Amos B., III Sodroski, Joseph Finzi, Andres TI Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors SO JOURNAL OF VIROLOGY LA English DT Article DE HIV-1; gp120; intrinsic envelope reactivity; soluble CD4; antibody resistance; HR1; gp41 ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 INNER DOMAIN; AMINO-ACID CHANGES; NEUTRALIZATION-RESISTANT VARIANT; INTERMOLECULAR DISULFIDE BOND; CRYO-EM STRUCTURE; HTLV-III; TRANSMEMBRANE GLYCOPROTEIN; MOLECULAR ARCHITECTURE; ANTIBODY-BINDING AB Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations. IMPORTANCE The development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state. C1 [Pacheco, Beatriz; Alsahafi, Nirmin; Debbeche, Olfa; Prevost, Jeremie; Ding, Shilei; Chapleau, Jean-Philippe; Finzi, Andres] Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ, Canada. [Alsahafi, Nirmin; Finzi, Andres] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Debbeche, Olfa; Prevost, Jeremie; Ding, Shilei; Chapleau, Jean-Philippe; Finzi, Andres] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Pacheco, Beatriz; Herschhorn, Alon; Madani, Navid; Princiotto, Amy; Gu, Christopher; Zeng, Xin; Mao, Youdong; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Melillo, Bruno; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Sodroski, Joseph] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Sodroski, Joseph] Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Pacheco, Beatriz] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. [Zeng, Xin] Williams Coll, Dept Biol, Williamstown, MA 01267 USA. RP Finzi, A (reprint author), Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ, Canada.; Finzi, A (reprint author), McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada.; Finzi, A (reprint author), Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada.; Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Sodroski, J (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA.; Sodroski, J (reprint author), Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. EM joseph_sodroski@dfci.harvard.edu; andres.finzi@umontreal.ca FU National Institutes of Health [AI24755, AI24982, GM56550, AI67854]; International AIDS Vaccine Initiative; Canada Foundation for Innovation Program Leader grant [29866]; CIHR Foundation grant [352417]; phase I of the amfAR Mathilde Krim Fellowship in Basic Biomedical Research [107963-49-RKVA]; phase II of the amfAR Mathilde Krim Fellowship in Basic Biomedical Research [107963-49-RKVA]; Canada Research Chair on Retroviral Entry [950-229930]; King Abdullah scholarship for higher education from the Saudi Government; amfAR [107431-45-RFNT]; NIH [AI090682]; Ragon Institute Innovation Award; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [108501-53-RKNT]; phase II amfAR research grant [109285-58-RKVA] FX This work was supported by grants from the National Institutes of Health (AI24755, AI24982, GM56550, and AI67854), by the International AIDS Vaccine Initiative, by a grant from the late William F. McCarty-Cooper to J.S., by Canada Foundation for Innovation Program Leader grant 29866, and by CIHR Foundation grant 352417 to A. F. A. F. was supported by phases I and II of the amfAR Mathilde Krim Fellowship in Basic Biomedical Research (107963-49-RKVA). A.F. is the recipient of a Canada Research Chair on Retroviral Entry (grant 950-229930). N.A. is the recipient of a King Abdullah scholarship for higher education from the Saudi Government. N.M. was supported by amfAR grant 107431-45-RFNT, NIH grant AI090682, and a Ragon Institute Innovation Award. A.H. is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (108501-53-RKNT) and was also supported by a phase II amfAR research grant (109285-58-RKVA) for independent investigators. NR 89 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 91 IS 5 AR UNSP e02219-16 DI 10.1128/JVI.02219-16 PG 20 WC Virology SC Virology GA EL1BV UT WOS:000394356400030 ER PT J AU Sakai, N Chun, J Duffield, JS Lagares, D Wada, T Luster, AD Tager, AM AF Sakai, Norihiko Chun, Jerold Duffield, Jeremy S. Lagares, David Wada, Takashi Luster, Andrew D. Tager, Andrew M. TI Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor SO KIDNEY INTERNATIONAL LA English DT Article DE CTGF; fibroblast; fibrosis; LPA1 ID SERUM RESPONSE FACTOR; PULMONARY-FIBROSIS; KIDNEY FIBROSIS; TRANSCRIPTION FACTOR; ACTIN DYNAMICS; DIABETIC-NEPHROPATHY; GENE-TRANSCRIPTION; RENAL FIBROSIS; LUNG FIBROSIS; MYOCARDIN AB The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA(1) expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA(1) signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA(1)-deficient (LPA(1)(-/-)) or -sufficient (LPA(1)(+/+)) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I procollagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction -induced increases in renal collagen were significantly, though not completely, attenuated in LPA(1)(-/-)Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA(1)(-/-)Col-GFP mice. LPA-LPA(1) signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardinrelated transcription factor-serum response factor pathway. Proximal tubular epithelial cell-derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum C1 [Sakai, Norihiko; Lagares, David; Luster, Andrew D.; Tager, Andrew M.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Harvard Med Sch, Boston, MA USA. [Sakai, Norihiko; Luster, Andrew D.] Massachusetts Gen Hosp, Harvard Med Sch, Div Rheumatol Allergy & Immunol, Boston, MA USA. [Tager, Andrew M.] Massachusetts Gen Hosp, Fibrosis Res Ctr, Harvard Med Sch, Boston, MA USA. [Lagares, David; Tager, Andrew M.] Massachusetts Gen Hosp, Harvard Med Sch, Div Pulm & Crit Care Med, Boston, MA USA. [Sakai, Norihiko; Wada, Takashi] Kanazawa Univ Hosp, Div Nephrol, Kanazawa, Ishikawa, Japan. [Sakai, Norihiko] Kanazawa Univ Hosp, Div Blood Purificat, Kanazawa, Ishikawa, Japan. [Wada, Takashi] Kanazawa Univ, Inst Med Pharmaceut & Hlth Sci, Dept Lab Med & Nephrol, Kanazawa, Ishikawa, Japan. [Chun, Jerold] Helen L Dorris Inst Neurol & Psychiat Disorders, Scripps Res Inst, Dept Mol Biol, La Jolla, CA USA. [Duffield, Jeremy S.] Univ Washington, Ctr Lung Biol, Dept Med, Div Nephrol, Seattle, WA USA. [Duffield, Jeremy S.] Univ Washington, Inst Stem Cell & Regenerat Med, Washington, DC USA. [Duffield, Jeremy S.] Biogen, Cambridge, MA USA. RP Sakai, N (reprint author), Kanazawa Univ Hosp, Div Nephrol, Div Blood Purificat, Kanazawa, Ishikawa, Japan.; Tager, AM (reprint author), Massachusetts Gen Hosp, Fibrosis Res Ctr, 149 13th St,Room 8301, Charlestown, MA 02129 USA. EM norin0826@yahoo.co.jp; amtager@mgh.harvard.edu FU JSPS Excellent Young Researcher Overseas Visit Program; JSPS [26461218]; NIH [R01-HL095732, R01-HL108975, R01-MH051699, R01-DA019674] FX The authors gratefully acknowledge support from the JSPS Excellent Young Researcher Overseas Visit Program and JSPS Grants-in-Aid for Scientific Research 26461218 to NS, NIH R01-HL095732 and R01-HL108975 to AMT, and NIH R01-MH051699 and R01-DA019674 to JC. The authors also thank B.A. Fontaine, M. Nakamura, and A. Franklin for their expert technical assistance. NR 50 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 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2017 VL 91 IS 3 BP 628 EP 641 DI 10.1016/j.kint.2016.09.030 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA EL9ED UT WOS:000394921400017 PM 27927603 ER PT J AU He, XM Cheng, R Park, K Benyajati, S Moiseyev, G Sun, CY Olson, LE Yang, YH Eby, BK Lau, K Ma, JX AF He, Xuemin Cheng, Rui Park, Kyoungmin Benyajati, Siribhinya Moiseyev, Gennadiy Sun, Chengyi Olson, Lorin E. Yang, Yanhui Eby, Bonnie K. Lau, Kai Ma, Jian-Xing TI Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway SO KIDNEY INTERNATIONAL LA English DT Article DE beta-catenin; fibrosis; inflammation; kidney; oxidative stress; PEDF; renal tubule epithelial cells; renoprotective; Wnt pathway ID RENAL INTERSTITIAL FIBROSIS; CHRONIC KIDNEY-DISEASE; PROXIMAL TUBULAR CELLS; DIABETIC-NEPHROPATHY; OBSTRUCTIVE NEPHROPATHY; MATRIX METALLOPROTEINASE-2; URETERAL OBSTRUCTION; INJURY; EXPRESSION; PATHOGENESIS AB Pigment epithelium-derived factor (PEDF) expression is downregulated in the kidneys of diabetic rats, and delivery of PEDF suppressed renal fibrotic factors in these animals. PEDF has multiple functions including anti-angiogenic, anti-inflammatory and antifibrotic activities. Since the mechanism underlying its antifibrotic effect remains unclear, we studied this in several murine models of renal disease. Renal PEDF levels were significantly reduced in genetic models of type 1 and type 2 diabetes (Akita and db/db, respectively), negatively correlating with Wnt signaling activity in the kidneys. In unilateral ureteral obstruction, an acute renal injury model, there were significant decreases of renal PEDF levels. The kidneys of PEDF knockout mice with ureteral obstruction displayed exacerbated expression of fibrotic and inflammatory factors, oxidative stress, tubulointerstitial fibrosis, and tubule epithelial cell apoptosis, compared to the kidneys of wild-type mice with obstruction. PEDF knockout enhanced Wnt signaling activation induced by obstruction, while PEDF inhibited the Wnt pathway-mediated fibrosis in primary renal proximal tubule epithelial cells. Additionally, oxidative stress was aggravated in renal proximal tubule epithelial cells isolated from knockout mice and suppressed by PEDF treatment of renal proximal tubule epithelial cells. PEDF also reduced oxidation-induced apoptosis in renal proximal tubule epithelial cells. Thus, the renoprotective effects of PEDF are mediated, at least partially, by inhibition of the Wnt pathway. Hence, restoration of renal PEDF levels may have therapeutic potential for renal fibrosis. C1 [He, Xuemin; Cheng, Rui; Benyajati, Siribhinya; Moiseyev, Gennadiy; Ma, Jian-Xing] Univ Oklahoma Hlth Sci Ctr, Coll Med, Dept Physiol, Oklahoma City, OK USA. [Park, Kyoungmin] Harvard Univ, Joslin Diabet Ctr, Harvard Med Sch, Boston, MA USA. [Sun, Chengyi; Olson, Lorin E.] Univ Oklahoma Hlth Sci Ctr, Coll Med, Dept Cell Biol, Oklahoma City, OK USA. [Sun, Chengyi; Olson, Lorin E.] Oklahoma Med Res Fdn, Cardiovas Biol Res Program, Oklahoma City, OK USA. [Yang, Yanhui] Tianjin Med Univ, Tianjin Metab Dis Hosp & Tianjin Inst Endocrinol, Key Lab Hormones & Dev, Tianjin, Peoples R China. [Eby, Bonnie K.; Lau, Kai] Univ Oklahorria Hlth Sci Ctr, Coll Med, Sect Nephrol, Oklahoma City, OK USA. RP Ma, JX (reprint author), 941 Stanton L Young Blvd BSEB 328B, Oklahoma City, OK 73104 USA. EM jian-xing-ma@ouhsc.edu FU NIH [EY012231, EY018659, EY019309, EY016507, GM104934]; American Heart Association [14PRE20460229]; Oklahoma Center for the Advancement of Science Technology [HR13-076, HR16-041]; Rui Cheng's Juvenile Diabetes Research Foundation fellowship [3-PDF-2014-107-A-N] FX We thank Dr. Xiang Wang (Director of the Cell Biology Imaging Facility) and the Diabetes COBRE Imaging Facility at the University of Oklahoma Health Science Center and COBRE Diabetic Animal Core for technical support. This study was supported by NIH grants EY012231, EY018659, EY019309, EY016507, and GM104934; a fellowship from the American Heart Association (14PRE20460229); grants from the Oklahoma Center for the Advancement of Science & Technology (HR13-076 and HR16-041); and a Rui Cheng's Juvenile Diabetes Research Foundation fellowship (3-PDF-2014-107-A-N). NR 63 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2017 VL 91 IS 3 BP 642 EP 657 DI 10.1016/j.kint.2016.09.036 PG 16 WC Urology & Nephrology SC Urology & Nephrology GA EL9ED UT WOS:000394921400018 PM 27914705 ER PT J AU Mendoza, JM Isakova, T Cai, X Bayes, LY Faul, C Scialla, JJ Lash, JP Chen, J He, J Navaneethan, S Negrea, L Rosas, SE Kretzler, M Nessel, L Xie, DW Anderson, AH Raj, DS Wolf, M AF Mendoza, Jair Munoz Isakova, Tamara Cai, Xuan Bayes, Liz Y. Faul, Christian Scialla, Julia J. Lash, James P. Chen, Jing He, Jiang Navaneethan, Sankar Negrea, Lavinia Rosas, Sylvia E. Kretzler, Matthias Nessel, Lisa Xie, Dawei Anderson, Amanda Hyre Raj, Dominic S. Wolf, Myles CA CRIC Study Investigators TI Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE CKD; FGF23; inflammation; mortality ID LEFT-VENTRICULAR HYPERTROPHY; RENAL-INSUFFICIENCY COHORT; GLOMERULAR-FILTRATION-RATE; TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; NF-KAPPA-B; CARDIOVASCULAR EVENTS; HEMODIALYSIS-PATIENTS; PLASMA INTERLEUKIN-6; ALL-CAUSE AB Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships among inflammation, FGF23, and risk of death. Therefore, we conducted a prospective investigation of 3875 participants in the Chronic Renal Insufficiency Cohort (CRIC) study with CKD stages 2 to 4 to test the associations of baseline plasma interleukin-6, high sensitivity C-reactive protein, and FGF23 levels with all cause mortality, censoring at the onset of end-stage renal disease. During a median follow-up of 6.9 years, 550 participants died (20.5/1000 person-years) prior to end stage renal disease. In separate multivariable-adjusted analyses, higher levels of interleukin-6 (hazard ratio per one standard deviation increase of natural log-transformed levels) 1.35 (95% confidence interval, 1.25-1.46), C reactive protein 1.28 (1.16-1.40), and FGF23 1.45 (1.32-1.60) were each independently associated with increased risk of death. With further adjustment for FGF23, the risks of death associated with interleukin-6 and C-reactive protein were minimally attenuated. Compared to participants in the lowest quartiles of inflammation and FGF23, the multivariable-adjusted hazard ratio of death among those in the highest quartiles of both biomarkers was 4.38 (2.65-7.23) for interleukin-6 and FGF23, and 5.54 (3.04-10.09) for C-reactive protein and FGF23. Thus, elevated levels of interleukin-6, C-reactive protein, and FGF23 are independent risk factors for mortality in CKD. C1 [Mendoza, Jair Munoz; Faul, Christian] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Isakova, Tamara; Cai, Xuan; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Nephrol & Hypertens, Chicago, IL 60611 USA. [Isakova, Tamara; Cai, Xuan; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Inst Publ Hlth & Med, Ctr Translat Metab & Hlth, Chicago, IL 60611 USA. [Bayes, Liz Y.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Scialla, Julia J.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Scialla, Julia J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Lash, James P.] Univ Illinois, Dept Med, Nephrol Sect, Chicago, IL USA. [Chen, Jing; He, Jiang] Tulane Sch Med, Dept Med, Sect Nephrol & Hypertens, New Orleans, LA USA. [Navaneethan, Sankar] Baylor Coll Med, Dept Med, Nephrol Sect, Selzman Inst Kidney Hlth, Houston, TX 77030 USA. [Navaneethan, Sankar] Michael E DeBakey VA Med Ctr, Nephrol Sect, Houston, TX USA. [Negrea, Lavinia] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Div Nephrol & Hypertens,Dept Med, Cleveland, OH USA. [Rosas, Sylvia E.] Harvard Med Sch, Beth Israel Deaconess Hosp, Joslin Diabet Ctr, Boston, MA USA. [Kretzler, Matthias] Univ Michigan, Dept Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Nessel, Lisa; Xie, Dawei; Anderson, Amanda Hyre] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Raj, Dominic S.] George Washington Univ, Div Renal Dis & Hypertens, Washington, DC USA. RP Wolf, M (reprint author), 2 Genome Court,Suite 2018, Durham, NC 27705 USA. EM myles.wolf@duke.edu FU Strategically Focused Research Network Center Grant from the American Heart Association; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01 DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health/National Center for Advancing Translational Sciences [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland General Clinic Research Center [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences component of the National Institutes of Health [UL1TR000439]; National Institutes of Health roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1TR000433]; University of Illinois at Chicago Clinical and Translational Science [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute [UL1 RR-024131]; [R01DK081374-S1]; [R01DK080033]; [R01DK073665]; [R01DK081374]; [K24DK093723] FX This study was supported by grants R01DK081374-S1 (to JMM), R01DK080033 (to SER), R01DK073665 (to DSR), R01DK081374 (to MW), K24DK093723 (to MW), and a Strategically Focused Research Network Center Grant from the American Heart Association (to MW).; Funding for the CRIC study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01 DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health/National Center for Advancing Translational Sciences UL1TR000003; Johns Hopkins University UL1 TR-000424; University of Maryland General Clinic Research Center M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health and National Institutes of Health roadmap for Medical Research; Michigan Institute for Clinical and Health Research UL1TR000433; University of Illinois at Chicago Clinical and Translational Science awards program UL1RR029879; Tulane University Translational Research in Hypertension and Renal Biology P30GM103337; and Kaiser Permanente National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute UL1 RR-024131. NR 58 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 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2017 VL 91 IS 3 BP 711 EP 719 DI 10.1016/j.kint.2016.10.021 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EL9ED UT WOS:000394921400025 ER PT J AU Greenwald, JL Cronin, PR Carballo, V Danaei, G Choy, G AF Greenwald, Jeffrey L. Cronin, Patrick R. Carballo, Victoria Danaei, Goodarz Choy, Garry TI A Novel Model for Predicting Rehospitalization Risk Incorporating Physical Function, Cognitive Status, and Psychosocial Support Using Natural Language Processing SO MEDICAL CARE LA English DT Article DE natural language processing; readmission; risk prediction; hospitalized patients; care transitions; hospital discharge ID HOSPITAL READMISSION; MEDICAL PATIENTS; HEART-FAILURE; RATES; CARE AB Background: With the increasing focus on reducing hospital readmissions in the United States, numerous readmissions risk prediction models have been proposed, mostly developed through analyses of structured data fields in electronic medical records and administrative databases. Three areas that may have an impact on readmission but are poorly captured using structured data sources are patients' physical function, cognitive status, and psychosocial environment and support. Objective of the Study: The objective of the study was to build a discriminative model using information germane to these 3 areas to identify hospitalized patients' risk for 30-day all cause readmissions. Research Design: We conducted clinician focus groups to identify language used in the clinical record regarding these 3 areas. We then created a dataset including 30,000 inpatients, 10,000 from each of 3 hospitals, and searched those records for the focus groupderived language using natural language processing. A 30-day readmission prediction model was developed on 75% of the dataset and validated on the other 25% and also on hospital specific subsets. Results: Focus group language was aggregated into 35 variables. The final model had 16 variables, a validated C-statistic of 0.74, and was well calibrated. Subset validation of the model by hospital yielded C-statistics of 0.70-0.75. Conclusions: Deriving a 30-day readmission risk prediction model through identification of physical, cognitive, and psychosocial issues using natural language processing yielded a model that per-forms similarly to the better performing models previously published with the added advantage of being based on clinically relevant factors and also automated and scalable. Because of the clinical relevance of the variables in the model, future research may be able to test if targeting interventions to identified risks results in reductions in readmissions. C1 [Greenwald, Jeffrey L.] Massachusetts Gen Hosp, Core Educator Fac, Dept Med, 50 Staniford St,Suite 503b, Boston, MA 02114 USA. [Cronin, Patrick R.] Massachusetts Gen Hosp, Lab Comp Sci, Boston, MA 02114 USA. [Carballo, Victoria] Partners HealthCare, Needham, MA USA. [Danaei, Goodarz] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Danaei, Goodarz] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Choy, Garry] Massachusetts Gen Hosp, QPID Informat, Boston, MA 02114 USA. [Choy, Garry] Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02114 USA. RP Greenwald, JL (reprint author), Massachusetts Gen Hosp, Core Educator Fac, Dept Med, 50 Staniford St,Suite 503b, Boston, MA 02114 USA. EM jlgreenwald@partners.org FU Partners HealthCare High Performance Team IV Readmissions Committee FX Supported by the Partners HealthCare High Performance Team IV Readmissions Committee. 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2017 VL 55 IS 3 BP 261 EP 266 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL3GD UT WOS:000394506700009 PM 27632767 ER PT J AU Burke, RE Schnipper, JL Williams, MV Robinson, EJ Vasilevskis, EE Kripalani, S Metlay, JP Fletcher, GS Auerbach, AD Donze, JD AF Burke, Robert E. Schnipper, Jeffrey L. Williams, Mark V. Robinson, Edmondo J. Vasilevskis, Eduard E. Kripalani, Sunil Metlay, Joshua P. Fletcher, Grant S. Auerbach, Andrew D. Donze, Jacques D. TI The HOSPITAL Score Predicts Potentially Preventable 30-Day Readmissions in Conditions Targeted by the Hospital Readmissions Reduction Program SO MEDICAL CARE LA English DT Article DE patient readmission; score; risk factors; transition of care ID ROOT CAUSE ANALYSES; REDUCING READMISSIONS; CARE; INTERVENTIONS; REHOSPITALIZATION; TRANSITIONS; PERFORMANCE; VALIDATION; FRAMEWORK; TRANSFERS AB Background/Objectives: New tools to accurately identify potentially preventable 30-day readmissions are needed. The HOSPITAL score has been internationally validated for medical inpatients, but its performance in select conditions targeted by the Hospital Readmission Reduction Program (HRRP) is unknown. Design: Retrospective cohort study. Setting: Six geographically diverse medical centers. Participants/Exposures: All consecutive adult medical patients discharged alive in 2011 with 1 of the 4 medical conditions targeted by the HRRP (acute myocardial infarction, chronic obstructive pulmonary disease, pneumonia, and heart failure) were included. Potentially preventable 30-day readmissions were identified using the SQLape algorithm. The HOSPITAL score was calculated for all patients. Measurements: A multivariable logistic regression model accounting for hospital effects was used to evaluate the accuracy (Brier score), discrimination (c-statistic), and calibration (Pearson goodness-of-fit) of the HOSPITAL score for each 4 medical conditions. Results: Among the 9181 patients included, the overall 30-day potentially preventable readmission rate was 13.6%. Across all 4 diagnoses, the HOSPITAL score had very good accuracy (Brier score of 0.11), good discrimination (c-statistic of 0.68), and excellent calibration (Hosmer-Lemeshow goodness-of-fit test, P=0.77). Within each diagnosis, performance was similar. In sensitivity analyses, performance was similar for all readmissions (not just potentially preventable) and when restricted to patients age 65 and above. Conclusions: The HOSPITAL score identifies a high-risk cohort for potentially preventable readmissions in a variety of practice settings, including conditions targeted by the HRRP. It may be a valuable tool when included in interventions to reduce readmissions within or across these conditions. C1 [Burke, Robert E.] Univ Colorado, Sch Med, Div Gen Internal Med, Dept Med, Aurora, CO USA. [Schnipper, Jeffrey L.; Donze, Jacques D.] Brigham & Womens Hosp, Div Gen Med, BWH Hospitalist Serv, Boston, MA 02115 USA. [Schnipper, Jeffrey L.; Donze, Jacques D.] Harvard Med Sch, Boston, MA USA. [Williams, Mark V.] Univ Kentucky, Coll Med, Ctr Hlth Serv Res, Lexington, KY USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Value Inst, Wilmington, DE USA. [Vasilevskis, Eduard E.; Kripalani, Sunil] Vanderbilt Univ, Div Gen Internal Med & Publ Hlth, Sect Hosp Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Vasilevskis, Eduard E.] VA Tennessee Valley, Geriatr Res Educ & Clin Ctr GRECC, Nashville, TN USA. [Kripalani, Sunil] Vanderbilt Univ, Ctr Clin Qual & Implementat Res, 221 Kirkland Hall, Nashville, TN 37235 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Fletcher, Grant S.] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98104 USA. [Auerbach, Andrew D.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Donze, Jacques D.] Univ Hosp Bern, Div Gen Internal Med, Bern, Switzerland. RP Burke, RE (reprint author), Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM robert.burke5@va.gov FU VA [HX-1796]; NIH/NIA [R03AG050885]; National Institutes of Health [K23AG040157]; Geriatric Research, Education and Clinical Center (GRECC); Swiss National Science Foundation; Swiss Foundation for Medical-Biological Scholarships; Sanofi Aventis FX R.E.B. is supported by the VA (Career Development Award HX-1796) and NIH/NIA (R03AG050885). E.E.V. is supported by the National Institutes of Health (K23AG040157) and the Geriatric Research, Education and Clinical Center (GRECC). J.D.D. was supported by the Swiss National Science Foundation and the Swiss Foundation for Medical-Biological Scholarships. The content of this article is that of the authors and does not necessarily reflect the views of the Department of Veterans Affairs or National Institutes of Health.; J.L.S. has received grant funding from Sanofi Aventis for an investigator-initiated study to design and evaluate an intensive discharge and follow-up intervention in patients with diabetes. The remaining authors declare no conflict of interest. NR 34 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2017 VL 55 IS 3 BP 285 EP 290 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL3GD UT WOS:000394506700012 PM 27755392 ER PT J AU Cochran, G Gordon, AJ Lo-Ciganic, WH Gellad, WF Frazier, W Lobo, C Chang, CCH Zheng, P Donohue, JM AF Cochran, Gerald Gordon, Adam J. Lo-Ciganic, Wei-Hsuan Gellad, Walid F. Frazier, Winfred Lobo, Carroline Chang, Chung-Chou H. Zheng, Ping Donohue, Julie M. TI An Examination of Claims-based Predictors of Overdose from a Large Medicaid Program SO MEDICAL CARE LA English DT Article DE opioid medication overdose; health claims; opioid medication misuse and abuse ID PRESCRIPTION OPIOID ABUSE; UNITED-STATES; CHRONIC PAIN; PRESCRIBING PATTERNS; IDENTIFY PATIENTS; RISK; DEATHS; MISUSE; CARE; INTERVENTIONS AB Background: Health systems may play an important role in identification of patients at-risk of opioid medication overdose. However, standard measures for identifying overdose risk in administrative data do not exist. Objective: Examine the association between opioid medication overdose and 2 validated measures of nonmedical use of prescription opioids within claims data. Research Design: A longitudinal retrospective cohort study that estimated associations between overdose and nonmedical use. Subjects: Adult Pennsylvania Medicaid program 2007-2012 patients initiating opioid treatment who were: nondual eligible, without cancer diagnosis, and not in long-term care facilities or receiving hospice. Measures: Overdose (International Classification of Disease, ninth edition, prescription opioid poisonings codes), opioid abuse (opioid use disorder diagnosis while possessing an opioid prescription), opioid misuse (a composite indicator of number of opioid prescribers, number of pharmacies, and days supplied), and dose exposure during opioid treatment episodes. Results: A total of 372,347 Medicaid enrollees with 583,013 new opioid treatment episodes were included in the cohort. Opioid overdose was higher among those with abuse (1.5%) compared with those without (0.2%, P<0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%) misuse compared with those without (0.2%, P<0.001). Abuse [adjusted rate ratio (ARR), 1.52; 95% confidence interval (CI), 1.10-2.10), probable misuse (ARR, 1.98; 95% CI, 1.46-2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48-2.09) were associated with significantly more events of opioid medication overdose compared with those without. Conclusions: Claims-based measures can be used by health systems to identify individuals at-risk of overdose who can be targeted for restrictions on opioid prescribing, dispensing, or referral to treatment. C1 [Cochran, Gerald] Univ Pittsburgh, Sch Social Work, 4200 Forbes Ave,2117 CL, Pittsburgh, PA 15260 USA. [Cochran, Gerald] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Cochran, Gerald; Gordon, Adam J.; Gellad, Walid F.; Donohue, Julie M.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA USA. [Gordon, Adam J.; Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gordon, Adam J.; Gellad, Walid F.; Frazier, Winfred] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Lo-Ciganic, Wei-Hsuan] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Lobo, Carroline; Chang, Chung-Chou H.; Zheng, Ping; Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Cochran, G (reprint author), Univ Pittsburgh, Sch Social Work, 4200 Forbes Ave,2117 CL, Pittsburgh, PA 15260 USA. EM gcochran@pitt.edu FU Centers for Disease Control and Prevention [U01CE002496] FX G.C., J.M.D, A.J.G., and W.F.G. are supported by a grant from the Centers for Disease Control and Prevention (U01CE002496). The remaining authors declare no conflict of interest. NR 49 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2017 VL 55 IS 3 BP 291 EP 298 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL3GD UT WOS:000394506700013 PM 27984346 ER PT J AU Linsky, A Simon, SR Stolzmann, K Meterko, M AF Linsky, Amy Simon, Steven R. Stolzmann, Kelly Meterko, Mark TI Patient Perceptions of Deprescribing Survey Development and Psychometric Assessment SO MEDICAL CARE LA English DT Article DE survey research; deprescribing; shared-decision making; medication safety ID ADVERSE DRUG EVENTS; DECISION-MAKING; RANDOMIZED-TRIAL; GENERAL-PRACTICE; HEALTH BELIEFS; MEDICATION; PREFERENCES; CARE; POLYPHARMACY; MEDICINES AB Background: Although clinicians ultimately decide when to discontinue (deprescribe) medications, patients' perspectives may guide the process. Objectives: To develop a survey instrument that assesses patients' experience with and attitudes toward deprescribing. Research Design: We developed a questionnaire with established and newly created items. We used exploratory factor analysis and confirmatory factor analysis (EFA and CFA) to assess the psychometric properties. Subjects: National sample of 1547 Veterans Affairs patients prescribed Z5 medications. Measures: In the EFA, percent variance, a scree plot, and conceptual coherence determined the number of factors. In the CFA, proposed factor structures were evaluated using standardized root mean square residual, root mean square error of approximation, and comparative fit index. Results: Respondents (n = 790; 51% response rate) were randomly assigned to equal derivation and validation groups. EFA yielded credible 4-factor and 5-factor models. The 4 factors were "Medication Concerns," "Provider Knowledge," "Interest in Stop-ping Medicines," and "Unimportance of Medicines." The 5-factor model added "Patient Involvement in Decision-Making." In the CFA, a modified 5-factor model, with 2 items with marginal loadings moved based upon conceptual fit, had an standardized root mean square residual of 0.06, an RMSEA of 0.07, and a CFI of 0.91. The new scales demonstrated internal consistency reliability, with Cronbach alpha's of: Concerns, 0.82; Provider Knowledge, 0.86; Interest, 0.77; Involvement, 0.61; and Unimportance, 0.70. Conclusions: The Patient Perceptions of Deprescribing questionnaire is a novel, multidimensional instrument to measure patients' attitudes and experiences related to medication discontinuation that can be used to determine how to best involve patients in deprescribing decisions. C1 [Linsky, Amy; Simon, Steven R.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. [Linsky, Amy; Simon, Steven R.; Stolzmann, Kelly] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Linsky, Amy; Simon, Steven R.; Stolzmann, Kelly] ENRM Vet Affairs Med Ctr, Boston, MA USA. [Linsky, Amy; Simon, Steven R.; Stolzmann, Kelly] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Linsky, Amy; Simon, Steven R.; Stolzmann, Kelly] ENRM Vet Affairs Med Ctr, Bedford, MA USA. [Linsky, Amy; Simon, Steven R.] Boston Med Ctr, Sect Gen Internal Med, Boston, MA USA. [Meterko, Mark] VHA Off Analyt & Business Intelligence, Performance Measurement, Bedford, MA USA. [Meterko, Mark] Boston Univ, Sch Publ Hlth, Hlth Law Policy & Management, Boston, MA USA. RP Linsky, A (reprint author), VA Boston Healthcare Syst, Gen Internal Med 152G, 150 S Huntington Ave, Boston, MA 02130 USA. EM amy.linsky@va.gov FU Department of Veterans Affairs (VA), Veterans Health Administration, Health Services Research and Development Career Development Award [CDA12-166] FX A.L. was supported by a Department of Veterans Affairs (VA), Veterans Health Administration, Health Services Research and Development Career Development Award (CDA12-166), and the study was conducted using resources of the VA Boston Healthcare 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. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; nor the decision to submit the manuscript for publication. NR 34 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2017 VL 55 IS 3 BP 306 EP 313 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL3GD UT WOS:000394506700015 PM 27579916 ER PT J AU Hernandez-Tejada, MA Acierno, R Sanchez-Carracedo, D AF Hernandez-Tejada, Melba A. Acierno, Ron Sanchez-Carracedo, David TI Addressing Dropout From Prolonged Exposure: Feasibility of Involving Peers During Exposure Trials SO MILITARY PSYCHOLOGY LA English DT Article DE PTSD; peer; social support; dropout; Prolonged Exposure therapy ID POSTTRAUMATIC-STRESS-DISORDER; PTSD TREATMENT; SERVICE; CARE AB Posttraumatic stress disorder ( PTSD) is a significant problem for combat veterans. Fortunately, effective treatments, such as Prolonged Exposure ( PE), are available and widely disseminated in the Veterans Affairs ( VA) health-care system. Nonetheless, despite well-documented effectiveness, attrition remains high at approximately 30% across evidence-based interventions. Early studies indicated that dropout was largely related to stigma and logistical barriers ( e. g., travel time and cost). However, research demonstrates that eliminating these logistical and stigma-based barriers ( e. g., through home-based telemedicine) has little effect on dropout. We surveyed 82 veterans who dropped out of PE treatment regarding reasons for leaving treatment. Approximately half indicated that in vivo homework assignments caused significant problems, and when asked to consider the possibility of peer support during in vivo exposure assignments, 52% indicated that they would consider returning to treatment with such assistance. In response to this feedback, we constructed an in vivo therapy peer support program wherein peers are directly involved with in vivo exposure exercises. The following brief report presents the rationale for, outline of, and initial feasibility data supporting this program to enhance both return to, and completion of, exposure therapy treatment for PTSD. C1 [Hernandez-Tejada, Melba A.; Sanchez-Carracedo, David] Univ Autonoma Barcelona, Dept Clin & Hlth Psychol, Barcelona, Spain. [Hernandez-Tejada, Melba A.; Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Acierno, Ron] Med Univ South Carolina, Coll Nursing, 99 Jonathan Lucas St,MSC160, Charleston, SC 29425 USA. RP Hernandez-Tejada, MA (reprint author), Med Univ South Carolina, Coll Nursing, 99 Jonathan Lucas St,MSC160, Charleston, SC 29425 USA. EM hernanma@musc.edu NR 17 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0899-5605 EI 1532-7876 J9 MIL PSYCHOL JI Milit. Psychol. PD MAR PY 2017 VL 29 IS 2 BP 157 EP 163 DI 10.1037/mil0000137 PG 7 WC Psychology, Multidisciplinary SC Psychology GA EN5MR UT WOS:000396050200006 ER PT J AU Rodriguez-Garcia, M Shen, Z Barr, FD Boesch, AW Ackerman, ME Kappes, JC Ochsenbauer, C Wira, CR AF Rodriguez-Garcia, M. Shen, Z. Barr, F. D. Boesch, A. W. Ackerman, M. E. Kappes, J. C. Ochsenbauer, C. Wira, C. R. TI Dendritic cells from the human female reproductive tract rapidly capture and respond to HIV SO MUCOSAL IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LEUKOCYTE PROTEASE INHIBITOR; MENSTRUAL-CYCLE; PIGTAIL MACAQUES; LANGERHANS CELLS; EX-VIVO; INFECTION; SUSCEPTIBILITY; SUBSETS; TYPE-1 AB Dendritic cells (DCs) throughout the female reproductive tract (FRT) were examined for phenotype, HIV capture ability and innate anti-HIV responses. Two main CD11c(+) DC subsets were identified: CD11b(+) and CD11b(low) DCs. CD11b(+)CD14(+) DCs were the most abundant throughout the tract. A majority of CD11c(+)CD14(+) cells corresponded to CD1c(+) myeloid DCs, whereas the rest lacked CD1c and CD163 expression (macrophage marker) and may represent monocyte-derived cells. In addition, we identified CD103(+) DCs, located exclusively in the endometrium, whereas DC-SIGN(+) DCs were broadly distributed throughout the FRT. Following exposure to GFP-labeled HIV particles, CD14(+) DC-SIGN(+) as well as CD14(+) DC-SIGN(-) cells captured virus, with similar to 30% of these cells representing CD1c(+) myeloid DCs. CD103(+) DCs lacked HIV capture ability. Exposure of FRT DCs to HIV induced secretion of CCL2, CCR5 ligands, interleukin (IL)-8, elafin, and secretory leukocyte peptidase inhibitor (SLPI) within 3 h of exposure, whereas classical pro-inflammatory molecules did not change and interferon-alpha 2 and IL-10 were undetectable. Furthermore, elafin and SLPI upregulation, but not CCL5, were suppressed by estradiol pre-treatment. Our results suggest that specific DC subsets in the FRT have the potential for capture and dissemination of HIV, exert antiviral responses and likely contribute to the recruitment of HIV-target cells through the secretion of innate immune molecules. C1 [Rodriguez-Garcia, M.; Shen, Z.; Barr, F. D.; Wira, C. R.] Geisel Sch Med, Dept Physiol & Neurobiol, Lebanon, NH USA. [Boesch, A. W.; Ackerman, M. E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Kappes, J. C.; Ochsenbauer, C.] Univ Alabama Birmingham, Dept Med, Res Serv Birmingham, Birmingham, AL USA. [Kappes, J. C.; Ochsenbauer, C.] Univ Alabama Birmingham, UAB Ctr AIDS Res, Birmingham, AL USA. [Kappes, J. C.] Birmingham Vet Affairs Med Ctr, Res Serv Birmingham, Birmingham, AL USA. RP Rodriguez-Garcia, M (reprint author), Geisel Sch Med, Dept Physiol & Neurobiol, Lebanon, NH USA. EM Marta.Rodriguez.Garcia@dartmouth.edu FU NIH [AI102838, AI117739, CA73479, P30 AI27767] FX We thank Dr John Fahey and Dr Yina Huang for critical comments and suggestions. We thank Richard Rossoll for technical assistance and Dr Rakesh Bakshi for help with preparing HIV-GFP VLPs. We thank the study participants, Pathologists, Obstetrics, and Gynecology surgeons, operating room nurses and support personnel at Dartmouth-Hitchcock Medical Center. Flow cytometric analysis was carried out in DartLab, the Immunoassay and Flow Cytometry Shared Resource at the Geisel School of Medicine at Dartmouth. Study supported by NIH grants AI102838 and AI117739 (CRW), CA73479 (JCK), and P30 AI27767 Birmingham Center for AIDS Research-Virology Core (CO; JCK) NR 67 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 10 IS 2 BP 531 EP 544 DI 10.1038/mi.2016.72 PG 14 WC Immunology SC Immunology GA EN1ZV UT WOS:000395810000023 PM 27579858 ER PT J AU Das, A Sampson, AL Lainscsek, C Muller, L Lin, WT Doyle, JC Cash, SS Halgren, E Sejnowski, TJ AF Das, Anup Sampson, Aaron L. Lainscsek, Claudia Muller, Lyle Lin, Wutu Doyle, John C. Cash, Sydney S. Halgren, Eric Sejnowski, Terrence J. TI Interpretation of the Precision Matrix and Its Application in Estimating Sparse Brain Connectivity during Sleep Spindles from Human Electrocorticography Recordings SO NEURAL COMPUTATION LA English DT Letter ID DECLARATIVE MEMORY CONSOLIDATION; INVERSE COVARIANCE ESTIMATION; FUNCTIONAL CONNECTIVITY; COMMUNITY STRUCTURE; MODEL SELECTION; GRAPHICAL MODEL; STAGE-2 SLEEP; MOTOR CORTEX; TIME-SERIES; NETWORKS AB The correlation method from brain imaging has been used to estimate functional connectivity in the human brain. However, brain regions might show very high correlation even when the two regions are not directly connected due to the strong interaction of the two regions with common input from a third region. One previously proposed solution to this problem is to use a sparse regularized inverse covariance matrix or precision matrix (SRPM) assuming that the connectivity structure is sparse. This method yields partial correlations to measure strong direct interactions between pairs of regions while simultaneously removing the influence of the rest of the regions, thus identifying regions that are conditionally independent. To test our methods, we first demonstrated conditions under which the SRPM method could indeed find the true physical connection between a pair of nodes for a spring-mass example and an RC circuit example. The recovery of the connectivity structure using the SRPM method can be explained by energy models using the Boltzmann distribution. We then demonstrated the application of the SRPM method for estimating brain connectivity during stage 2 sleep spindles from human electrocorticography (ECoG) recordings using an 8 x 8 electrode array. The ECoG recordings that we analyzed were from a 32-year-old male patient with long-standing pharmaco-resistant left temporal lobe complex partial epilepsy. Sleep spindles were automatically detected using delay differential analysis and then analyzed with SRPM and the Louvain method for community detection. We found spatially localized brain networks within and between neighboring cortical areas during spindles, in contrast to the case when sleep spindles were not present. C1 [Das, Anup; Sejnowski, Terrence J.] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. [Das, Anup; Sampson, Aaron L.; Lainscsek, Claudia; Muller, Lyle; Lin, Wutu] Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Doyle, John C.] CALTECH, Div Engn & Appl Sci, Pasadena, CA 91125 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Cort Physiol Lab, Boston, MA 02114 USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. RP Das, A (reprint author), Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA.; Das, A (reprint author), Salk Inst Biol Studies, Computat Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM a1das@eng.ucsd.edu; asampson@salk.edu; claudia@salk.edu; lmuller@salk.edu; wulin@salk.edu; doyle@caltech.edu; scash@partners.org; ehalgren@ucsd.edu; terry@salk.edu FU Howard Hughes Medical Institute; NIH [R01EB009282]; Office of Naval Research [N000141310672] FX This research was supported by the Howard Hughes Medical Institute, the NIH under grant R01EB009282, and the Office of Naval Research under grant N000141310672. We also like to thank Dr. David J. C. MacKay for interesting discussions on the spring-mass model. NR 94 TC 0 Z9 0 U1 0 U2 0 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0899-7667 EI 1530-888X J9 NEURAL COMPUT JI Neural Comput. PD MAR PY 2017 VL 29 IS 3 BP 603 EP 642 DI 10.1162/NECO_a_00936 PG 40 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA EM8LZ UT WOS:000395564100003 PM 28095202 ER PT J AU Schiffer, CA Brunner, AM Stock, W AF Schiffer, Charles A. Brunner, Andrew M. Stock, Wendy TI Standard vs Investigational Agents as Upfront Treatment for High-Risk AML SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID ACUTE MYELOID-LEUKEMIA; MINIMAL RESIDUAL DISEASE; OLDER PATIENTS; INHIBITION; PATIENT; IMPACT; CARE C1 [Schiffer, Charles A.] Harvard Med Sch, Med, Boston, MA 02115 USA. [Brunner, Andrew M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Stock, Wendy] Univ Chicago, Med Comprehens Canc Ctr, Leukemia Res, Chicago, IL 60637 USA. RP Schiffer, CA (reprint author), Harvard Med Sch, Med, Boston, MA 02115 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2017 VL 31 IS 3 BP 190 EP 192 PG 3 WC Oncology SC Oncology GA EN8BU UT WOS:000396226700005 ER PT J AU Choi, CJ Stagner, AM Jakobiec, FA Chodosh, J Yoon, MK AF Choi, Catherine J. Stagner, Anna M. Jakobiec, Frederick A. Chodosh, James Yoon, Michael K. TI Eyelid Mass in Boston Keratoprosthesis Type 2 SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID II KERATOPROSTHESIS AB Boston keratoprosthesis type 2 is used to treat severe corneal blindness secondary to cicatricial or autoimmune ocular surface disease. This case report describes an atypical eyelid mass in a 41-year-old woman with StevensJohnson syndrome who underwent placement of Boston keratoprosthesis type 2 in the left eye. The postoperative course was complicated by methicillin-sensitive Staphylococcus aureus keratitis and endophthalmitis requiring replacement of the keratoprosthesis. Three months thereafter, the patient presented with a progressively enlarging upper eyelid mass adjacent to the keratoprosthesis optic causing distortion of the eyelid. Excisional biopsy revealed an elongated cystic mass abutting the superior aspect of the optic. Pathologic examination was consistent with a conjunctival cyst with lipogranulomatous reaction. Removal of eyelid margins and conjunctiva, and placement of a full-thickness blepharotomy are standard steps in placement of Boston keratoprosthesis type 2, which can lead to conjunctival cysts and lipogranulomas that present as eyelid masses. C1 [Choi, Catherine J.; Yoon, Michael K.] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg, Boston, MA 02114 USA. [Choi, Catherine J.; Stagner, Anna M.; Jakobiec, Frederick A.; Chodosh, James; Yoon, Michael K.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Stagner, Anna M.; Jakobiec, Frederick A.] Massachusetts Eye & Ear Infirm, David G Cogan Ophthalm Pathol Lab, Boston, MA 02114 USA. [Chodosh, James] Massachusetts Eye & Ear Infirm, Cornea & Refract Surg, Boston, MA 02114 USA. RP Yoon, MK (reprint author), Massachusetts Eye & Ear Infirm, Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM Michael_Yoon@meei.harvard.edu 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAR-APR PY 2017 VL 33 IS 2 BP E39 EP E41 DI 10.1097/IOP.0000000000000712 PG 4 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EN4ZF UT WOS:000396014700006 PM 27163939 ER PT J AU Jimenez-Perez, JC Chou, J Freitag, SK AF Jimenez-Perez, Juan C. Chou, Jonathan Freitag, Suzanne K. TI Chocolate Cyst After an Orbital Floor Fracture Repair SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material C1 [Jimenez-Perez, Juan C.; Chou, Jonathan; Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, Boston, MA 02114 USA. RP Chou, J (reprint author), Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, Boston, MA 02114 USA. EM jchou87@gmail.com 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 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAR-APR PY 2017 VL 33 IS 2 BP E52 EP E52 DI 10.1097/IOP.0000000000000718 PG 1 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EN4ZF UT WOS:000396014700012 PM 27218812 ER PT J AU Hawkins, EJ Malte, CA Hagedorn, HJ Berger, D Frank, A Lott, A Achtmeyer, CE Mariano, AJ Saxon, AJ AF Hawkins, Eric J. Malte, Carol A. Hagedorn, Hildi J. Berger, Douglas Frank, Anissa Lott, Aline Achtmeyer, Carol E. Mariano, Anthony J. Saxon, Andrew J. TI Survey of Primary Care and Mental Health Prescribers' Perspectives on Reducing Opioid and Benzodiazepine Co-Prescribing Among Veterans SO PAIN MEDICINE LA English DT Article DE Chronic Pain; Concurrent Opioid and Benzodiazepine Use; Primary Care; Mental Health; Beliefs; Attitudes; High-Risk Conditions ID POSTTRAUMATIC-STRESS-DISORDER; CHRONIC PAIN; GENERAL-PRACTITIONERS; PARIHS FRAMEWORK; PHYSICIANS PERSPECTIVES; OLDER-ADULTS; US VETERANS; IMPLEMENTATION; ATTITUDES; DOCTORS AB Background. Due to the involvement of opioids and benzodiazepines in rising pharmaceutical overdoses, a reduction in coprescribing of these medications is a national priority, particularly among patients with substance use disorders and other high-risk conditions. However, little is known about primary care (PC) and mental health (MH) prescribers' perspectives on these medications and efforts being implemented to reduce coprescribing. Design. An anonymous survey. Setting. One multisite VA health care system. Subjects. Participants were 55 PC and 31 MH prescribers. Methods. Survey development was guided by the Promoting Action on Research Implementation in Health Services (PARIHS) conceptual framework. PC and MH prescribers of opioids or benzodiazepines were invited to complete an anonymous electronic survey. Responses were collapsed to highlight agreement, disagreement, and neutrality and summarized with means and percentages. Results. Over 80% of both prescriber groups reported concern about concurrent use and > 75% strongly agreed with clinical practice guidelines (CPG) that recommend caution in coprescribing among patients with high-risk conditions. More than 40% of both prescriber groups indicated that coprescribing continues because of beliefs that patients appear stable without adverse events and tapering/discontinuation is too difficult. Over 70% of prescribers rated strategies for addressing patients who refuse to discontinue, more time with patients, and identification of high-risk patients as helpful in reducing coprescribing. Conclusion. Despite strong agreement with CPGs, prescribers reported several barriers that contribute to coprescribing of opioids and benzodiazepines and challenge their ability to taper these medications. Multiple interventions are likely needed to reduce opioid and benzodiazepine coprescribing. C1 [Hawkins, Eric J.; Malte, Carol A.; Frank, Anissa; Lott, Aline; Achtmeyer, Carol E.; Saxon, Andrew J.] Seattle Ctr Innovat Veteran Centered & Value Driv, Veteran Affairs VA Puget Sound Hlth Care Syst, HSR&D, Seattle, WA USA. [Hawkins, Eric J.; Malte, Carol A.; Frank, Anissa; Lott, Aline; Achtmeyer, Carol E.; Saxon, Andrew J.] Ctr Excellence Substance Abuse Treatment & Educ, VA Puget Sound Hlth Care Syst Seattle, Div S116ATC, 1660 S Columbian Way, Seattle, WA 98108 USA. [Hawkins, Eric J.; Hagedorn, Hildi J.] VA Qual Enhancement Res Initiat Substance Use Dis, Palo Alto, CA USA. [Hawkins, Eric J.; Mariano, Anthony J.; Saxon, Andrew J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Hagedorn, Hildi J.] Minneapolis VA Hlth Care Syst, Minneapolis, MN USA. [Berger, Douglas; Achtmeyer, Carol E.] Primary & Specialty Med Care Serv, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Berger, Douglas] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Mariano, Anthony J.] VA Northwest Vet Integrated Serv Network VISN 20, VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Hawkins, EJ (reprint author), Ctr Excellence Substance Abuse Treatment & Educ, VA Puget Sound Hlth Care Syst Seattle, Div S116ATC, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Eric.Hawkins@va.gov FU U.S. Department of Veterans Affairs, Veterans Health Administration; VA Center of Excellence in Substance Abuse Treatment Education; VA Health Services Research and Development (HSR&D) Quality Enhancement Research Initiative Rapid Response Project (RRP) [12-527]; Quality Enhancement Research Initiative for Substance Use Disorders (SUD QUERI) FX This material is based upon work supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, the VA Center of Excellence in Substance Abuse Treatment & Education, the VA Health Services Research and Development (HSR&D) Quality Enhancement Research Initiative Rapid Response Project (RRP) # 12-527, and the Quality Enhancement Research Initiative for Substance Use Disorders (SUD QUERI). Supporting organizations had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 58 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD MAR PY 2017 VL 18 IS 3 BP 454 EP 467 DI 10.1093/pm/pnw140 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EP0VE UT WOS:000397104000009 ER PT J AU Brellenthin, AG Crombie, KM Cook, DB Sehgal, N Koltyn, KF AF Brellenthin, Angelique G. Crombie, Kevin M. Cook, Dane B. Sehgal, Nalini Koltyn, Kelli F. TI Psychosocial Influences on Exercise-Induced Hypoalgesia SO PAIN MEDICINE LA English DT Article DE Sex; Family; Psychological; Exercise; Modulation; Catastrophizing ID CONDITIONED PAIN MODULATION; ISOMETRIC-EXERCISE; SEX-DIFFERENCES; POSTOPERATIVE PAIN; TEMPORAL SUMMATION; CATASTROPHIZING SCALE; PSYCHOLOGICAL-FACTORS; QUESTIONNAIRE-III; FAMILY-HISTORY; BLOOD-PRESSURE AB Objective. The purpose of this study was to examine psychosocial influences on exercise-induced hypoalgesia (EIH). Design. Randomized controlled trial. Setting. Clinical research unit in a hospital. Subjects. Fifty-eight healthy men and women (mean age=21 +/- 3 years) participated in this study. Methods. Participants were first asked to complete a series of baseline demographic and psychological questionnaires including the Pain Catastrophizing Scale, the Fear of Pain Questionnaire, and the Family Environment Scale. Following this, they were familiarized with both temporal summation of heat pain and pressure pain testing protocols. During their next session, participants completed the Profile of Mood States, rated the intensity of heat pulses, and indicated their pressure pain thresholds and ratings before and after three minutes of submaximal, isometric exercise. Situational catastrophizing was assessed at the end of the experimental session. Results. Results indicated that experimental pain sensitivity was significantly reduced after exercise (P < 0.05). Men and women did not differ on any of the measured psychosocial variables (P > 0.05). Positive family environments predicted attenuated pain sensitivity and greater EIH, whereas negative and chronic pain-present family environments predicted worse pain and EIH outcomes. Situational catastrophizing and negative mood state also predicted worse pain and EIH outcomes and were additionally associated with increased ratings of perceived exertion and muscle pain during exercise. Conclusions. This study provides preliminary evidence that psychosocial variables, such as the family environment and mood states, can affect both pain sensitivity and the ability to modulate pain through exercise-induced hypoalgesia. C1 [Brellenthin, Angelique G.; Crombie, Kevin M.; Cook, Dane B.; Koltyn, Kelli F.] Univ Wisconsin Madison, Dept Kinesiol, Madison, WI USA. [Sehgal, Nalini] Univ Wisconsin Madison, Dept Rehabil Med, Madison, WI USA. [Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Koltyn, KF (reprint author), Univ Wisconsin, 2000 Observ Dr, Madison, WI 53706 USA. EM koltyn@education.wisc.edu FU National Institutes of Health [R21AR057159, 1UL1RR025011] FX This research was supported by National Institutes of Health grants R21AR057159 and 1UL1RR025011. NR 70 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD MAR PY 2017 VL 18 IS 3 BP 538 EP 550 DI 10.1093/pm/pnw275 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA EP0VE UT WOS:000397104000016 ER PT J AU Bergsland, E Roy, R Elvin, J Graeme-Cook, F Bailey, M Stephens, P Ross, J Olshen, A AF Bergsland, Emily Roy, Ritu Elvin, Julia Graeme-Cook, Fiona Bailey, Mark Stephens, Phil Ross, Jeffrey Olshen, Adam TI Genomic Profiling Distinguishes Gastroenteropancreatic Poorly Differentiated Neuroendocrine Carcinomas (GEP-NEC) from Small Cell Lung Carcinoma (SCLC) SO PANCREAS LA English DT Meeting Abstract C1 [Bergsland, Emily; Roy, Ritu; Olshen, Adam] UCSF, San Francisco, CA USA. [Elvin, Julia; Graeme-Cook, Fiona; Bailey, Mark; Stephens, Phil; Ross, Jeffrey] Fdn Med Inc, Cambridge, MA USA. [Graeme-Cook, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Olshen, Adam] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, 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 MAR PY 2017 VL 46 IS 3 BP 427 EP 427 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600028 ER PT J AU da Silva, A Qian, ZR Zhang, S Masugi, Y Rodig, S Brais, L Dutton, T Chan, J Hodi, S Ogino, S Kulke, M AF da Silva, Annacarolina Qian, Zhirong Zhang, Sui Masugi, Yohei Rodig, Scott Brais, Lauren Dutton, Trevor Chan, Jennifer Hodi, Stephen Ogino, Shuji Kulke, Matthew TI Immune Checkpoint Markers and Immune Response in Well Differentiated Neuroendocrine Tumors (NET) of the Small Intestine and Pancreas SO PANCREAS LA English DT Meeting Abstract C1 [da Silva, Annacarolina; Qian, Zhirong; Zhang, Sui; Masugi, Yohei; Brais, Lauren; Dutton, Trevor; Chan, Jennifer; Hodi, Stephen; Ogino, Shuji; Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rodig, Scott] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 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 MAR PY 2017 VL 46 IS 3 BP 427 EP 427 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600030 ER PT J AU Fazio, N Buzzoni, R Delle Fave, G Tesselaar, MET Wolin, E Van Cutsem, E Tomassetti, P Strosberg, J Voi, M Pacaud, L Ridolfi, A Singh, S Pavel, M Kulke, M Yao, J AF Fazio, Nicola Buzzoni, Roberto Delle Fave, Gianfranco Tesselaar, Margot E. T. Wolin, Edward Van Cutsem, Eric Tomassetti, Paola Strosberg, Jonathan Voi, Maurizio Pacaud, Lida Ridolfi, Antonia Singh, Simron Pavel, Marianne Kulke, Matthew Yao, James TI Efficacy and Safety of Everolimus in Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Lung: A Subgroup Analysis of the Phase 3 RADIANT-4 Study SO PANCREAS LA English DT Meeting Abstract C1 [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Milan, Italy. [Buzzoni, Roberto] Ist Nazl Tumori, Fdn IRCCS, Milan, Italy. [Delle Fave, Gianfranco] Univ Roma La Sapienza, Azienda Osped St Andrea, Rome, Italy. [Tesselaar, Margot E. T.] Netherlands Canc Inst, Amsterdam, Netherlands. [Wolin, Edward] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Van Cutsem, Eric] Univ Hosp Gasthuisberg Leuven, Leuven, Belgium. [Van Cutsem, Eric] Katholieke Univ Leuven, Leuven, Belgium. [Tomassetti, Paola] Univ Bologna, S Orsola Malpighi Hosp, Dept Med & Surg Sci, Bologna, Italy. [Strosberg, Jonathan] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Voi, Maurizio] Novartis Pharmaceut, E Hanover, NJ USA. [Pacaud, Lida] Novartis Pharma AG, Basel, Switzerland. [Ridolfi, Antonia] Novartis Pharma SAS, Rueil Malmaison, France. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Pavel, Marianne] Charite Univ Med Berlin, Campus Virchow Klinikum, Berlin, Germany. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yao, James] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 433 EP 433 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600051 ER PT J AU Pavel, M Gross, D Benavent, M Caplin, M Perros, P Srirajaskanthan, R Valle, J Warner, R Kulke, M Anthony, L Kunz, P Horsch, D Ouml;berg, K Lapuerta, P Jackson, S Banks, P Biran, T Garcia-Carbonero, R AF Pavel, Marianne Gross, David Benavent, Marta Caplin, Martyn Perros, Petros Srirajaskanthan, Raj Valle, Juan Warner, Richard Kulke, Matthew Anthony, Lowell Kunz, Pamela Hoersch, Dieter Oberg, Kjell Lapuerta, Pablo Jackson, Shanna Banks, Phillip Biran, Talia Garcia-Carbonero, Rocio TI Efficacy and Safety Results of Telotristat Ethyl in Patients With Carcinoid Syndrome During the Double-blind Treatment Period of the TELECAST Phase 3 Clinical Trial SO PANCREAS LA English DT Meeting Abstract C1 [Pavel, Marianne] Charite Univ Med Berlin, CVK, Med Klin Schwerpunkt, Berlin, Germany. [Gross, David] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Benavent, Marta] Hosp Univ Virgen Rocio, Seville, Spain. [Caplin, Martyn] Royal Free Hosp, Hampstead, England. [Perros, Petros] Royal Victoria Infirm, Newcastle Upon Tyne, Tyne & Wear, England. [Srirajaskanthan, Raj] Kings Coll Hosp London, London, England. [Valle, Juan] Christie NHS Fdn Trust, Manchester, Lancs, England. [Warner, Richard] Mt Sinai Sch Med, New York, NY USA. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA USA. [Anthony, Lowell] Univ Kentucky, Lexington, KY 40506 USA. [Kunz, Pamela] Stanford Univ, Stanford, CA 94305 USA. [Hoersch, Dieter] Klin Innere Med, Bad Berka, Germany. [Oberg, Kjell] Univ Uppsala Hosp, Uppsala, Sweden. [Lapuerta, Pablo; Jackson, Shanna; Banks, Phillip; Biran, Talia] Lexicon Pharmaceut Inc, The Woodlands, TX USA. [Garcia-Carbonero, Rocio] Hosp Univ Doce Octubre, Madrid, Spain. 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 MAR PY 2017 VL 46 IS 3 BP 434 EP 435 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600055 ER PT J AU Raymond, E Kulke, M Qin, S Schenker, M Cubillo, A Lou, WH Tomasek, J Thiis-Evensen, E Xu, JM Racz, K Croitoru, A Khasraw, M Sedlackova, E Borbath, I Ruff, P Oberstein, P Ito, T Fernandez, K Rosbrook, B Fazio, N AF Raymond, Eric Kulke, Matthew Qin, Shukui Schenker, Michael Cubillo, Antonio Lou, Wenhui Tomasek, Jiri Thiis-Evensen, Espen Xu, Jianming Racz, Karoly Croitoru, Adina Khasraw, Mustafa Sedlackova, Eva Borbath, Ivan Ruff, Paul Oberstein, Paul Ito, Tetsuhide Fernandez, Kathrine Rosbrook, Brad Fazio, Nicola TI The Efficacy and Safety of Sunitinib in Patients With Advanced Well-differentiated Pancreatic Neuroendocrine Tumors SO PANCREAS LA English DT Meeting Abstract C1 [Raymond, Eric] Paris St Joseph Hosp Grp, Paris, France. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA USA. [Qin, Shukui] Nanjing Bayi Hosp, PLA Canc Ctr, Nanjing, Jiangsu, Peoples R China. [Schenker, Michael] Cent Oncol Sf Nectarie, Oncol Med, Craiova, Romania. [Cubillo, Antonio] Hosp Univ Madrid Sanchinarro, Ctr Integral Oncol Clara Campal, Madrid, Spain. [Lou, Wenhui] Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China. [Tomasek, Jiri] Masarykuv Onkol Ustav, Klin Komplexni Onkolk Pece, Brno, Czech Republic. [Thiis-Evensen, Espen] Oslo Univ Hosp, Dept Gastroenterol, Oslo, Norway. [Xu, Jianming] Acad Mil Med Sci, Hosp 307, Beijing, Peoples R China. [Racz, Karoly] Semmelweis Univ, Fac Med, Dept Internal Med 2, H-1085 Budapest, Hungary. [Croitoru, Adina] Fundeni Clin Inst, Dept Med Oncol, Bucharest, Romania. [Khasraw, Mustafa] Geelong Hosp, Andrew Love Canc Ctr, Geelong, Vic, Australia. [Sedlackova, Eva] Vseobecne Fak Nemocnice Praze, Onkol Klin, Prague, Czech Republic. [Borbath, Ivan] Clin Univ St Luc, King Albert II Inst Cancerol, Woluwe St Lambert, Belgium. [Ruff, Paul] Univ Witwatersrand, Fac Hlth Sci, ZA-2050 Johannesburg, South Africa. [Oberstein, Paul] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY 10027 USA. [Ito, Tetsuhide] Kyushu Univ Hosp, Fukuoka, Japan. [Fernandez, Kathrine; Rosbrook, Brad] Pfizer Inc, New York, NY USA. [Fazio, Nicola] European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine, Milan, Italy. 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 MAR PY 2017 VL 46 IS 3 BP 435 EP 435 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600057 ER PT J AU Singh, S Carnaghi, C Buzzoni, R Raderer, M Lahner, H Valle, J Voi, M Pacaud, L Lincy, J Okita, N Kulke, M Strosberg, J Yao, J Pavel, M Fazio, N AF Singh, Simron Carnaghi, Carlo Buzzoni, Roberto Raderer, Markus Lahner, Harald Valle, Juan Voi, Maurizio Pacaud, Lida Lincy, Jeremie Okita, Natsuko Kulke, Matthew Strosberg, Jonathan Yao, James Pavel, Marianne Fazio, Nicola TI Everolimus for Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Gastrointestinal (GI) Tract: Efficacy and Safety from a RADIANT-4 Subgroup Analysis SO PANCREAS LA English DT Meeting Abstract C1 [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Carnaghi, Carlo] IRCCS Ist Clin Humanitas, Rozzano, Italy. [Buzzoni, Roberto] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Raderer, Markus] AKH, Univ Klin Innere Med 1, Vienna, Austria. [Lahner, Harald] Univ Klinikum Essen, Zentrum Innere Med, Essen, Germany. [Valle, Juan] Univ Manchester, Christie Hosp, Inst Canc Studies, Manchester, Lancs, England. [Voi, Maurizio] Novartis Pharmaceut, E Hanover, NJ USA. [Pacaud, Lida; Lincy, Jeremie] Novartis Pharma AG, Basel, Switzerland. [Okita, Natsuko] Natl Canc Ctr, Chuo Ku, Tokyo, Japan. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA USA. [Strosberg, Jonathan] H Lee Moffitt Canc Ctr & Res Inst, Dept Med, Tampa, FL USA. [Yao, James] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Pavel, Marianne] Charite Univ Med Berlin, Campus Virchow Klinikum, Berlin, Germany. [Fazio, Nicola] Ist Europeo Oncol IRCCS, Milan, Italy. 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 MAR PY 2017 VL 46 IS 3 BP 436 EP 436 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600060 ER PT J AU Strosberg, J Chan, J Mita, A Kundu, M Hermosillo, K Hu, K Wolin, E Yao, J AF Strosberg, Jonathan Chan, Jennifer Mita, Alain Kundu, Madan Hermosillo, Karina Hu, Ke Wolin, Edward Yao, James TI Phase I, Multi-center, Open-label, Dose-escalation Study of Pasireotide LAR (PAS) in Patients With Advanced Neuroendocrine Tumors (NET) SO PANCREAS LA English DT Meeting Abstract C1 [Strosberg, Jonathan] H Lee Moffitt Canc Ctr & Res Inst, Dept Med, Tampa, FL USA. [Chan, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mita, Alain; Wolin, Edward] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Kundu, Madan; Hu, Ke] Novartis Pharmaceut, E Hanover, NJ USA. [Hermosillo, Karina] Novartis Pharma AG, Basel, Switzerland. [Yao, James] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 437 EP 437 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600061 ER PT J AU Yao, J Fazio, N Singh, S Buzzoni, R Carnaghi, C Wolin, E Tomasek, J Raderer, M Lahner, H Voi, M Pacaud, L Lincy, J Valle, J Delle Fave, G Van Cutsem, E Oh, DY Strosberg, J Kulke, M Pavel, M AF Yao, James Fazio, Nicola Singh, Simron Buzzoni, Roberto Carnaghi, Carlo Wolin, Edward Tomasek, Jiri Raderer, Markus Lahner, Harald Voi, Maurizio Pacaud, Lida Lincy, Jeremie Valle, Juan Delle Fave, Gianfranco Van Cutsem, Eric Oh, Do-Youn Strosberg, Jonathan Kulke, Matthew Pavel, Marianne TI Everolimus (EVE) in Advanced, Nonfunctional, Well-differentiated Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin: Second Interim Overall Survival (OS) Results From the RADIANT-4 Study SO PANCREAS LA English DT Meeting Abstract C1 [Yao, James; Pavel, Marianne] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Milan, Italy. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Buzzoni, Roberto] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. [Carnaghi, Carlo] IRCCS, Ist Clin Humanitas, Rozzano, Italy. [Wolin, Edward] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Tomasek, Jiri] Masaryk Univ, Fac Med, Mem Canc Inst 7Masaryk, Brno, Czech Republic. [Raderer, Markus] AKH, Univ Klin Innere Med 1, Vienna, Austria. [Lahner, Harald] Univ Klinikum Essen, Zentrum Innere Med, Essen, Germany. [Voi, Maurizio] Novartis Pharmaceut, E Hanover, NJ USA. [Pacaud, Lida; Lincy, Jeremie] Novartis Pharma AG, Basel, Switzerland. [Valle, Juan] Univ Manchester, Christie Hosp, Inst Canc Studies, Manchester, Lancs, England. [Delle Fave, Gianfranco] Univ Roma La Sapienza, Azienda Osped St Andrea, Rome, Italy. [Van Cutsem, Eric] Univ Hosp Gasthuisberg Leuven, Digest Oncol, Leuven, Belgium. [Van Cutsem, Eric] KULeuven, Leuven, Belgium. [Oh, Do-Youn] Seoul Natl Univ Hosp, Dept Internal Med, Seoul, South Korea. [Strosberg, Jonathan] H Lee Moffitt Canc Ctr & Res Inst, Dept Med, Tampa, FL USA. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. Charite, Campus Virchow Klinikum, Berlin, Germany. 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 MAR PY 2017 VL 46 IS 3 BP 437 EP 438 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600063 ER PT J AU Strosberg, J Wolin, E Chasen, B Kulke, M Bushnell, D Caplin, M Baum, R Kunz, P Hobday, T Hendifar, A Oberg, K Sierra, ML Kwekkeboom, D Ruszniewski, P Krenning, E AF Strosberg, Jonathan Wolin, Edward Chasen, Beth Kulke, Matthew Bushnell, David Caplin, Martin Baum, Richard Kunz, Pamela Hobday, Timothy Hendifar, Andrew Oberg, Kjell Sierra, Maribel Lopera Kwekkeboom, Dik Ruszniewski, Philippe Krenning, Eric TI NETTER-1 Phase III in Patients With Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate: Efficacy, Safety, QoL Results, and Subgroup Analysis SO PANCREAS LA English DT Meeting Abstract C1 [Strosberg, Jonathan] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Wolin, Edward] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA. [Chasen, Beth] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Kulke, Matthew] Dana Faber Canc Inst, Boston, MA USA. [Bushnell, David] Univ Iowa, Iowa City, IA 52242 USA. [Caplin, Martin] Royal Free Hosp, Hampstead, England. [Baum, Richard] Zentralklinik, Bad Berka, Germany. [Kunz, Pamela] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Hobday, Timothy] Mayo Clin, Coll Med, Rochester, MN USA. [Hendifar, Andrew] Cedars Sinai Med Ctr, Los Angeles, CA USA. [Sierra, Maribel Lopera] Adv Accelerator Applicat Inc, St Genis Pouilly, France. [Kwekkeboom, Dik; Krenning, Eric] Erasmus MC, Rotterdam, Netherlands. [Ruszniewski, Philippe] Hop Beaujon, Clichy, France. 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 MAR PY 2017 VL 46 IS 3 BP 440 EP 440 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600073 ER PT J AU Pavel, ME Strosberg, JR Pacaud, L Degtyarev, E Neary, MP Hunger, M Eriksson, J Ricci, JF Fazio, N Kulke, M Singh, S Yao, JC AF Pavel, Marianne E. Strosberg, Jonathan R. Pacaud, Lida Degtyarev, Evgeny Neary, Maureen P. Hunger, Matthias Eriksson, Jennifer Ricci, Jean-Francois Fazio, Nicola Kulke, Matthew Singh, Simron Yao, James C. TI Health-related Quality of Life (HRQoL) in Patients With Advanced Neuroendocrine Tumors (NET) by Tumor Origin in the Phase 3 RADIANT-4 Trial SO PANCREAS LA English DT Meeting Abstract C1 [Pavel, Marianne E.] Charite Berlin Campus Virchow Klinikum, Berlin, Germany. [Strosberg, Jonathan R.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Pacaud, Lida; Degtyarev, Evgeny] Novartis Pharma AG, Basel, Switzerland. [Neary, Maureen P.] Novartis Pharmaceut, Basel, Switzerland. [Hunger, Matthias; Eriksson, Jennifer] Mapi, Ness Ziona, Israel. [Ricci, Jean-Francois] Wellmera AG, Basel, Switzerland. [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Genoa, Italy. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 446 EP 447 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600096 ER PT J AU Pavel, ME Strosberg, JR Bubuteishvili-Pacaud, L Degtyarev, E Neary, MP Hunger, M Eriksson, J Fazio, N Kulke, M Singh, S Yao, JC AF Pavel, Marianne E. Strosberg, Jonathan R. Bubuteishvili-Pacaud, Lida Degtyarev, Evgeny Neary, Maureen P. Hunger, Matthias Eriksson, Jennifer Fazio, Nicola Kulke, Matthew Singh, Simron Yao, James C. TI Health-related Quality of Life (HRQoL) in Patients With Advanced, Nonfunctional, Well-differentiated Gastrointestinal (GI) or Lung Neuroendocrine Tumors (NET) in the Phase 3 RADIANT-4 Trial SO PANCREAS LA English DT Meeting Abstract C1 [Pavel, Marianne E.] Charite Berlin Campus Virchow Klinikum, Berlin, Germany. [Strosberg, Jonathan R.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Bubuteishvili-Pacaud, Lida; Degtyarev, Evgeny] Novartis Pharma AG, Basel, Switzerland. [Neary, Maureen P.] Novartis Pharmaceut, Basel, Switzerland. [Hunger, Matthias; Eriksson, Jennifer] Mapi, Ness Ziona, Israel. [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Genoa, Italy. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 446 EP 446 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600095 ER PT J AU Singh, S Pavel, ME Strosberg, JR Bubuteishvili-Pacaud, L Degtyarev, E Neary, MP Hunger, M Eriksson, J Fazio, N Kulke, M Yao, JC AF Singh, Simron Pavel, Marianne E. Strosberg, Jonathan R. Bubuteishvili-Pacaud, Lida Degtyarev, Evgeny Neary, Maureen P. Hunger, Matthias Eriksson, Jennifer Fazio, Nicola Kulke, Matthew Yao, James C. TI Association of Disease Progression, Health-related Quality of Life (HRQoL), and Utility in Patients With Advanced, Nonfunctional, Well-differentiated Gastrointestinal (GI) or Lung Neuroendocrine Tumors (NET) in the Phase 3 RADIANT-4 Trial SO PANCREAS LA English DT Meeting Abstract C1 [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Pavel, Marianne E.] Charite Berlin Campus Virchow Klinikum, Berlin, Germany. [Strosberg, Jonathan R.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Bubuteishvili-Pacaud, Lida; Degtyarev, Evgeny] Novartis Pharma AG, Basel, Switzerland. [Neary, Maureen P.] Novartis Pharmaceut, Basel, Switzerland. [Hunger, Matthias; Eriksson, Jennifer] Mapi, Ness Ziona, Israel. [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Genoa, Italy. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 448 EP 448 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600100 ER PT J AU Goetghebeur, M Samaha, D Khoury, H O'Neil, WM Khoury, H Bennetts, L Lavoie, L Wagner, M Badgley, D Gabriel, S Berthon, A Dolan, J Kulke, MH AF Goetghebeur, Mireille Samaha, Dima Khoury, Hanane O'Neil, William M. Khoury, Hanane Bennetts, Liga Lavoie, Louis Wagner, Monika Badgley, Danielle Gabriel, Sylvie Berthon, Anthony Dolan, James Kulke, Matthew H. TI To Treat or Watch? Identifying Drivers of Decisions for Patients With GEP-NET Using Reflective Multi-Criteria Decision Analysis SO PANCREAS LA English DT Meeting Abstract C1 [Goetghebeur, Mireille] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Goetghebeur, Mireille; Samaha, Dima; Khoury, Hanane; O'Neil, William M.; Khoury, Hanane; Bennetts, Liga; Lavoie, Louis; Wagner, Monika; Badgley, Danielle] LASER Analyt, Montreal, PQ, Canada. [Gabriel, Sylvie; Berthon, Anthony] Ipsen Pharma, Paris, France. [Dolan, James] Univ Rochester, Rochester, NY 14627 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 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 MAR PY 2017 VL 46 IS 3 BP 449 EP 449 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600105 ER PT J AU Goetghebeur, M Samaha, D O'Neil, WM Eagle, K Bennetts, L Lavoie, L Wagner, M Badgley, D Gabriel, S Berthon, A Dolan, J Kulke, MH AF Goetghebeur, Mireille Samaha, Dima O'Neil, William M. Eagle, Khoury Bennetts, Liga Lavoie, Louis Wagner, Monika Badgley, Danielle Gabriel, Sylvie Berthon, Anthony Dolan, James Kulke, Matthew H. TI What Matters Most? An Exploration of Decision Criteria Considered by Patients With GEP-NET and Physicians Using Holistic Multi-Criteria Decision Analysis SO PANCREAS LA English DT Meeting Abstract C1 [Goetghebeur, Mireille] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Goetghebeur, Mireille; Samaha, Dima; O'Neil, William M.; Eagle, Khoury; Bennetts, Liga; Lavoie, Louis; Wagner, Monika; Badgley, Danielle] LASER Analyt, Montreal, PQ, Canada. [Gabriel, Sylvie; Berthon, Anthony] Ipsen Pharma, Paris, France. [Dolan, James] Univ Rochester, Rochester, NY 14627 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 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 MAR PY 2017 VL 46 IS 3 BP 449 EP 449 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600104 ER PT J AU Eads, JR Catalano, P Fisher, GA Klimstra, D Zhang, Z Rubin, D Iagaru, A Wong, TZ O'Dwyer, P AF Eads, Jennifer R. Catalano, Paul Fisher, George A. Klimstra, David Zhang, Zheng Rubin, Daniel Iagaru, Andrei Wong, Terence Z. O'Dwyer, Peter TI Cisplatin and Etoposide or Temozolomide and Capecitabine in Treating Patients With Neuroendocrine Carcinoma of the Gastrointestinal Tract or Pancreas That Is Metastatic or Cannot Be Removed by Surgery SO PANCREAS LA English DT Meeting Abstract C1 [Eads, Jennifer R.] Univ Hosp Seidman Canc Ctr, Cleveland, OH USA. [Eads, Jennifer R.] Case Comprehens Canc Ctr, Cleveland, OH USA. [Catalano, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. [Catalano, Paul] ECOG ACRIN Biostat Ctr, Boston, MA USA. [Fisher, George A.; Rubin, Daniel; Iagaru, Andrei] Stanford Univ, Stanford, CA 94305 USA. [Klimstra, David] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zhang, Zheng] Brown Univ, Providence, RI 02912 USA. [Wong, Terence Z.] Univ N Carolina, Chapel Hill, NC USA. [Wong, Terence Z.] Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [O'Dwyer, Peter] Univ Penn, Philadelphia, PA 19104 USA. [O'Dwyer, Peter] Abramson Canc Ctr, Philadelphia, PA 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 MAR PY 2017 VL 46 IS 3 BP 451 EP 451 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600112 ER PT J AU Raj, N Chan, J Dasari, A Capanu, M Tang, L Reidy-Lagunes, D AF Raj, Nitya Chan, Jennifer Dasari, Arvind Capanu, Marinela Tang, Laura Reidy-Lagunes, Diane TI A Phase II Trial of LEE011 in Combination With Everolimus in the Treatment of AdvancedWell Differentiated Neuroendocrine Tumors of Foregut Origin SO PANCREAS LA English DT Meeting Abstract C1 [Raj, Nitya; Capanu, Marinela; Tang, Laura; Reidy-Lagunes, Diane] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chan, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dasari, Arvind] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR PY 2017 VL 46 IS 3 BP 451 EP 451 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600113 ER PT J AU Reidy-Lagunes, D Kulke, M Wolin, E Singh, S Ferone, D Mirakhur, B Hoffmanns, P Houchard, A Caplin, M Baudin, E AF Reidy-Lagunes, Diane Kulke, Matthew Wolin, Edward Singh, Simron Ferone, Diego Mirakhur, Beloo Hoffmanns, Philipp Houchard, Aude Caplin, Martyn Baudin, Eric TI SPINET: A Randomized, Double-blind, Placebo-controlled Phase III Study of Lanreotide Autogel/Depot (LAN) in Patients with Advanced Lung Neuroendocrine Tumors SO PANCREAS LA English DT Meeting Abstract C1 [Reidy-Lagunes, Diane] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolin, Edward] Markey Canc Ctr, Lexington, KY USA. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Ferone, Diego] IRCCS AOU San Martino IST, Genoa, Italy. [Mirakhur, Beloo; Hoffmanns, Philipp; Houchard, Aude] Ipsen, Paris, France. [Caplin, Martyn] Royal Free Hosp, Hampstead, England. [Baudin, Eric] Gustave Roussy Canc Campus, Paris, France. 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 MAR PY 2017 VL 46 IS 3 BP 451 EP 451 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600114 ER PT J AU Baer, TE Feraco, AM Sagalowsky, ST Williams, D Litman, HJ Vinci, RJ AF Baer, Tamara Elizabeth Feraco, Angela M. Sagalowsky, Selin Tuysuzoglu Williams, David Litman, Heather J. Vinci, Robert J. TI Pediatric Resident Burnout and Attitudes Toward Patients SO PEDIATRICS LA English DT Article ID INTERNAL-MEDICINE RESIDENTS; QUALITY-OF-LIFE; PROSPECTIVE COHORT; HOUR RESTRICTIONS; EDUCATION; CARE; INTERVENTIONS; ASSOCIATION; EMPATHY; ERRORS AB BACKGROUND AND OBJECTIVES: Burnout occurs in up to 75% of resident physicians. Our study objectives were to: (1) determine the prevalence of burnout, and (2) examine the association between burnout and self-reported patient care attitudes and behaviors among pediatric residents. METHODS: A total of 258 residents (53% response rate) from 11 pediatric residency programs completed a cross-sectional Web-based survey. Burnout was measured with 2 items from the Maslach Burnout Inventory. Patient care attitudes and behaviors were measured with 7 questions from a standardized qualitative survey. x(2) and logistic regression tested the association between burnout and self-reported patient care attitudes and behavior. RESULTS: A total of 39% of respondents (mean age, 29.4 years +/- 2.3 SD; 79% female; 83% white; 35% postgraduate year [PGY] -1, 34% PGY-2, and 31% PGY-3), endorsed burnout. Residents with burnout had significantly greater odds (P <.01) of reporting suboptimal patient care attitudes and behaviors, including: discharging patients to make the service more manageable (adjusted odds ratio [aOR] 4.2; 95% confidence interval [CI], 1.6-11.1), not fully discussing treatment options or answering questions (aOR 3.5; 95% CI, 1.7-7.1), making treatment or medication errors (aOR 7.1; 95% CI, 2.0-25.8), ignoring the social or personal impact of an illness (aOR 9.6; 95% CI, 3.2-28.9), and feeling guilty about how a patient was treated (aOR 6.0; 95% CI, 1.6-22.1). CONCLUSIONS: Burnout is highly prevalent among pediatric residents and is associated with self-reported negative patient care attitudes and behaviors. Residency programs should develop interventions addressing burnout and its potential negative impact on patient care. C1 [Baer, Tamara Elizabeth] Boston Childrens Hosp, Div Adolescent Young Adult Med, Boston, MA USA. [Feraco, Angela M.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Williams, David] Boston Childrens Hosp, Clin Res Ctr, Boston, MA USA. [Baer, Tamara Elizabeth; Feraco, Angela M.] Harvard Med Sch, Dept Med, Boston, MA USA. [Feraco, Angela M.] Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. [Sagalowsky, Selin Tuysuzoglu] Columbia Univ Coll Phys & Surg, Dept Pediat, Div Emergency Med, New York, NY 10032 USA. [Litman, Heather J.] Corrona LLC, Dept Biostat & Epidemiol, Southborough, MA USA. [Vinci, Robert J.] Boston Univ, Sch Med, Dept Pediat, Boston Med Ctr, Boston, MA 02118 USA. RP Baer, TE (reprint author), Boston Childrens Hosp, Div Adolescent Young Adult Med, Boston, MA USA. FU Boston Children's Hospital's Fred Lovejoy Resident Research Award; Leadership Education in Adolescent Health Training grant from the Maternal and Child Health Bureau, Health Resources and Services Administration [T71MC00009] FX This study was supported by the Boston Children's Hospital's Fred Lovejoy Resident Research Award and Leadership Education in Adolescent Health Training grant T71MC00009 from the Maternal and Child Health Bureau, Health Resources and Services Administration. NR 30 TC 1 Z9 1 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 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2017 VL 139 IS 3 AR e20162163 DI 10.1542/peds.2016-2163 PG 8 WC Pediatrics SC Pediatrics GA EM0IY UT WOS:000395003200022 ER PT J AU Fasano, A AF Fasano, Alessio TI Celiac Disease, Gut-Brain Axis, and Behavior: Cause, Consequence, or Merely Epiphenomenon? SO PEDIATRICS LA English DT Editorial Material C1 [Fasano, Alessio] MassGen Hosp Children, Mucosal Immunol & Biol Res Ctr, Boston, MA USA. [Fasano, Alessio] MassGen Hosp Children, Ctr Celiac Res & Treatment, Boston, MA USA. [Fasano, Alessio] MassGen Hosp Children, Div Pediat Gastroenterol & Nutr, Boston, MA USA. RP Fasano, A (reprint author), Massachusetts Gen Hosp East, Ctr Celiac Res & Treatment, Bldg 114,16th St,Mail Stop 114-3503, Charlestown, MA 02129 USA.; Fasano, A (reprint author), Massachusetts Gen Hosp East, Mucosal Immunol & Biol Res Ctr, Bldg 114,16th St,Mail Stop 114-3503, Charlestown, MA 02129 USA. EM afasano@mgh.harvard.edu NR 9 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 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2017 VL 139 IS 3 AR e20164323 DI 10.1542/peds.2016-4323 PG 2 WC Pediatrics SC Pediatrics GA EM0IY UT WOS:000395003200086 ER PT J AU Wei, NJ AF Wei, Nancy J. TI Clinical Aspects of Testing for Diabetes Mellitus SO POINT OF CARE LA English DT Article DE diabetes; diagnosis; point-of-care testing ID EMERGENCY-DEPARTMENT; BLOOD-GLUCOSE; KETOACIDOSIS; ASSOCIATION AB This article serves as an introduction to the clinical aspects of testing for diabetes mellitus. Topics covered include the role of testing in diabetes diagnosis, presentation and monitoring in the acute setting, chronic disease management and monitoring, and treatment targets. C1 [Wei, Nancy J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Diabet, 55 Fruit St,Bulfinch 130, Boston, MA 02114 USA. RP Wei, NJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Diabet, 55 Fruit St,Bulfinch 130, Boston, MA 02114 USA. EM ncwei@partners.org NR 15 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 1 EP 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300001 ER PT J AU Lewandrowski, K AF Lewandrowski, Kent TI Capillary Blood Glucose Meters in the Home, Clinic, and Hospital SO POINT OF CARE LA English DT Review DE diabetes; glucose meter; capillary blood glucose ID QUALITY C1 [Lewandrowski, Kent] Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. [Lewandrowski, Kent] Harvard Med Sch, Boston, MA USA. RP Lewandrowski, K (reprint author), Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. EM klewandrowski@partners.org NR 7 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 3 EP 4 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300002 ER PT J AU Sluss, PM AF Sluss, Patrick M. TI Hemoglobin A1c Testing in Patients With Diabetes SO POINT OF CARE LA English DT Article DE diabetes; hemoglobin A1c; point-of-care testing ID HBA(1C) AB Measurement of hemoglobin A1c (HbA1c) is clinically useful for both the diagnosis of diabetes and for monitoring glycemic control in patients with type 1 or type 2 diabetes. This chapter focuses on testing the monitoring of glycemic control in patients with diabetes. Although laboratory values are method specific and no clinical cutoffs for monitoring therapy or risk prediction are currently recognized, HbA1c levels typically range between 4.5% and 7.0% of total blood hemoglobin. Thus, current American Diabetes Association-recommended treatment goal is to achieve HbA1c levels lower than 7%. American Diabetes Association guidance also includes the recommendation that only HbA1c methods that have been certified by the National Glycohemoglobin Standardization Program be used and that testing of patients with stable glycemic control be performed annually. More frequent testing is recommended during periods when treatment adjustments are required to achieve glycemic control. It is important to note that HbA1c measurements are useful for assessing hyperglycemia but not hypoglycemia. C1 [Sluss, Patrick M.] Massachusetts Gen Hosp, Clin Pathol Core Labs, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. [Sluss, Patrick M.] Harvard Med Sch, Boston, MA USA. RP Sluss, PM (reprint author), Massachusetts Gen Hosp, Clin Pathol Core Labs, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. EM sluss.patrick@mgh.harvard.edu NR 9 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 9 EP 11 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300004 ER PT J AU Lewandrowski, K AF Lewandrowski, Kent TI Lipid Testing in Patients With Diabetes Mellitus Typ. 2 SO POINT OF CARE LA English DT Review DE cholesterol; diabetes; lipids; point-of-care testing C1 [Lewandrowski, Kent] Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. [Lewandrowski, Kent] Harvard Med Sch, Boston, MA USA. RP Lewandrowski, K (reprint author), Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. EM klewandrowski@partners.org 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 32 EP 33 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300006 ER PT J AU Lewandrowski, K AF Lewandrowski, Kent TI The Clinical Utility of Urinary Microalbumin in the Management of Diabetes Mellitus SO POINT OF CARE LA English DT Review DE diabetes; urine microalbumin; point-of-care testing ID ACADEMIC-MEDICAL-CENTER; AMBULATORY PRACTICE C1 [Lewandrowski, Kent] Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. [Lewandrowski, Kent] Harvard Med Sch, Boston, MA USA. RP Lewandrowski, K (reprint author), Massachusetts Gen Hosp, Pathol Labs & Mol Med, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. EM klewandrowski@partners.org NR 9 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 34 EP 36 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300007 ER PT J AU Kahanovitz, L Sluss, PM Russell, SJ AF Kahanovitz, Lindy Sluss, Patrick M. Russell, Steven J. TI Type 1 Diabetes-A Clinical Perspective SO POINT OF CARE LA English DT Article DE Type 1 diabetes; hemoglobin A1c; C-peptide; point-of-care; self-monitoring blood glucose; continuous glucose monitoring; insulin ID SEVERE HYPOGLYCEMIA; INSULIN DELIVERY; BIONIC PANCREAS; DISEASE; ADULTS AB Type 1 diabetes mellitus is a disorder of glucose regulation characterized by autoimmune destruction of the insulin-producing pancreatic beta-cells and the need for lifelong insulin replacement therapy. Both glucose and HbA1c criteria are available for the diagnosis of diabetes. Achieving and maintaining near-normal blood glucose concentrations with appropriate administration of insulin is critical for successful long-term care of patients with diabetes mellitus and prevention of diabetic complications, but it is very difficult to achieve. Efforts to intensify therapy usually result in hypoglycemia. Point-of-care blood glucose testing provides the information needed by patients for clinical decision-making. Despite the ease of use and rapid reporting of modern point-of-care glucose monitoring devices, they provide measurements only intermittently. Continuous glucose monitoring devices can provide new glucose measurements every 5 minutes and may facilitate better glucose control. The development of new technologies that integrate continuous glucose monitoring technology with insulin pumps and a control algorithm to create a system for automated insulin delivery has the potential to significantly improve glycemic control, reduce hypoglycemia, and reduce the burden of care in type 1 diabetes mellitus. C1 [Kahanovitz, Lindy] Ben Gurion Univ Negev, Dept Biotechnol Engn, Beer Sheva, Israel. [Kahanovitz, Lindy; Russell, Steven J.] Harvard Med Sch, Massachusetts Gen Hosp, Diabet Res Ctr, 50 Staniford St,Suite 340, Boston, MA 02114 USA. [Sluss, Patrick M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Russell, SJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Diabet Res Ctr, 50 Staniford St,Suite 340, Boston, MA 02114 USA. EM sjrussell@mgh.harvard.edu NR 35 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 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD MAR PY 2017 VL 16 IS 1 BP 37 EP 40 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM9RH UT WOS:000395648300008 ER PT J AU Johnson, RS Fowler, JC Jani, SN Eichelberger, HL Oldham, JM Poa, E Graham, DP AF Johnson, R. Scott Fowler, J. Christopher Jani, Suni N. Eichelberger, Hillary L. Oldham, John M. Poa, Edward Graham, David P. TI A Systematic Analysis of Treatment Effects on Depressive Symptom Severity by Level of Coercion SO PSYCHIATRIC QUARTERLY LA English DT Article DE Depression; PHQ-9; Coercion; Fitness for duty ID VOLUNTARY; ABUSE; OUTCOMES; CLIENTS; DISORDERS; VALIDITY; DRUG AB Few studies examine the effect of interpersonal, regulatory or legal coercion on the treatment of depressive symptoms. This retrospective case-control study compared the recovery rates of 574 adults whose level of coercion was scored on a 0-3 scale from fully voluntary to severe coercion when admitted to the Menninger Clinic between 2009 and 2014. The change in Patient Health Questionnaire-9 (PHQ-9) scores (measuring depression severity) from admission to discharge served as the primary outcome measure. Level of coercion was not associated with a difference in rate of improvement in PHQ-9 score. Greater improvement in PHQ-9 scores was associated with (a) older age, (b) lack of a psychotic spectrum disorder diagnosis, (c) stronger working alliance with treatment team, and (d) less difficulty with emotional regulation [lower Difficulties in Emotion Regulation Scale (DERS) scores]. DERS scores were the most impactful factor. This study suggests that licensure boards can continue to mandate treatment despite concerns that coercion may decrease treatment effectiveness. C1 [Johnson, R. Scott] Harvard Med Sch, MGH Law & Psychiat Serv, 1 Bowdoin Sq,10th Floor, Boston, MA 02114 USA. [Fowler, J. Christopher; Oldham, John M.; Poa, Edward; Graham, David P.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX USA. [Jani, Suni N.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Eichelberger, Hillary L.] Univ Texas Med Sch Houston, Houston, TX USA. [Graham, David P.] Michael E DeBakey Vet Affairs VA Med Ctr, Neurorehabil Neurons Networks Traumat Brain Injur, Houston, TX USA. [Graham, David P.] Michael E DeBakey Vet Affairs VA Med Ctr, Houston, TX USA. [Graham, David P.] South Cent Mental Illness Res Educ & Clin Ctr MIR, Dept Vet Affairs, Little Rock, AR USA. [Fowler, J. Christopher] Menninger Clin, Clin Res, Houston, TX USA. [Oldham, John M.] Menninger Clin, Houston, TX USA. RP Johnson, RS (reprint author), Harvard Med Sch, MGH Law & Psychiat Serv, 1 Bowdoin Sq,10th Floor, Boston, MA 02114 USA. EM rscottjohnson3@gmail.com NR 23 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-2720 EI 1573-6709 J9 PSYCHIAT QUART JI Psychiatr. Q. PD MAR PY 2017 VL 88 IS 1 BP 39 EP 46 DI 10.1007/s11126-016-9433-3 PG 8 WC Psychiatry SC Psychiatry GA EL3RE UT WOS:000394535800004 ER PT J AU Glynn, SM Marder, SR Noordsy, DL O'Keefe, C Becker, DR Drake, RE Sugar, CA AF Glynn, Shirley M. Marder, Stephen R. Noordsy, Douglas L. O'Keefe, Christopher Becker, Deborah R. Drake, Robert E. Sugar, Catherine A. TI An RCT Evaluating the Effects of Skills Training and Medication Type on Work Outcomes Among Patients With Schizophrenia SO PSYCHIATRIC SERVICES LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; SEVERE MENTAL-ILLNESS; SUPPORTED EMPLOYMENT; INDIVIDUAL PLACEMENT; WORKPLACE SKILLS; SCALE; MODEL AB Objective: Although supported employment increases job acquisition for people with serious mental illness, data on participants' job tenure have been variable. This study evaluated the effects of a standardized work skills training program (the Workplace Fundamentals Module [WPFM]) on job tenure and other work outcomes among individuals receiving individual placement and support (IPS). The effects of two atypical antipsychotic medications on side effects were also tested. The primary hypothesis testedwas that participants in IPS plus WPFM would have increased job tenure compared with those enrolled in IPS only, and the secondary hypothesis was that different antipsychoticmedicationswould yield unique side effects. Methods: A 232 randomized controlled trial compared work outcomes, including job tenure, of participants receiving IPS with or without WPFM for up to two years after obtaining a job. Participants were also randomly assigned to olanzapine or risperidone. Measures of work outcomes, clinical status, and medication side effects were collected. Results: Among 107 participants, 63% obtained at least one job. WPFM did not increase job tenure (51.53 and 41.37 total weeks worked for IPS only and IPS plus WPFM, respectively) or affect other work outcomes. Participants on olanzapine experienced increased body mass index, whereas those on risperidone lost weight, but medications did not differentially affect clinical or job outcomes. Conclusions: Clinic-based skills training did not improve work outcomes accruing from IPS. Risperidone, compared with olanzapine, may reduce body mass but has no differential effect on other work or clinical outcomes. C1 [Glynn, Shirley M.; Marder, Stephen R.] US Dept Vet Affairs, Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Glynn, Shirley M.; Marder, Stephen R.; Sugar, Catherine A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Noordsy, Douglas L.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. [O'Keefe, Christopher] Southern New Hampshire Univ, Manchester, NH USA. [Becker, Deborah R.; Drake, Robert E.] WESTAT Corp, Rockville Inst, Lebanon, NH USA. [Sugar, Catherine A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Noordsy, Douglas L.; O'Keefe, Christopher; Becker, Deborah R.; Drake, Robert E.] Dartmouth Coll, Geisel Sch Med, Dept Psychiat, Hanover, NH USA. [Becker, Deborah R.; Drake, Robert E.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Hanover, NH USA. RP Glynn, SM (reprint author), US Dept Vet Affairs, Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA.; Glynn, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. EM sglynn@ucla.edu FU National Institute of Mental Health [5R0MH 041573-15] FX This research was supported by a National Institute of Mental Health grant (5R0MH 041573-15) to Dr. Marder. The authors thank the employment specialists and staff who worked on the project and Jim Mintz, Ph.D., and Robert P. Liberman, M.D., for their contributions in the development of the study. NR 24 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD MAR 1 PY 2017 VL 68 IS 3 BP 271 EP 277 DI 10.1176/appi.ps.201500171 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EP0RB UT WOS:000397093300012 PM 27799019 ER PT J AU Meyer, OL Sisco, SM Harvey, D Zahodne, LB Glymour, MM Manly, JJ Marsiske, M AF Meyer, Oanh L. Sisco, Shannon M. Harvey, Danielle Zahodne, Laura B. Glymour, M. Maria Manly, Jennifer J. Marsiske, Michael TI Neighborhood Predictors of Cognitive Training Outcomes and Trajectories in ACTIVE SO RESEARCH ON AGING LA English DT Article DE neighborhood; cognition; cognitive training; plasticity; social determinants ID OLDER MEXICAN-AMERICANS; SOCIOECONOMIC-STATUS; AFRICAN-AMERICANS; HEALTH CONSEQUENCES; URBAN NEIGHBORHOOD; ALZHEIMER-DISEASE; ETHNIC PATTERNS; LATE-LIFE; ADULTS; CONTEXT AB We examined the influence of neighborhood socioeconomic position (SEP), racial/ethnic composition, and living in a major city on cognitive trajectories and intervention outcomes. Data came from the Advanced Cognitive Training for Independent and Vital Elderly study (N = 2,438). Mixed effects analyses examined the associations between neighborhood variables and memory, reasoning, speed of processing, and everyday cognition, estimating differences in initial gains (potentially related to practice) and long-term rate of change over 10 years. The effect of reasoning training on initial gain was weaker for individuals in a major city. For everyday cognition, there was a stronger initial gain for memory-trained and control participants in areas with more racial/ethnic minorities and for speed-trained and control individuals in higher SEP areas. The racial/ethnic minority effect was no longer significant after adjustment for multiple comparisons. Neighborhood factors may be more important in practice-related improvement than in long-term change. C1 [Meyer, Oanh L.] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA. [Harvey, Danielle] Univ Calif Davis, Sch Med, Div Biostat Publ Hlth Sci, Sacramento, CA 95817 USA. [Sisco, Shannon M.] US Dept Vet Affairs, Danville, IL USA. [Zahodne, Laura B.] Columbia Univ, Dept Neurol, Cognit Neurosci Div, New York, NY USA. [Manly, Jennifer J.] Columbia Univ, Neuropsychol, New York, NY USA. [Glymour, M. Maria] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Marsiske, Michael] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Clin & Hlth Psychol, Gainesville, FL USA. RP Meyer, OL (reprint author), Univ Calif Davis, Sch Med, Dept Neurol, Alzheimers Dis Ctr, 4860 Y St, Sacramento, CA 95817 USA. EM olmeyer@ucdavis.edu FU Advanced Psychometrics Methods in Cognitive Aging Research [R13AG030995]; National Institutes of Health [P30AG010129, P30AG043097, UL1 TR 000002]; National Institute on Aging; National Institute of Nursing Research [U01NR04507, U01NR04508, U01AG14260, U01AG14282, U01AG14263, U01AG14289, U01AG14276] 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 the Advanced Psychometrics Methods in Cognitive Aging Research (R13AG030995) and by National Institutes of Health grants to the University of California, Davis Alzheimer's Disease Center (P30AG010129), the Latino Aging Research Resource Center (P30AG043097), and the Clinical and Translational Science Center (UL1 TR 000002). The ACTIVE intervention trials were supported by grants from the National Institute on Aging and the National Institute of Nursing Research to Hebrew Senior Life (U01NR04507), Indiana University School of Medicine (U01NR04508), Johns Hopkins University (U01AG14260), New England Research Institutes (U01AG14282), Pennsylvania State University (U01AG14263), the University of Alabama at Birmingham (U01AG14289), and the University of Florida (U01AG14276). NR 71 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 0164-0275 EI 1552-7573 J9 RES AGING JI Res. Aging PD MAR PY 2017 VL 39 IS 3 BP 443 EP 467 DI 10.1177/0164027515618242 PG 25 WC Gerontology SC Geriatrics & Gerontology GA EN7RE UT WOS:000396199100004 PM 26667987 ER PT J AU Quach, LT Chang, BH Brophy, MT Thwin, SS Hannagan, K O'Dell, JR AF Quach, Lien T. Chang, Bei-Hung Brophy, Mary T. Thwin, Soe Soe Hannagan, Keri O'Dell, James R. TI Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events SO RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; clinical trials and methods; biological therapies; DMARDs; infection and arthritis ID MODIFYING ANTIRHEUMATIC DRUGS; SERIOUS BACTERIAL-INFECTIONS; FACTOR-ALPHA ANTAGONISTS; METHOTREXATE; RECOMMENDATIONS; TUBERCULOSIS; AGENTS; TRIAL; RISK AB Objective. The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial. Methods. The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies. Results. Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [ 12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [ 6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%). Conclusion. This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX. C1 [Quach, Lien T.; Brophy, Mary T.; Thwin, Soe Soe; Hannagan, Keri] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Cooperat Studies Program, Boston, MA USA. [Quach, Lien T.] Univ Massachusetts, Dept Gerontol, Boston, MA 02125 USA. [Chang, Bei-Hung] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Brophy, Mary T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Thwin, Soe Soe] Boston Univ, Sch Publ Hlth, Boston, MA USA. [O'Dell, James R.] VA Nebraska Western Iowa Healthcare Syst, Omaha, NE USA. [O'Dell, James R.] Univ Nebraska Med Ctr, Dept Internal Med, Div Rheumatol, Omaha, NE USA. RP Quach, LT (reprint author), Massachusetts Vet Epidemiol Res & Informat Ctr, 150 S Huntington Ave, Boston, MA 02130 USA. EM lien.quach@va.gov FU Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; Canadian Institutes for Health Research; National Institutes of Health; American Recovery & Reinvestment Act by inter-agency agreements FX This study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; Canadian Institutes for Health Research; and the National Institutes of Health and the American Recovery & Reinvestment Act by inter-agency agreements; placebo etanercept was donated by Amgen. NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 IS 3 BP 378 EP 383 DI 10.1093/rheumatology/kew412 PG 6 WC Rheumatology SC Rheumatology GA EP0BQ UT WOS:000397052200008 ER PT J AU Ames, D Tessier, J Erickson, Z Meyer, H Baker, M Gelberg, H Arnold, I Kwan, C Chamberlin, V Rosen, J Shah, C Hellemann, G Lewis, M Nguyen, C Sachinvala, N Amrami, B Pierre, J AF Ames, Donna Tessier, Jillian Erickson, Zachary Meyer, Hilary Baker, Matthew Gelberg, Hollie Arnold, Irina Kwan, Crystal Chamberlin, Valery Rosen, Jennifer Shah, Chandresh Hellemann, Gerhard Lewis, Melissa Nguyen, Charles Sachinvala, Neena Amrami, Binyamin Pierre, Joseph TI THERAPEUTIC LIFESTYLE CHANGES (TLC) FOR ADULTS WITH SERIOUS MENTAL ILLNESS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Ames, Donna; Tessier, Jillian; Erickson, Zachary; Meyer, Hilary; Baker, Matthew; Gelberg, Hollie; Arnold, Irina; Kwan, Crystal; Chamberlin, Valery; Shah, Chandresh; Lewis, Melissa; Sachinvala, Neena; Amrami, Binyamin; Pierre, Joseph] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ames, Donna; Gelberg, Hollie; Chamberlin, Valery; Hellemann, Gerhard; Sachinvala, Neena; Amrami, Binyamin; Pierre, Joseph] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Rosen, Jennifer] VA Northern Calif Healthcare Syst, Martinez, CA USA. [Rosen, Jennifer] Univ Pacific, Sch Pharm, Stockton, CA 95211 USA. [Rosen, Jennifer] Univ Southern Calif, Sch Pharm, Los Angeles, CA USA. [Nguyen, Charles] VA Long Beach Healthcare Syst, Long Beach, CA USA. [Amrami, Binyamin] Western Univ Hlth Sci, Pomona, CA USA. FU US Department of Veterans Affairs Rehabilitation Research and Development Merit Review Award FX Research supported by US Department of Veterans Affairs Rehabilitation Research and Development Merit Review Award. 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M14 BP S216 EP S216 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200581 ER PT J AU Baran, B Karahanoglu, FI Demanuele, C Fowler, RA Vuper, TC Seicol, B Correll, D Callahan, CE Parr, E Stickgold, R Manoach, DS AF Baran, Bengi Karahanoglu, F. Isik Demanuele, Charmaine Fowler, Rachel A. Vuper, Tessa C. Seicol, Benjamin Correll, David Callahan, Cameron E. Parr, Elaine Stickgold, Robert Manoach, Dara S. TI INTEGRITY OF THALAMOCORTICAL CIRCUITRY IS ASSOCIATED WITH SLEEP SPINDLE DEFICITS IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Baran, Bengi; Karahanoglu, F. Isik; Demanuele, Charmaine; Fowler, Rachel A.; Vuper, Tessa C.; Correll, David; Manoach, Dara S.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Seicol, Benjamin; Callahan, Cameron E.; Parr, Elaine; Stickgold, Robert] Harvard Med Sch, Beth Israel Deaconess Med Ctr, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA.4 BP S114 EP S114 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200308 ER PT J AU Buck, K Leonhardt, B George, S James, A Vohs, J Lysaker, P AF Buck, Kelly Leonhardt, Bethany George, Sunita James, Alison Vohs, Jenifer Lysaker, Paul TI METACOGNITIVE DEFICITS IN SCHIZOPHRENIA; COMPARISONS WITH BORDERLINE PERSONALITY DISORDER AND SUBSTANCE USE DISORDER SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Buck, Kelly] VA Med Ctr, Indianapolis, IN USA. [Leonhardt, Bethany; Vohs, Jenifer; Lysaker, Paul] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [George, Sunita] Univ Indianapolis, Indianapolis, IN 46227 USA. [James, Alison] San Francisco VA Med Ctr, San Francisco, CA 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M42 BP S226 EP S226 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200608 ER PT J AU Chung, Y Haut, K He, G Van Erp, T McEwen, S Addington, J Bearden, C Cadenhead, K Cornblatt, B Mathalon, D McGlashan, T Perkins, D Seidman, L Tsuang, M Walker, E Woods, S Cannon, T AF Chung, Yoonho Haut, Kristen He, George Van Erp, Theo McEwen, Sarah Addington, Jean Bearden, Carrie Cadenhead, Kristin Cornblatt, Barbara Mathalon, Daniel McGlashan, Thomas Perkins, Diana Seidman, Larry Tsuang, Ming Walker, Elaine Woods, Scott Cannon, Tyrone TI VENTRICULAR ENLARGEMENT AND PROGRESSIVE REDUCTION IN CORTICAL GRAY MATTER ARE LINKED IN PRODROMAL YOUTH WHO DEVELOP PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Chung, Yoonho; He, George; McGlashan, Thomas; Woods, Scott; Cannon, Tyrone] Yale Univ, New Haven, CT 06520 USA. [Haut, Kristen] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Van Erp, Theo] Univ Calif Irvine, Irvine, CA USA. [McEwen, Sarah; Bearden, Carrie] Univ Calif Los Angeles, Los Angeles, CA USA. [Addington, Jean] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Cadenhead, Kristin; Tsuang, Ming] Univ Calif San Diego, San Diego, CA 92103 USA. [Cornblatt, Barbara] Zuker Hillside Hosp, New York, NY USA. [Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Perkins, Diana] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry] Harvard Med Sch, Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Seidman, Larry] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Walker, Elaine] Emory Univ, Atlanta, GA 30322 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 83 BP S46 EP S47 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200124 ER PT J AU del Re, E Konishi, J Bouix, S Petryshen, T Blokland, G Kikinis, Z Niznikiewicz, M Seidman, LJ McCarley, R Shenton, M AF del Re, Elisabetta Konishi, Jun Bouix, Sylvain Petryshen, Tracey Blokland, Gabriella Kikinis, Zora Niznikiewicz, Margaret Seidman, Larry J. McCarley, Robert Shenton, Martha TI LATERAL VENTRICLE VOLUMES AND FRACTIONAL ANISOTROPY OF THE CORPUS CALLOSUM ARE NEGATIVELY ASSOCIATED IN FIRST-EPISODE SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Konishi, Jun; Petryshen, Tracey; Kikinis, Zora] Harvard Med Sch, Boston, MA USA. VA Boston Healthcare Syst, Boston, MA USA. [Bouix, Sylvain] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Blokland, Gabriella] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Niznikiewicz, Margaret] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Seidman, Larry J.] Harvard Med Sch, Div Psychiat, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr Publ, Boston, MA USA. [McCarley, Robert] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Shenton, Martha] Harvard Med Sch, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Vet Affairs Boston Healthcare Syst, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SU80 BP S190 EP S190 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200513 ER PT J AU Demyanovich, H Rowland, L Wijtenburg, A Eaton, W Rodriquez, K Cihakova, D Vladut, M Jackson, J Feldman, S Carpenter, W Fasano, A Santora, D Sullivan, K Gaston, F Hong, E Kelly, D AF Demyanovich, Haley Rowland, Laura Wijtenburg, Andrea Eaton, William Rodriquez, Kierstyn Cihakova, Daniela Vladut, Monica Jackson, Jessica Feldman, Stephanie Carpenter, William Fasano, Alessio Santora, Deborah Sullivan, Kelli Gaston, Frank Hong, Elliott Kelly, Deanna TI HIGH ANTIGLIADIN ANTIBODIES (IGG) ARE LINKED TO PERIPHERAL AND CENTRAL MEASURES OF INFLAMMATION IN A SUBSET OF PEOPLE WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Demyanovich, Haley; Santora, Deborah] Univ Maryland, College Pk, MD 20742 USA. [Rowland, Laura; Wijtenburg, Andrea; Jackson, Jessica; Carpenter, William; Gaston, Frank; Hong, Elliott; Kelly, Deanna] Maryland Psychiat Res Ctr, Catonsville, MD USA. [Rowland, Laura; Wijtenburg, Andrea; Jackson, Jessica; Carpenter, William; Gaston, Frank; Hong, Elliott; Kelly, Deanna] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, College Pk, MD 20742 USA. [Eaton, William; Rodriquez, Kierstyn; Cihakova, Daniela; Vladut, Monica] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Feldman, Stephanie] Univ Maryland Baltimore, Baltimore, MD USA. [Fasano, Alessio] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sullivan, Kelli] Univ N Carolina, Chapel Hill, NC 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 122 BP S68 EP S68 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200183 ER PT J AU Dunn, W Wynn, JK Rassovsky, Y Wu, A Iacoboni, M Hellemann, G Green, MF AF Dunn, Walter Wynn, Jonathan K. Rassovsky, Yuri Wu, Allan Iacoboni, Marco Hellemann, Gerhard Green, Michael F. TI THE EFFECT OF BILATERAL TRANSCRANIAL DIRECT CURRENT STIMULATION ON TONE MATCHING TASK PERFORMANCE AND MISMATCH NEGATIVITY IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Wynn, Jonathan K.] VISN 22 MIRECC, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Wynn, Jonathan K.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Rassovsky, Yuri] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, Ramat Gan, Israel. [Wu, Allan; Iacoboni, Marco; Hellemann, Gerhard; Green, Michael F.] Univ Calif Los Angeles, Los Angeles, CA 90024 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SU103 BP S198 EP S198 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200535 ER PT J AU Ferri, J Fryer, S Roach, BJ Loewy, R Ford, JM Mathalon, D AF Ferri, Jamie Fryer, Susanna Roach, Brian J. Loewy, Rachel Ford, Judith M. Mathalon, Daniel TI THALAMIC DYSCONNECTIVITY IN INDIVIDUALS AT CLINICALLY HIGH RISK FOR SCHIZOPHRENIA AND DURING EARLY ILLNESS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Ferri, Jamie; Fryer, Susanna; Roach, Brian J.; Loewy, Rachel; Ford, Judith M.; Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Loewy, Rachel] San Francisco VA Med Ctr, San Francisco, CA 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 77 BP S44 EP S44 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200118 ER PT J AU Francis, A Mothi, S Mathew, I Tandon, N Clementz, B Pearlson, G Sweeney, J Tamminga, C Keshavan, M AF Francis, Alan Mothi, S. Mathew, I. Tandon, N. Clementz, B. Pearlson, G. Sweeney, J. Tamminga, C. Keshavan, M. TI IS THE ANTERIOR SPLENIUM AN INTERMEDIATE PHENOTYPE ACROSS THE PSYCHOSIS DIMENSION? SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Keshavan, M.] Harvard Med Sch, Boston, MA USA. [Mothi, S.] MGH, Boston, MA USA. [Mathew, I.; Tandon, N.] BIDMC, Boston, MA USA. [Pearlson, G.] Yale Univ, New Haven, CT 06520 USA. [Sweeney, J.; Tamminga, C.] UT Southwestern, Dallas, TX 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SU83 BP S191 EP S191 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200515 ER PT J AU Fryer, S Townsend, JD Ford, JM Roach, BJ Calhoun, VD Pearlson, GD Kiehl, KA Srihari, VH Woods, SW McGlashan, TH Mathalon, DH AF Fryer, Susanna Townsend, Jennifer D. Ford, Judith M. Roach, Brian J. Calhoun, Vince D. Pearlson, Godfrey D. Kiehl, Kent A. Srihari, Vinod H. Woods, Scott W. McGlashan, Thomas H. Mathalon, Daniel H. TI FMRI RESPONSE DURING ERROR PROCESSING IN CLINICAL HIGH RISK AND EARLY ILLNESS SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Fryer, Susanna; Townsend, Jennifer D.; Ford, Judith M.; Roach, Brian J.; Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Townsend, Jennifer D.; Ford, Judith M.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Calhoun, Vince D.; Kiehl, Kent A.] Mind Res Network, Daytona Beach, FL USA. [Calhoun, Vince D.; Kiehl, Kent A.] Univ New Mexico, Albuquerque, NM 87131 USA. [Pearlson, Godfrey D.] Yale Univ, Inst Living, Olin Neuropsychiat Res Ctr, New Haven, CT 06520 USA. [Srihari, Vinod H.; Woods, Scott W.; McGlashan, Thomas H.] Yale Univ, Sch Med, New Haven, CT 06520 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 76 BP S43 EP S44 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200117 ER PT J AU Gelberg, H Erickson, Z Kwan, C Arnold, I Chamberlin, V Rosen, J Shah, C Nguyen, C Hellemann, G Aragaki, D Kunkel, C Lewis, M Sachinvala, N Sonza, P Baker, M Mena, S Meyer, H Tessier, J Pierre, J Ames, D AF Gelberg, Hollie Erickson, Zachary Kwan, Crystal Arnold, Irina Chamberlin, Valery Rosen, Jennifer Shah, Chandresh Nguyen, Charles Hellemann, Gerhard Aragaki, Dixie Kunkel, Charles Lewis, Melissa Sachinvala, Neena Sonza, Patrick Baker, Matthew Mena, Shirley Meyer, Hilary Tessier, Jillian Pierre, Joseph Ames, Donna TI BEHAVIORAL INTERVENTIONS FOR ANTIPSYCHOTIC MEDICATION-ASSOCIATED OBESITY: A RANDOMIZED, CONTROLLED FOUR-SITE TRIAL SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Gelberg, Hollie; Erickson, Zachary; Kwan, Crystal; Arnold, Irina; Chamberlin, Valery; Shah, Chandresh; Aragaki, Dixie; Kunkel, Charles; Lewis, Melissa; Sachinvala, Neena; Sonza, Patrick; Baker, Matthew; Mena, Shirley; Meyer, Hilary; Tessier, Jillian; Pierre, Joseph; Ames, Donna] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Gelberg, Hollie; Chamberlin, Valery; Hellemann, Gerhard; Aragaki, Dixie; Kunkel, Charles; Sachinvala, Neena; Sonza, Patrick; Pierre, Joseph; Ames, Donna] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Rosen, Jennifer] VA Northern Calif Healthcare Syst, Mather, CA USA. [Rosen, Jennifer] Univ Pacific, Sch Pharm, Stockton, CA 95211 USA. [Rosen, Jennifer] Univ Southern Calif, Sch Pharm, Los Angeles, CA USA. [Nguyen, Charles] VA Long Beach Healthcare Syst, Long Beach, CA USA. FU US Department of Veterans Affairs Rehabilitation Research and Development Merit Review Award FX Research supported by US Department of Veterans Affairs Rehabilitation Research and Development Merit Review Award. 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA15 BP S118 EP S118 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200319 ER PT J AU Greenberg, J Wynn, JK Lee, JH Hellemann, G Green, MF AF Greenberg, Jared Wynn, Jonathan K. Lee, Junghee Hellemann, Gerhard Green, Michael F. TI RESILIENCE IN HOMELESS VETERANS WITH AND WITHOUT A HISTORY OF PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Greenberg, Jared] VA Greater Los Angeles Healthcare Syst VISN 22 MI, Los Angeles, CA USA. [Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lee, Junghee] Univ Calif Los Angeles, Los Angeles, CA USA. [Hellemann, Gerhard; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 95 BP S51 EP S51 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200136 ER PT J AU Horton, L Haas, G Stepp, S AF Horton, Leslie Haas, Gretchen Stepp, Stephanie TI CHILDHOOD SOCIAL AND EMOTIONAL FUNCTIONING DEFICITS IN A COMMUNITY SAMPLE OF WOMEN WITH PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Horton, Leslie] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Haas, Gretchen] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. [Haas, Gretchen; Stepp, Stephanie] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M7 BP S213 EP S213 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200574 ER PT J AU Ivleva, E Clementz, B Dutcher, A Aslan, S Witte, B Poudyal, G Lu, H Meda, S Pearlson, GD Sweeney, J Keshavan, M Tamminga, C AF Ivleva, Elena Clementz, Brett Dutcher, Anthony Aslan, Sina Witte, Bradley Poudyal, Gaurav Lu, Hanzhang Meda, Shashwath Pearlson, Godfrey D. Sweeney, John Keshavan, Matcheri Tamminga, Carol TI BRAIN STRUCTURE BIOMARKERS AT THE PSYCHOSIS/NONPSYCHOSIS INTERPHASE: FINDINGS FROM THE BIPOLAR-SCHIZOPHRENIA NETWORK FOR INTERMEDIATE PHENOTYPES SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Ivleva, Elena; Dutcher, Anthony; Witte, Bradley; Poudyal, Gaurav; Sweeney, John; Tamminga, Carol] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Clementz, Brett] Univ Georgia, Athens, GA 30602 USA. [Aslan, Sina] Adv MRI LLC, Frisco, TX USA. [Aslan, Sina; Lu, Hanzhang] UT Southwestern Med Ctr, Dallas, TX USA. [Lu, Hanzhang] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Meda, Shashwath] Hartford Hosp, Inst Living, Hartford, CT 06115 USA. [Pearlson, Godfrey D.] Yale Sch Med, New Haven, CT USA. [Pearlson, Godfrey D.] Olin Res Ctr, New Haven, CT USA. [Keshavan, Matcheri] Harvard Med Sch, BIDMC, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 10 BP S10 EP S10 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200031 ER PT J AU Jacob, M Ford, J Roach, B Calhoun, V Mathalon, D AF Jacob, Michael Ford, Judith Roach, Brian Calhoun, Vince Mathalon, Daniel TI SEMANTIC PRIMING ABNORMALITIES IN SCHIZOPHRENIA: AN ERP-FMRI FUSION STUDY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Jacob, Michael; Ford, Judith; Mathalon, Daniel] UCSF, San Francisco, CA USA. [Jacob, Michael; Ford, Judith; Mathalon, Daniel] San Francisco VA Med Ctr, San Francisco, CA USA. [Roach, Brian] SFVAMC, San Francisco, CA USA. [Calhoun, Vince] Univ New Mexico, Mind Res Network, Albuquerque, NM 87131 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 145 BP S76 EP S77 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200206 ER PT J AU Jahshan, C Wynn, JK Dolinsky, M Mathalon, D Green, MF AF Jahshan, Carol Wynn, Jonathan K. Dolinsky, Michelle Mathalon, Daniel Green, Michael F. TI COGNITIVE CORRELATES OF VISUAL CORTICAL PLASTICITY IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Jahshan, Carol] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Wynn, Jonathan K.] VA Greater Los Angeles Healthcare Syst, VISN MIRECC 22, Los Angeles, CA USA. [Dolinsky, Michelle] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mathalon, Daniel] UCSF, San Francisco, CA USA. [Mathalon, Daniel] SFVAMC, San Francisco, CA USA. [Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA70 BP S138 EP S138 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200374 ER PT J AU James, A Johannesen, J Buck, K Lysaker, P AF James, Alison Johannesen, Jason Buck, Kelly Lysaker, Paul TI RELATIVELY MORE INTACT LEVELS OF SOCIAL COGNITION PREDICT FEWER IMPAIRMENTS IN NEUROCOGNITION, METACOGNITION, AND HEALTHIER PERSONALITY FUNCTIONING IN A SAMPLE WITH PROLONGED SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [James, Alison] UCSF, San Francisco, CA USA. [James, Alison] San Francisco VA Med Ctr, San Francisco, CA USA. [Johannesen, Jason] Yale Univ, New Haven, CT 06520 USA. [Buck, Kelly; Lysaker, Paul] Roudebush VA Med Ctr, Indianapolis, IN USA. [Lysaker, Paul] Indiana Univ Sch Med, Indianapolis, IN 46202 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M121 BP S254 EP S255 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200683 ER PT J AU Jimenez, A Lee, JH Wynn, JK Horan, W Iglesias, J Hoy, J Green, MF AF Jimenez, Amy Lee, Junghee Wynn, Jonathan K. Horan, William Iglesias, Julio Hoy, Jennifer Green, Michael F. TI THE ROLE OF PREFRONTAL CORTEX IN SELF-REFERENTIAL MEMORY RETRIEVAL IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Jimenez, Amy] VA Greater Los Angeles Healthcare Syst Univ Calif, Los Angeles, CA USA. [Lee, Junghee; Iglesias, Julio] Univ Calif Los Angeles, Los Angeles, CA USA. [Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Horan, William] Univ Calif Los Angeles, Semel Inst, Los Angeles, CA USA. [Hoy, Jennifer] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 56 BP S29 EP S29 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200077 ER PT J AU Kelsven, S Addington, J Bearden, C Cannon, T Cornblatt, B Mathalon, D McGlashan, T Perkins, D Seidman, L Walker, E Woods, S Cadenhead, K AF Kelsven, Skylar Addington, Jean Bearden, Carrie Cannon, Tyrone Cornblatt, Barbara Mathalon, Daniel McGlashan, Thomas Perkins, Diana Seidman, Larry Walker, Elaine Woods, Scott Cadenhead, Kristin TI METABOLIC ABNORMALITIES AND OMEGA-3 FATTY ACIDS IN LATINOS AT CLINICAL HIGH RISK FOR PSYCHOSIS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Kelsven, Skylar] SDSU UCSD Joint Program, San Diego, CA USA. [Addington, Jean] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Cannon, Tyrone; McGlashan, Thomas; Woods, Scott] Yale Univ, New Haven, CT 06520 USA. [Cornblatt, Barbara] Zuker Hillside Hosp, New York, NY USA. [Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Perkins, Diana] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Boston, MA 02215 USA. [Seidman, Larry] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Walker, Elaine] Emory Univ, Atlanta, GA 30322 USA. [Cadenhead, Kristin] Univ Calif San Diego, San Diego, CA 92103 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 20 BP S14 EP S15 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200041 ER PT J AU Levitt, J Kubicki, M McCarley, R Shenton, M Rathi, Y AF Levitt, James Kubicki, Marek McCarley, Robert Shenton, Martha Rathi, Yogesh TI FRONTOSTRIATAL MISWIRING IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Levitt, James] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Boston, MA USA. [Kubicki, Marek; Shenton, Martha; Rathi, Yogesh] Harvard Med Sch, Boston, MA USA. [McCarley, Robert] VA Boston Healthcare Syst, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 161 BP S82 EP S82 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200222 ER PT J AU Lyall, A Fitzgerald, Z Pasternak, O Molokotos, E Lutz, O Mesholam-Gately, R Wojcik, J Ben Brent, Thermenos, H Whitfield-Gabrieli, S Gabrieli, J Keshavan, MS Kubicki, M Seidman, LJ AF Lyall, Amanda Fitzgerald, Zachary Pasternak, Ofer Molokotos, Elena Lutz, Olivia Mesholam-Gately, Raquel Wojcik, Joanne Ben Brent Thermenos, Heidi Whitfield-Gabrieli, Susan Gabrieli, John Keshavan, Matcheri S. Kubicki, Marek Seidman, Larry J. TI THE RELATIONSHIP BETWEEN WHITE MATTER CONNECTIONS AND COGNITIVE DOMAINS IN CHILDREN AT GENETIC RISK FOR SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Lyall, Amanda] Harvard Med Sch, Boston, MA USA. [Fitzgerald, Zachary] Harvard Med Sch, Univ Washington, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Molokotos, Elena; Lutz, Olivia; Mesholam-Gately, Raquel; Wojcik, Joanne; Keshavan, Matcheri S.; Seidman, Larry J.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Publ Psychiat Div, Massachusetts Mental Hlth Ctr, Boston, MA USA. [Ben Brent] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thermenos, Heidi] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Whitfield-Gabrieli, Susan; Gabrieli, John] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Whitfield-Gabrieli, Susan; Gabrieli, John] MIT, Poitras Ctr Affect Disorders Res, Cambridge, MA 02139 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M84 BP S241 EP S241 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200647 ER PT J AU McCleery, A Wynn, JK Reavis, E Kutasevich, E Morales, J Roach, BJ Mathalon, D Green, MF AF McCleery, Amanda Wynn, Jonathan K. Reavis, Eric Kutasevich, Eugene Morales, Jaime Roach, Brian J. Mathalon, Daniel Green, Michael F. TI CORTICAL PLASTICITY IN SCHIZOPHRENIA: ASSOCIATIONS WITH COGNITION AND COMMUNITY FUNCTIONING SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [McCleery, Amanda; Wynn, Jonathan K.; Reavis, Eric; Kutasevich, Eugene; Morales, Jaime; Green, Michael F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Roach, Brian J.; Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mathalon, Daniel] San Francisco VA Med Ctr, San Francisco, CA USA. FU VA Desert Pacific VISN 22 Mental Illness Research, Education, and Clinical Center Pala grant; NIMH Career Development Award [K23MH108829] FX This research was supported by a VA Desert Pacific VISN 22 Mental Illness Research, Education, and Clinical Center Pala grant (PI: McCleery). Dr. McCleery is supported by a NIMH Career Development Award (K23MH108829). 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M72 BP S236 EP S236 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200635 ER PT J AU Prasad, K Nimgaonkar, V Keshavan, M AF Prasad, Konasale Nimgaonkar, Vish Keshavan, Matcheri TI INFLAMMATION ALTERS BRAIN FUNCTION IN CRITICAL REGIONS AND COGNITIVE PERFORMANCE IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Prasad, Konasale] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Nimgaonkar, Vish; Keshavan, Matcheri] Harvard Med Sch, BIDMC, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 140 BP S74 EP S75 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200201 ER PT J AU Ramsay, I Fryer, S Boos, A Roach, BJ Fisher, M Loewy, R Vinogradov, S Mathalon, D AF Ramsay, Ian Fryer, Susanna Boos, Alison Roach, Brian J. Fisher, Melissa Loewy, Rachel Vinogradov, Sophia Mathalon, Daniel TI TARGETED COGNITIVE TRAINING IS NEUROPROTECTIVE AGAINST THALAMIC VOLUME LOSS IN EARLY SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Ramsay, Ian; Fisher, Melissa; Vinogradov, Sophia] Univ Minnesota, Minneapolis, MN 55455 USA. [Fryer, Susanna; Roach, Brian J.; Loewy, Rachel; Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Boos, Alison] San Francisco VA Med Ctr, San Francisco, CA 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 90 BP S49 EP S49 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200131 ER PT J AU Roffman, J AF Roffman, Joshua TI BRIDGING THE "TWO HITS": TOWARD MECHANISMS THAT CONNECT EARLY AND LATE NEURODEVELOPMENTAL RISK PERIODS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Roffman, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 115 BP S60 EP S60 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200160 ER PT J AU Roffman, J Soare, T Eryilmaz, H Rodriguez-Thompson, A Lee, P Holmes, A Smoller, J Buckner, R AF Roffman, Joshua Soare, Thomas Eryilmaz, Hamdi Rodriguez-Thompson, Anais Lee, Phil Holmes, Avram Smoller, Jordan Buckner, Randy TI IMPACT OF FETAL GENE EXPRESSION ON CORTICAL THICKNESS IN YOUNG ADULTS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Roffman, Joshua; Soare, Thomas; Eryilmaz, Hamdi; Rodriguez-Thompson, Anais; Lee, Phil; Smoller, Jordan; Buckner, Randy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Holmes, Avram] Yale Univ, New Haven, CT 06520 USA. [Buckner, Randy] Harvard Univ, Cambridge, MA 02138 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 115.2 BP S60 EP S61 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200162 ER PT J AU Sayer, M Love, R Freudenreich, O Sanders, K McLean, A Adair, D Hepburn, B Walker, A Gordon, S Patchan, K Stock, V Kelly, D AF Sayer, MacKenzie Love, Raymond Freudenreich, Oliver Sanders, Kathy McLean, Andrew Adair, Dale Hepburn, Brian Walker, Aaron Gordon, Stuart Patchan, Kathleen Stock, Veronika Kelly, Deanna TI IMPROVING CLOZAPINE USE IN THE UNITED STATES: A SURVEY OF BARRIERS AND SOLUTIONS INFORMING A WORKGROUP TO DEVISE A NATIONAL STRATEGY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Sayer, MacKenzie; Love, Raymond; Patchan, Kathleen] Univ Maryland, College Pk, MD 20742 USA. [Freudenreich, Oliver] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sanders, Kathy] Massachusetts Dept Mental Hlth, New Bedford, MA USA. [McLean, Andrew] Univ North Dakota, Sch Med & Hlth Sci, Grand Forks, ND USA. [Adair, Dale] Penn Off Mental Hlth & Subst Abuse Serv, Harrisburg, PA USA. [Hepburn, Brian; Walker, Aaron; Gordon, Stuart] Natl Assoc State Mental Hlth Program Directors, Alexandria, VA USA. [Stock, Veronika] Harvard Med Sch, Boston, MA USA. [Kelly, Deanna] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, College Pk, MD 20742 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M115 BP S252 EP S252 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200678 ER PT J AU Schneider, Z Parker, D Kittle, F McDowell, J Buckley, P Keedy, S Gershon, E Sweeney, J Keshavan, M Pearlson, G Tamminga, C Clementz, B AF Schneider, Zoe Parker, David Kittle, Frances McDowell, Jennifer Buckley, Peter Keedy, Sarah Gershon, Elliot Sweeney, John Keshavan, Matcheri Pearlson, Godfrey Tamminga, Carol Clementz, Brett TI INVESTIGATION OF THE VISUAL STEADY-STATE RESPONSE IN SCHIZOPHRENIA, SCHIZOAFFECTIVE, PSYCHOTIC, AND NONPSYCHOTIC BIPOLAR DISORDERS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Parker, David; Kittle, Frances; McDowell, Jennifer; Clementz, Brett] Univ Georgia, Athens, GA 30602 USA. [Buckley, Peter] Augusta Univ, Augusta, GA USA. [Keedy, Sarah; Gershon, Elliot] Univ Chicago, Chicago, IL 60637 USA. [Sweeney, John] Univ Cincinnati, Cincinnati, OH 45221 USA. [Keshavan, Matcheri] Harvard Med Sch, BIDMC, Boston, MA USA. [Pearlson, Godfrey] Yale Univ, New Haven, CT 06520 USA. [Tamminga, Carol] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SU5 BP S162 EP S162 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200440 ER PT J AU Tamminga, C Clementz, B Keshavan, M Gershon, E Pearlson, G Ivleva, E AF Tamminga, Carol Clementz, Brett Keshavan, Matcheri Gershon, Elliot Pearlson, Godfrey Ivleva, Elena TI ENDOPHENOTYPES GUIDE PSYCHOSIS NEUROBIOLOGY FORMULATIONS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Tamminga, Carol; Ivleva, Elena] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Clementz, Brett] Univ Georgia, Athens, GA 30602 USA. [Keshavan, Matcheri] Harvard Med Sch, BIDMC, Boston, MA USA. [Gershon, Elliot] Univ Chicago, Chicago, IL 60637 USA. [Pearlson, Godfrey] Yale Univ, New Haven, CT 06520 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 5.3 BP S7 EP S7 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200021 ER PT J AU Tamminga, C Ivleva, E Clementz, B Sweeney, J Pearlson, G Keshavan, M AF Tamminga, Carol Ivleva, Elena Clementz, Brett Sweeney, John Pearlson, Godfrey Keshavan, Matcheri TI CAN NEUROBIOLOGICAL SUBGROUPS IN PSYCHOTIC ILLNESS ADVANTAGE DRUG DISCOVERY? SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Tamminga, Carol; Ivleva, Elena; Sweeney, John] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Clementz, Brett] Univ Georgia, Athens, GA 30602 USA. [Pearlson, Godfrey] Yale Univ, New Haven, CT 06520 USA. [Keshavan, Matcheri] Harvard Med Sch, BIDMC, 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 3.2 BP S3 EP S3 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200010 ER PT J AU Tuominen, L DeCross, S Nasr, S Boeke, E Wolthusen, R Tootell, R Freudenreich, O Shinn, A Holt, D AF Tuominen, Lauri DeCross, Stephanie Nasr, Shahin Boeke, Emily Wolthusen, Rick Tootell, Roger Freudenreich, Oliver Shinn, Ann Holt, Daphne TI ABNORMAL ANTERIOR INSULA ACTIVITY DURING FEAR GENERALIZATION IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Tuominen, Lauri; DeCross, Stephanie; Nasr, Shahin; Boeke, Emily; Wolthusen, Rick; Tootell, Roger; Freudenreich, Oliver; Holt, Daphne] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shinn, Ann] McLean Hosp, 115 Mill St, Belmont, MA 02178 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 52 BP S27 EP S27 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200073 ER PT J AU Wynn, J McCleery, A Szewczyk, W Kutasevich, E Roach, BJ Mathalon, D Green, MF AF Wynn, Jonathan McCleery, Amanda Szewczyk, Warren Kutasevich, Eugene Roach, Brian J. Mathalon, Daniel Green, Michael F. TI DYSFUNCTIONAL PREDICTION ERROR CODING IN SCHIZOPHRENIA: TEST-RETEST RELIABILITY OF AUDITORY MISMATCH NEGATIVITY AND REPETITION POSITIVITY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Wynn, Jonathan] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [McCleery, Amanda; Szewczyk, Warren; Kutasevich, Eugene; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Roach, Brian J.; Mathalon, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mathalon, Daniel] San Francisco VA Med Ctr, San Francisco, CA USA. [Green, Michael F.] VA Greater Los Angeles Healthcare Syst, VISN MIRECC 22, Los Angeles, CA 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 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA68 BP S137 EP S138 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200372 ER PT J AU Rai, RR Gonzalez-Gonzalez, LA Papakostas, TD Siracuse-Lee, D Dunphy, R Fanciullo, L Cakiner-Egilmez, T Daly, MK AF Rai, Ruju R. Gonzalez-Gonzalez, Luis A. Papakostas, Thanos D. Siracuse-Lee, Donna Dunphy, Robert Fanciullo, Lisa Cakiner-Egilmez, Tulay Daly, Mary K. TI Management of Corneal Bee Sting Injuries SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE Bee sting; cornea; endothelial cell; hymenoptera; keratitis; specular microscopy; stinger removal; trauma; venom ID RETAINED STINGER; OPTIC NEURITIS AB Purpose: To review the management of keratitis after corneal bee stings and to report a case of deep stromal corneal infiltrate secondary to a retained bee stinger managed conservatively in a patient who presented three days after unsanitary manipulation of the stinger apparatus. Methods: Case report and review of literature. Results: A 57-year-old male beekeeper was evaluated for pain, blurry vision, and photosensitivity after a corneal bee sting. Of note, the venom sac had been removed with dirty tweezers three days prior to his visit. On exam, a focal infiltrate with diffuse edema was seen surrounding a retained bee stinger in the peripheral cornea. Trace cells in the anterior chamber were also noted. Based on a high suspicion for infectious keratitis, a conservative treatment strategy was elected. Administration of broad-spectrum topical antibiotics with concomitant abstention of corticosteroids led to rapid resolution of the symptoms. Over 16 months of follow-up, the stinger has remained in situ without migration and the patient has maintained 20/20 visual acuity without complications. There is debate on the preferred method for the management of corneal injury secondary to bee stings, especially when it is associated with a retained stinger. We herein present our findings in our appraisal of reported cases. Conclusion: In the aftermath of an ocular bee sting, close surveillance for inflammation and infection is essential. Individual manifestations of these injuries vary in timing, type, and severity; therefore, the accessibility of the stinger and the evolving clinical picture should guide therapeutic decisions. C1 [Rai, Ruju R.; Gonzalez-Gonzalez, Luis A.; Papakostas, Thanos D.; Siracuse-Lee, Donna; Dunphy, Robert; Fanciullo, Lisa; Cakiner-Egilmez, Tulay; Daly, Mary K.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Rai, Ruju R.; Siracuse-Lee, Donna; Daly, Mary K.] Boston Univ Sch Med, Dept Ophthalmol, Boston, MA USA. [Rai, Ruju R.; Gonzalez-Gonzalez, Luis A.; Papakostas, Thanos D.; Daly, Mary K.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Rai, Ruju R.; Gonzalez-Gonzalez, Luis A.; Papakostas, Thanos D.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. RP Daly, MK (reprint author), Vet Affairs Boston Healthcare Syst, Dept Ophthalmol, 150 S Huntington Ave,8C-29, Boston, MA 02130 USA. EM mary.daly2@va.gov NR 35 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR PY 2017 VL 32 IS 2 BP 177 EP 181 DI 10.3109/08820538.2015.1045301 PG 5 WC Ophthalmology SC Ophthalmology GA EL6IM UT WOS:000394725400005 PM 26161915 ER PT J AU Gottlieb, DJ Somers, VK Punjabi, NM Winkelman, JW AF Gottlieb, Daniel J. Somers, Virend K. Punjabi, Naresh M. Winkelman, John W. TI Restless legs syndrome and cardiovascular disease: a research roadmap SO SLEEP MEDICINE LA English DT Review DE Restless legs syndrome; Cardiovascular; Epidemiology ID OBSTRUCTIVE SLEEP-APNEA; POSITIVE AIRWAY PRESSURE; RANDOMIZED CONTROLLED-TRIAL; VASCULAR RISK-FACTORS; GLUCOSE-METABOLISM; BLOOD-PRESSURE; INTERMITTENT HYPOXIA; ENDOTHELIAL DYSFUNCTION; SYMPATHETIC ACTIVITY; ARTERIAL STIFFNESS AB In this paper, we first critically appraise the epidemiologic literature examining the association of restless legs syndrome (RLS) with cardiovascular disease (CVD) and then consider whether lessons learned from the study of cardiovascular consequences of other sleep disorders might inform a research agenda to examine the potential mechanisms of cardiovascular morbidity of RLS. Cross-sectional and longitudinal studies are both mixed as to whether there is a meaningful association of RLS and CVD. On the other hand, numerous cross-sectional and longitudinal observational studies have shown a strong association of obstructive sleep apnea (OSA) with CVD risk. Each of the potential mediating mechanisms in OSA may also be assessed in RLS, including 1) neural mechanisms such as increased central sympathetic outflow, impaired baroreflex function, diminished heart rate and blood pressure variability, and increased chemoreflex sensitivity, 2) metabolic mechanisms such as glucose intolerance and reduced insulin sensitivity/diabetes as a result of sleep disturbance in RLS, 3) oxidative stress, 4) systemic or vascular inflammatory mechanisms, and 5) vascular mechanisms including impaired endothelial functioning, increased aortic stiffness, hypothalamic-pituitary axis activation or renin-angiotensin-aldosterone activation. Three known characteristics of RLS may contribute to these specific mechanisms of increased cardiovascular risk: 1) periodic limb movements of sleep, which are associated with large increases in heart rate and blood pressure, 2) sleep fragmentation and sleep deprivation, which are known to produce adverse consequences for neural, metabolic, oxidative, inflammatory, and vascular systems, and 3) iron deficiency, which is an emerging risk for cardiovascular disease. Future research priorities include additional epidemiologic studies which characterize multiple CVD risk factors, case-control studies which examine known markers of cardiovascular risk, and small clinical trials which assess the effects of RLS treatment on intermediate physiological markers such as sympathetic activity or baroreflex control, measures of vascular stiffness and reactivity, or measures of insulin sensitivity and glucose tolerance. Published by Elsevier B.V. C1 [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Med Serv, Boston, MA USA. [Gottlieb, Daniel J.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 221 Longwood Ave,BLI 225E, Boston, MA 02115 USA. [Gottlieb, Daniel J.] Harvard Med Sch, Boston, MA USA. [Somers, Virend K.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA. [Punjabi, Naresh M.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Winkelman, John W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Winkelman, John W.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gottlieb, DJ (reprint author), Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 221 Longwood Ave,BLI 225E, Boston, MA 02115 USA. EM djgottlieb@partners.org FU CSRD VA [I01 CX000578]; NHLBI NIH HHS [R01 HL065176, R01 HL114024, R01 HL114676, U01 HL053941] NR 77 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD MAR PY 2017 VL 31 BP 10 EP 17 DI 10.1016/j.sleep.2016.08.008 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO8WJ UT WOS:000396970900003 PM 28065687 ER PT J AU Partovi, S Kalva, SP Walker, TG Taj, SM Ganguli, S AF Partovi, Sasan Kalva, Sanjeeva P. Walker, T. Gregory Taj, Sabir M. Ganguli, Suvranu TI Long term follow-up of endo-vascular recanalization of chronic inferior vena cava occlusion secondary to inferior vena cava filters SO VASA-EUROPEAN JOURNAL OF VASCULAR MEDICINE LA English DT Article DE Inferior vana cava filter; inferior vena cava occlusion; endovascular recanalization; stenting; long term follow-up ID ANTICOAGULATED PATIENTS AB Background: The long term efficacy of endovascular recanalization for chronic iliocaval occlusion secondary to inferior vena cava (IVC) filters is unknown. The purpose of this study was to evaluate the effectiveness of endovascular recanalization and stent placement across the filter in patients with filter-associated chronic iliocaval occlusion. Patients and Methods: Seven patients (mean age 56 +/- 15 yrs; seven males) with symptomatic chronic iliocaval occlusion and occluded IVC filter were included. Immediate technical success rate, long term clinical effectiveness of endovascular recanalization and patency rate of the stents were assessed. Results: In all patients, the endovascular treatment consisted of percutaneous venous access, recanalization of the occluded iliac veins and the IVC, transluminal angioplasty and stenting of the infrarenal inferior vena cava and iliac veins with self-expanding stents. The IVC filter was not removed, but rather the stents were extended across the filter. In four of seven patients (57 %), adjunctive pharmaco-mechanical thrombolysis was performed. All patients received anticoagulation post procedure. The mean clinical follow-up was 51.1 +/- 27 months. Technical success rate was 100 %. Clinical success rate with symptomatic improvement was 85.7 %; one patient developed post-thrombotic syndrome on long term follow-up despite initial symptomatic improvement. Poststenting, the primary patency rate was 85.7 % (six of seven patients) and the secondary patency rate was 100 % (seven of seven patients). Conclusions: Endovascular recanalization with balloon angioplasty and placement of a self-expanding stent across a chronically occluded IVC filer can be performed safely and effectively for patients with symptomatic iliocaval thrombosis. An adjunctive pharmacologic-mechanical thrombolysis may be considered for selected patients. C1 [Partovi, Sasan] Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Dept Radiol,Div Vasc & Intervent Radiol, Cleveland, OH 44106 USA. [Kalva, Sanjeeva P.] Univ Texas Southwestern Med Ctr Dallas, Dept Radiol, Div Intervent Radiol, Dallas, TX 75390 USA. [Walker, T. Gregory; Taj, Sabir M.; Ganguli, Suvranu] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiol, Div Intervent Radiol, Boston, MA 02114 USA. RP Ganguli, S (reprint author), Massachusetts Gen Hosp, Ctr Image Guided Canc Therapy, Intervent Radiol, 55 Fruit St,GRB 290, Boston, MA 02114 USA. EM sganguli@mgh.harvard.edu NR 17 TC 0 Z9 0 U1 0 U2 0 PU VERLAG HANS HUBER HOGREFE AG PI BERN 9 PA LAENGGASS-STRASSE 76, CH-3000 BERN 9, SWITZERLAND SN 0301-1526 J9 VASA JI Vasa PD MAR PY 2017 VL 46 IS 2 BP 121 EP 126 DI 10.1024/0301-1526/a000593 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO7XE UT WOS:000396902600008 PM 28247824 ER PT J AU Carson, RC Bernacki, R AF Carson, Rachel C. Bernacki, Rachelle TI Is the End in Sight for the "Don't Ask, Don't Tell" Approach to Advance Care Planning? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID SERIOUS ILLNESS; COMMUNICATION; DIRECTIVES; UNIT C1 [Carson, Rachel C.] Nanaimo Reg Hosp, Isl Hlth, Nanaimo, BC, Canada. [Bernacki, Rachelle] Dana Farber Canc Inst, Div Adult Palliat Care, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Bernacki, Rachelle] Brigham & Womens Hosp, Ariadne Labs, 75 Francis St, Boston, MA 02115 USA. [Bernacki, Rachelle] Harvard Sch Publ Hlth, Boston, MA USA. RP Carson, RC (reprint author), Nanaimo Reg Gen Hosp, Internal Med, 1200 Dufferin Cr, Nanaimo, BC V9S 2B7, Canada. EM rachel.carson@viha.ca NR 23 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2017 VL 12 IS 3 BP 380 EP 381 DI 10.2215/CJN.00980117 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EO6SE UT WOS:000396822000002 PM 28232404 ER PT J AU Tamura, MK Montez-Rath, ME Hall, YN Katz, R O'Hare, AM AF Tamura, Manjula Kurella Montez-Rath, Maria E. Hall, Yoshio N. Katz, Ronit O'Hare, Ann M. TI Advance Directives and End-of-Life Care among Nursing Home Residents Receiving Maintenance Dialysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID DECISION-MAKING; KIDNEY-DISEASE; HOSPITAL DEATH; QUALITY; INTERVENTION; HEMODIALYSIS; ESRD AB Background and objectives Little is known about the relation between the content of advance directives and downstream treatment decisions among patients receiving maintenance dialysis. In this study, we determined the prevalence of advance directives specifying treatment limitations and/or surrogate decision-makers in the last year of life and their association with end-of-life care among nursing home residents. Design, setting, participants, & measurements Using national data from 2006 to 2007, we compared the content of advance directives among 30,716 nursing home residents receiving dialysis to 30,825 nursing home residents with other serious illnesses during the year before death. Among patients receiving dialysis, we linked the content of advance directives to Medicare claims to ascertain site of death and treatment intensity in the last month of life. Results In the last year of life, 36% of nursing home residents receiving dialysis had a treatment-limiting directive, 22% had a surrogate decision-maker, and 13% had both in adjusted analyses. These estimates were 13%-27%, 5%-11%, and 6%-13% lower, respectively, than for decedents with other serious illnesses. For patients receiving dialysis who had both a treatment-limiting directive and surrogate decision-maker, the adjusted frequency of hospitalization, intensive care unit admission, intensive procedures, and inpatient death were lower by 13%, 17%, 13%, and 14%, respectively, and hospice use and dialysis discontinuation were 5% and 7% higher compared with patients receiving dialysis lacking both components. Conclusions Among nursing home residents receiving dialysis, treatment-limiting directives and surrogates were associated with fewer intensive interventions and inpatient deaths, but were in place much less often than for nursing home residents with other serious illnesses. C1 [Tamura, Manjula Kurella] Palo Alto Vet Affairs Hlth Care Syst, Geriatr Res & Educ Clin Ctr, Palo Alto, CA USA. [Tamura, Manjula Kurella; Montez-Rath, Maria E.] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Hall, Yoshio N.; Katz, Ronit; O'Hare, Ann M.] Grp Hlth Cooperat Puget Sound, Dept Med, Seattle, WA USA. [Hall, Yoshio N.; Katz, Ronit; O'Hare, Ann M.] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [O'Hare, Ann M.] Vet Affairs Puget Sound Hlth Care Syst, Dept Hosp & Specialty Med, Seattle, WA USA. RP Tamura, MK (reprint author), Vet Affairs Palo Alto Hlth Care Syst, 3801 Miranda Ave, Palo Alto, CA 94304 USA. EM mktamura@stanford.edu FU National Institutes of Diabetes and Digestive and Kidney Diseases [U01DK102150] FX This work is supported by grant U01DK102150 from the National Institutes of Diabetes and Digestive and Kidney Diseases. NR 30 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2017 VL 12 IS 3 BP 435 EP 442 DI 10.2215/CJN.07510716 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EO6SE UT WOS:000396822000011 ER PT J AU Ialynytchev, A Sear, AM Williams, AR Langland-Orban, B Zhang, NH AF Ialynytchev, Anna Sear, Alan M. Williams, Arthur R. Langland-Orban, Barbara Zhang, Nanhua TI Factors associated with lumbar fusion surgery: a case-control study SO EUROPEAN SPINE JOURNAL LA English DT Article DE Lumbar fusion surgery; Spinal fusion surgery; Lower back surgery ID UNITED-STATES TRENDS; SPINE SURGERY; BACK-PAIN; GUIDELINE; CHARGES AB The objective of this study is to identify the demographic and payer factors that are associated with lumbar fusion surgery. A case-control study was conducted utilizing a population of 38,092 patients from the 2010 Florida Agency for Health Care Administration (AHCA), USA hospital discharge data. The case population included 16,236 records with any of five ICD-9-CM principal procedure codes for initial lumbar fusion. The control group was comprised of 21,856 patients who were admitted for the same principal diagnoses as the cases, but who did not have initial fusion surgery. Logistic regression was used to analyze the association of age, gender, race and principal payer type with initial lumbar fusions. The interaction between age and payer was also examined, as payer type may moderate the association between age and lumbar fusion surgery. Gender, race, principal payer and age were all found to be significantly associated with lumbar fusion surgery. The interaction of payer and age was also found to be significant. Being female was significantly associated with having a fusion (OR = 1.11, 95 % CI 1.07-1.16). The association between age and receiving surgery was greatest for the less than 20 age group (OR = 10.43, 95 % CI 8.74-12.45). Employees and dependents of Federal government agencies (Tricare, etc.) and patients with commercial insurance were significantly associated with surgery (OR = 1.48, 95 % CI 1.29-1.70 and OR = 1.12, 95 % CI 1.04-1.20, respectively). Patients insured through Medicaid (a social health care program for those with low incomes and limited resources), and the uninsured were negatively associated with surgery (OR = 0.53, 95 % CI 0.47-0.60 and OR = 0.52, 95 % CI 0.46-0.58, respectively). Lumbar fusion surgery is not recommended in clinical practice guidelines for the top four principal diagnoses in this study. Yet, patients covered by certain types of insurance were found to be significantly associated with fusion surgery. C1 [Ialynytchev, Anna; Sear, Alan M.; Langland-Orban, Barbara] Univ S Florida, Dept Hlth Policy & Management, 13201 Bruce B. Downs Blvd. MDC 56, Tampa, FL 33612 USA. [Williams, Arthur R.] US Dept Vet Affairs, CINDRR, Tampa, FL 33637 USA. [Williams, Arthur R.] George Mason Univ, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. [Zhang, Nanhua] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, 3333 Burnet Ave,MLC 5041, Cincinnati, OH 45229 USA. [Zhang, Nanhua] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45229 USA. RP Ialynytchev, A (reprint author), Univ S Florida, Dept Hlth Policy & Management, 13201 Bruce B. Downs Blvd. MDC 56, Tampa, FL 33612 USA. EM annai@mail.usf.edu NR 24 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 EI 1432-0932 J9 EUR SPINE J JI Eur. Spine J. PD MAR PY 2017 VL 26 IS 3 BP 698 EP 707 DI 10.1007/s00586-016-4591-4 PG 10 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EN5JR UT WOS:000396042000015 PM 27154167 ER PT J AU Bono, CM Leonard, DA Cha, TD Schwab, JH Wood, KB Harris, MB Schoenfeld, AJ AF Bono, Christopher M. Leonard, Dana A. Cha, Thomas D. Schwab, Joseph H. Wood, Kirkham B. Harris, Mitchel B. Schoenfeld, Andrew J. TI The effect of short (2-weeks) versus long (6-weeks) post-operative restrictions following lumbar discectomy: a prospective randomized control trial SO EUROPEAN SPINE JOURNAL LA English DT Article DE Lumbar discetomy; Rehabilitation; Post-operative restriction; Reherniation; Randomized trial ID NONOPERATIVE TREATMENT; DISC HERNIATION; OUTCOMES; SPINE; SPORT; MANAGEMENT; SCIATICA; REGISTRY AB We sought to evaluate how short (2-week) versus long (6-week) post-operative restrictions following lumbar discectomy impacted outcomes and reherniation rates for a period up to 1 year following surgery. This study included 108 patients undergoing index lumbar discectomy. Patients were randomized immediately following surgery. Outcomes included back and leg visual analog pain scales (VAS), Oswestry Disability Index (ODI), and reherniation rates at 2-weeks, 6-weeks, 3-months, and 1-year following surgery. Differences in reherniation rates were analyzed using Fisher's exact test. VAS and ODI scores were evaluated using Student's t test. Six patients (11%) in the 2-week restriction group had a reherniation event and four patients (7%) in the 6-week restriction group experienced a reherniation (p = 0.52). VAS back pain (p < 0.001), leg pain (p < 0.001), and ODI scores (p < 0.001) were significantly improved for both cohorts as compared to baseline at the 2-week time point and remained significantly improved through 1-year [VAS back (p < 0.001); VAS leg (p < 0.001); ODI (p < 0.001)]. No significant differences in ODI, VAS back, or VAS leg scores were detected at any of the time points between the 2- and 6-week restriction groups. The results of this randomized trial suggest equivalent clinical outcomes irrespective of the length of post-operative restriction. From a clinical perspective, if patients are deemed at low risk for a reherniation event they may be confidence that early return to activity at 2 weeks will not compromise outcomes and may not adversely impact the risk of reherniation. Level of Evidence II. C1 [Bono, Christopher M.; Leonard, Dana A.; Harris, Mitchel B.; Schoenfeld, Andrew J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. [Cha, Thomas D.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. [Wood, Kirkham B.] Stanford Univ, Dept Orthopaed Surg, Med Ctr, 300 Pasteur Dr, Stanford, CA 94304 USA. RP Bono, CM (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. EM bonocm@me.com NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 EI 1432-0932 J9 EUR SPINE J JI Eur. Spine J. PD MAR PY 2017 VL 26 IS 3 BP 905 EP 912 DI 10.1007/s00586-016-4821-9 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EN5JR UT WOS:000396042000040 PM 27807771 ER PT J AU Comfort, AB Krezanoski, PJ AF Comfort, Alison B. Krezanoski, Paul J. TI The effect of price on demand for and use of bednets: evidence from a randomized experiment in Madagascar SO HEALTH POLICY AND PLANNING LA English DT Article DE Malaria; price; demand; bednets; randomized controlled trial; Madagascar ID INSECTICIDE-TREATED NETS; MALARIA PREVENTION; FIELD EXPERIMENT; CONTROLLED-TRIAL; AFRICA; COVERAGE; TANZANIA; DECISION; KENYA; INDIA AB There is an on-going debate about whether health products, such as insecticide-treated bednets (ITNs) for protection against malaria, should be distributed for free or at a positive price to maximize ownership and use. One argument in favour of free distribution is related to positive externalities. Like vaccines, individual use of ITNs provides a community-wide protective effect against malaria even for non-users. In addition, price may act as a barrier to ownership particularly among those most at-risk who are frequently poor. Alternatively, charging a positive price may reduce donor dependence, more efficiently allocate nets to those most at risk of malaria, and encourage use through a hypothesized sunk cost effect, where individuals are more likely to use goods they pay for. Using a randomized experiment in Madagascar, we evaluate the impact of price on demand for and use of ITNs. We find that price negatively affects both demand and use of ITNs. When price increases by $0.55, demand falls by 23.1% points (CI 19.6-26.6; P < 0.01) and effective coverage falls by 23.1% points (CI 19.6-26.6; P < 0.01). We fail to find evidence of a screening effect for prices greater than zero, but households eligible for free ITNs are more likely to use them if they have more self-reported fevers in the household at baseline. We also fail to find evidence of a sunk cost effect, meaning that households are not more likely to use nets that they pay for. Our results suggest that: (1) only partially subsidizing ITNs significantly limits ownership and (2) distributing ITNs for free or at a small nominal price will maximize demand and effective coverage. Alternative sources of financing should be identified to completely (or almost completely) subsidize the cost of ITNs in order to maximize coverage of ITNs among poor populations at risk of malaria. C1 [Comfort, Alison B.] Abt Associates Inc, 55 Wheeler St, Cambridge, MA 02138 USA. [Krezanoski, Paul J.] Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Krezanoski, Paul J.] Massachusetts Gen Hosp, Dept Pediat, 55 Fruit St, Boston, MA 02114 USA. [Krezanoski, Paul J.] Havard Med Sch, 25 Shattuck St, Boston, MA USA. RP Comfort, AB (reprint author), Abt Associates Inc, 55 Wheeler St, Cambridge, MA 02138 USA. EM alisoncomfort2011@gmail.com FU Weatherhead Center for International Affairs at Harvard University; Daniel McGillis Development and Dissemination Grant Program at Abt Associates FX Funding for this study came from the Justice, Welfare and Economics Dissertation Fellowship from the Weatherhead Center for International Affairs at Harvard University, the Daniel McGillis Development and Dissemination Grant Program at Abt Associates, and private donors. NR 48 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1080 EI 1460-2237 J9 HEALTH POLICY PLANN JI Health Policy Plan. PD MAR PY 2017 VL 32 IS 2 BP 178 EP 193 DI 10.1093/heapol/czw108 PG 16 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EP0VO UT WOS:000397105000004 PM 28207055 ER PT J AU McLellan, DL Williams, JA Katz, JN Pronk, NP Wagner, GR Caban-Martinez, AJ Nelson, CC Sorensen, G AF McLellan, Deborah L. Williams, Jessica A. Katz, Jeffrey N. Pronk, Nicolaas P. Wagner, Gregory R. Caban-Martinez, Alberto J. Nelson, Candace C. Sorensen, Glorian TI Key Organizational Characteristics for Integrated Approaches to Protect and Promote Worker Health in Smaller Enterprises SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID SMALL BUSINESS; BEHAVIOR-CHANGE; UNITED-STATES; WORKPLACE; EMPLOYERS; SAFETY; IMPLEMENTATION; INTERVENTION; WELLWORKS-2; PERFORMANCE AB Objective: The aim of this study was to investigate relationships between worksite organizational characteristics (size, industrial sector, leadership commitment, and organizational supports) and integrated approaches to protecting and promoting worker health implemented in smaller enterprises. Methods: We analyzed web-based survey data of Human Resource Managers at 114 smaller enterprises (<750 employees) to identify organizational factors associated with levels of integrated approaches among their work sites. Results: The companies' mean integration score was 13.6 (SD = 9.6) of a possible 44. In multivariate analyses, having a safety committee (P = 0.035) and top leadership support for health promotion (HP) (P = 0.004) were positively associated with higher integration scores. Conclusions: Smaller enterprises in one U.S. region have relatively low levels of implementing integrated safety and promotion approaches. Having a safety committee and leadership support for HP may be important contributors to implementing integrated approaches in smaller enterprises. C1 [McLellan, Deborah L.; Williams, Jessica A.; Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [McLellan, Deborah L.; Katz, Jeffrey N.; Pronk, Nicolaas P.; Wagner, Gregory R.; Caban-Martinez, Alberto J.; Sorensen, Glorian] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Williams, Jessica A.] Univ Kansas, Sch Med, Kansas City, KS USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Pronk, Nicolaas P.] HealthPartners Inc, Minneapolis, MN USA. [Wagner, Gregory R.] NIOSH, CDC, Washington, DC USA. [Caban-Martinez, Alberto J.] Univ Miami, Miller Sch Med, Sch Med, Miami, FL 33136 USA. [Nelson, Candace C.] Massachusetts Dept Publ Hlth, Boston, MA USA. RP McLellan, DL (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW715, Boston, MA 02215 USA. EM deborah_mclellan@dfci.harvard.edu FU National Institute for Occupational Safety and Health [U19 OH008861] FX This work was supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard School of Public Health Center for Work, Health and Well-being. NR 40 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 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD MAR PY 2017 VL 59 IS 3 BP 289 EP 294 DI 10.1097/JOM.0000000000000949 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN3JM UT WOS:000395904800010 PM 28267100 ER PT J AU Allen, SR Pascual, J Martin, N Reilly, P Luckianow, G Datner, E Davis, KA Kaplan, LJ AF Allen, Steven R. Pascual, Jose Martin, Niels Reilly, Patrick Luckianow, Gina Datner, Elizabeth Davis, Kimberly A. Kaplan, Lewis J. TI A novel method of optimizing patient- and family-centered care in the ICU SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Patient- and family-centered care; communication; satisfaction; quality ID CRITICALLY-ILL PATIENTS; EVALUATION APACHE IV; LENGTH-OF-STAY; CARDIOPULMONARY-RESUSCITATION; ACUTE PHYSIOLOGY; UNIT PATIENTS; SATISFACTION; NEEDS; GUIDELINES; MORTALITY AB BACKGROUND Patient- and family-centered care permeates critical care where there are often multiple teams involved in management. A method of facilitating information sharing to support shared decision making is essential in appropriately rendering care. This study sought to determine whether incorporating family members on rounds in the intensive care unit (ICU) improves patient and family knowledge and whether doing so improves team time management and satisfaction with the process. METHODS A nonrandomized comparative before-and-after trial of incorporating family members on rounds (July to December 2009 vs January to July 2010) in a single quarternary center's surgical ICU assessed (1) family members' knowledge, (2) nurse's and physician's satisfaction with the intervention, (3) frequency and timing of family meetings, and (4) physician's workflow. RESULTS Intensive care unit demographics and use were similar between time frames. Presurvey (n = 412 family members; 49 nurses) and postsurvey (n = 427 family members; 47 nurses) were coupled with presurvey (n = 5) and postsurvey (n = 6) physicians' informal feedback. Family knowledge of the clinical course and plans increased from 146 (35.4%) of 412 to 374 (87.6%) of 427 (p < 0.0001). Nurses were nearly uniformly satisfied with planned family interaction on rounds (presurvey: 9/49 [18.4%] vs postsurvey: 46/47 [97.9%]; p < 0.0001). Family meetings per week outside of rounds substantially decreased from a mean of 5.3 2.7 to 0.3 0.9; p < 0.001). Goals of therapy including end-of-life care became an element frequently discussed on rounds with families (presurvey: 9.4% +/- 4.7% vs postsurvey: 82.5% +/- 14.8%; p < 0.0001). One intensivist was dissatisfied with the process. CONCLUSION Incorporating family members on rounds in the ICU improves communication and satisfaction and shifts the team's time away from family communication events outside of rounds, condensing most of those activities within the rounding structure. Critical care nurses and intensivists were principally satisfied with the process. LEVEL OF EVIDENCE Therapeutic, level III. C1 [Allen, Steven R.; Pascual, Jose; Martin, Niels; Reilly, Patrick; Datner, Elizabeth; Kaplan, Lewis J.] Univ Penn, Perelman Sch Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Allen, Steven R.; Pascual, Jose; Datner, Elizabeth; Kaplan, Lewis J.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Luckianow, Gina; Davis, Kimberly A.] Yale Sch Med, New Haven, CT USA. RP Kaplan, LJ (reprint author), Univ Penn, Perelman Sch Med, Div Trauma Surg Crit Care & Emergency Surg, 3900 Woodland Ave, Philadelphia, PA 19104 USA.; Kaplan, LJ (reprint author), Corporal Michael J Crescenz VA Med Ctr, Surg Crit Care Sect, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Lewis.Kaplan@uphs.upenn.edu 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 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD MAR PY 2017 VL 82 IS 3 BP 582 EP 586 DI 10.1097/TA.0000000000001332 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EM8XV UT WOS:000395595300020 PM 28030488 ER PT J AU Cannon, JW Khan, MA Raja, AS Cohen, MJ Como, JJ Cotton, BA Dubose, JJ Fox, EE Inaba, K Rodriguez, CJ Holcomb, JB Duchesne, JC AF Cannon, Jeremy W. Khan, Mansoor A. Raja, Ali S. Cohen, Mitchell J. Como, John J. Cotton, Bryan A. Dubose, Joseph J. Fox, Erin E. Inaba, Kenji Rodriguez, Carlos J. Holcomb, John B. Duchesne, Juan C. TI Damage control resuscitation in patients with severe traumatic hemorrhage: A practice management guideline from the Eastern Association for the Surgery of Trauma SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Damage control resuscitation; massive transfusion protocol; coagulopathy of trauma; recombinant factor VIIa; tranexamic acid ID ACTIVATED FACTOR-VII; FRESH-FROZEN PLASMA; RECOMBINANT-FACTOR-VIIA; REQUIRING MASSIVE TRANSFUSION; RANDOMIZED-CLINICAL-TRIAL; BLOOD-CELL RATIOS; IMPROVED SURVIVAL; TRANEXAMIC ACID; HEMOSTATIC RESUSCITATION; CIVILIAN TRAUMA AB Background The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA). Methods Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR. Result A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA. Conclusion DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients. C1 [Cannon, Jeremy W.] Univ Penn, Perelman Sch Med, Div Traumatol Surg Crit Care & Emergency Surg, Philadelphia, PA USA. [Khan, Mansoor A.] Imperial Coll Healthcare NHS Trust, London, England. [Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Raja, Ali S.] Harvard Med Sch, Boston, MA USA. [Cohen, Mitchell J.] Denver Hlth Med Ctr, Dept Surg, Denver, CO USA. [Como, John J.] Metrohlth Med Ctr, Dept Surg, Cleveland, OH 44109 USA. [Cotton, Bryan A.; Fox, Erin E.; Holcomb, John B.] Univ Texas Hlth Sci Ctr Houston, Div Acute Care Surg, Houston, TX 77030 USA. [Dubose, Joseph J.] David Grant Med Ctr, Div Vasc Surg, Travis AFB, CA USA. [Inaba, Kenji] Univ Southern Calif, Div Trauma & Crit Care, Los Angeles, CA USA. [Rodriguez, Carlos J.] Uniformed Serv Univ Hlth Sci, Walter Reed Dept Surg, Gen Surg, Bethesda, MD USA. [Duchesne, Juan C.] North Oaks Shock Trauma Program, Hammond, LA USA. RP Cannon, JW (reprint author), Penn Presbyterian Med Ctr, MOB Suite 120,51 N 39th St, Philadelphia, PA 19104 USA. EM jeremy.cannon@uphs.upenn.edu FU U.S. patents Haemonetics; TEM Systems, Inc.; LFB Biotechnologies FX Ernest E. Moore, Editor: PI, research support and shared U.S. patents Haemonetics; PI, research support, TEM Systems, Inc. Ronald V. Maier, Associate editor: consultant, consulting fee, LFB Biotechnologies. Associate editors: David Hoyt and Steven Shackford have nothing to disclose. Editorial staff: Jennifer Crebs, Jo Fields, and Angela Sauaia have nothing to disclose." NR 97 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 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD MAR PY 2017 VL 82 IS 3 BP 605 EP 617 DI 10.1097/TA.0000000000001333 PG 13 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EM8XV UT WOS:000395595300024 PM 28225743 ER PT J AU Yeh, DD Heyland, DK AF Yeh, D. Dante Heyland, Daren K. TI Enteral nutrition in traumatic brain injury SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Letter ID CRITICALLY-ILL PATIENTS C1 [Yeh, D. Dante] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Heyland, Daren K.] Queens Univ, Kingston Gen Hosp, Dept Crit Care Med, Clin Evaluat Res Unit, Kingston, ON, Canada. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. NR 5 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 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD MAR PY 2017 VL 82 IS 3 BP 649 EP 650 DI 10.1097/TA.0000000000001342 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EM8XV UT WOS:000395595300031 PM 28030493 ER PT J AU Hammad, SM Baker, NL El Abiad, JM Spassieva, SD Pierce, JS Rembiesa, B Bielawski, J Lopes-Virella, MF Klein, RL AF Hammad, Samar M. Baker, Nathaniel L. El Abiad, Jad M. Spassieva, Stefanka D. Pierce, Jason S. Rembiesa, Barbara Bielawski, Jacek Lopes-Virella, Maria F. Klein, Richard L. CA DCCT EDIC Grp Investigators TI Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study SO NEUROMOLECULAR MEDICINE LA English DT Article DE Type 1 diabetes; Neuropathy; Deoxysphingolipid; Ceramide; Deoxy-ceramide; Cysteine ID HEREDITARY SENSORY NEUROPATHY; SERINE PALMITOYLTRANSFERASE; BIOPHYSICAL PROPERTIES; PERIPHERAL NEUROPATHY; CHAIN LENGTH; SPHINGOLIPIDS; LONG; 1-DEOXYSPHINGOLIPIDS; MELLITUS; COMPLICATIONS AB Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ae4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy. C1 [Hammad, Samar M.; El Abiad, Jad M.] Med Univ South Carolina, Dept Regenerat Med & Cell Biol, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. [Baker, Nathaniel L.] Med Univ South Carolina, Dept Publ Hlth Sci, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. [Spassieva, Stefanka D.] Med Univ South Carolina, Div Hematol Oncol, Dept Med, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. [Pierce, Jason S.; Rembiesa, Barbara; Bielawski, Jacek] Med Univ South Carolina, Dept Biochem & Mol Biol, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. [Lopes-Virella, Maria F.; Klein, Richard L.] Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. [Klein, Richard L.] Med Univ South Carolina, Dept Med, Div Endocrinol Metab & Med Genet, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. RP Hammad, SM (reprint author), Med Univ South Carolina, Dept Regenerat Med & Cell Biol, 173 Ashley Ave,BSB 645,MSC 508, Charleston, SC 29425 USA. EM hammadsm@musc.edu FU NIDDK Diabetic Complications Consortium [DK076169]; National Institutes of Health [P01-HL55782]; Department of Veterans Affairs Merit Review Program; Lipidomics Shared Resource, Hollings Cancer Center [P30 CA138313]; Lipidomics Core in the SC Lipidomics and Pathobiology COBRE, Department Biochemistry, MUSC [P20 RR017677]; National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK); National Institutes of Health; National Center for Research Resources through the GCRC program; Genentech, Inc.; NIDDK FX Financial support for this work was provided by the NIDDK Diabetic Complications Consortium (DiaComp, www.diacomp.org), Grant DK076169 (RLK). This work was also supported by the National Institutes of Health Grant P01-HL55782 (MLV). Additional funding was obtained from the Department of Veterans Affairs Merit Review Program (MLV and RLK). The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. Sphingolipid analyses were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center (P30 CA138313), and the Lipidomics Core in the SC Lipidomics and Pathobiology COBRE, Department Biochemistry (P20 RR017677), MUSC. The DCCT/EDIC is sponsored through research contracts from the National Institute of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) and the National Institutes of Health. Additional support was provided by the National Center for Research Resources through the GCRC program and by Genentech, Inc. through a cooperative research and development agreement with the NIDDK. NR 33 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2017 VL 19 IS 1 BP 46 EP 56 DI 10.1007/s12017-016-8423-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EN5EX UT WOS:000396029500005 PM 27388466 ER PT J AU Gakis, G Schubert, T Alemozaffar, M Bellmunt, J Bochner, BH Boorjian, SA Daneshmand, S Huang, WC Kondo, T Konety, BR Laguna, MP Matin, SF Siefker-Radtke, AO Shariat, SF Stenzl, A AF Gakis, Georgios Schubert, Tina Alemozaffar, Mehrdad Bellmunt, Joaquim Bochner, Bernard H. Boorjian, Steven A. Daneshmand, Siamak Huang, William C. Kondo, Tsunenori Konety, Badrinath R. Laguna, Maria Pilar Matin, Surena F. Siefker-Radtke, Arlene O. Shariat, Shahrokh F. Stenzl, Arnulf TI Update of the ICUD-SIU consultation on upper tract urothelial carcinoma 2016: treatment of localized high-risk disease SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Chemotherapy; Lymph node dissection; Nephroureterectomy; Renal-sparing; Salvage; upper tract urothelial carcinoma ID UPPER URINARY-TRACT; TRANSITIONAL-CELL CARCINOMA; NEOADJUVANT CHEMOTHERAPY; RADICAL NEPHROURETERECTOMY; INTRAVESICAL INSTILLATION; SEGMENTAL URETERECTOMY; ADJUVANT CHEMOTHERAPY; BLADDER RECURRENCE; RENAL PELVIS; LYMPH-NODES AB To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Soci,t, Internationale d'Urologie for the treatment of localized high-risk upper tract urothelial carcinoma (UTUC). A detailed analysis of the literature was conducted reporting on treatment modalities and outcomes in localized high-risk UTUC. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine modified by the ICUD. Radical nephroureterectomy (RNU) is the standard of treatment for high-grade or clinically infiltrating UTUC and includes the removal of the entire kidney, ureter and ipsilateral bladder cuff. The distal ureter can be managed either by extravesical or transvesical approach, whereas endoscopically assisted procedures are associated with decreased intravesical recurrence-free survival. Post-operative intravesical chemotherapy decreases the risk of subsequent bladder tumour recurrence. Regional lymph node dissection is of prognostic importance in infiltrative UTUC, but its extent has not been standardized. Renal-sparing surgery is an option for manageable, high-grade tumours of any part of the upper tract, especially of the distal ureter, as an alternative to RNU. Endoscopy-based renal-sparing procedures are associated with a higher risk of recurrence and progression. A multimodal approach should be considered in localized high-risk UTUC to improve outcomes. RNU is the standard of treatment in high-risk disease. Renal-sparing approaches may be oncologically equivalent alternatives to RNU in well-selected patients, especially in those with distal ureteric tumours. C1 [Gakis, Georgios; Schubert, Tina; Stenzl, Arnulf] Univ Tubingen Hosp, Dept Urol, Hoppe Seyler St 3, D-72076 Tubingen, Germany. [Alemozaffar, Mehrdad; Daneshmand, Siamak] USC Norris Comprehens Canc Ctr, Inst Urol, Los Angeles, CA USA. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bochner, Bernard H.] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Boorjian, Steven A.] Mayo Clin, Dept Urol, Rochester, MN USA. [Huang, William C.] NYU, Dept Urol, Langone Med Ctr, New York, NY USA. [Kondo, Tsunenori] Tokyo Womens Med Univ, Dept Urol, Tokyo, Japan. [Konety, Badrinath R.] Univ Minnesota, Dept Urol, Masonic Canc Ctr, Minneapolis, MN USA. [Laguna, Maria Pilar] Univ Amsterdam, Dept Urol, AMC, Amsterdam, Netherlands. [Matin, Surena F.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Siefker-Radtke, Arlene O.] Univ Texas MD Anderson Canc Ctr, Dept Med Oncol, Houston, TX 77030 USA. [Shariat, Shahrokh F.] Med Univ Vienna, Dept Urol, Vienna, Austria. RP Gakis, G (reprint author), Univ Tubingen Hosp, Dept Urol, Hoppe Seyler St 3, D-72076 Tubingen, Germany. EM georgios.gakis@web.de OI Huang, William/0000-0001-5261-0650 NR 41 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD MAR PY 2017 VL 35 IS 3 BP 327 EP 335 DI 10.1007/s00345-016-1819-1 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EN2XG UT WOS:000395873000002 PM 27043218 ER PT J AU Yuan, F Xiong, GX Cohen, NA Cohen, AS AF Yuan, Feng Xiong, Guoxiang Cohen, Noam A. Cohen, Andakiva S. TI Optimized Protocol of Methanol Treatment for Immunofluorescent Staining in Fixed Brain Slices SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE brain ventricle; cilia; gamma-tubulin; beta-tubulin; immunohistochemistry ID IMMUNOHISTOCHEMISTRY; FIXATION; IMMUNOREACTIVITY; GUSTDUCIN; FORMALIN AB We optimized methanol treatment in paraformaldehyde- fixed slices for immunofluorescent staining of ependymal basal bodies in brain ventricles. As 100% methanol induced severe deformations to the slices (including rolling and folding over), we tried to decrease methanol concentration. We found that 33.3% to 75% methanol could result in ideal immunostaining of basal bodies without inducing obvious deformations. Instead of treating slices at -20 degrees C (without proper cryoprotection measurements) as suggested in previous studies, we carried out methanol treatment at room temperature. Our modified protocol can not only raise immunostaining efficiency in tissue slices, it may also prevent potential freezing damages to the samples. C1 [Yuan, Feng] Hosp Tongji Univ, Dept Orthoped, Shanghai, Peoples R China. [Xiong, Guoxiang; Cohen, Andakiva S.] Univ Penn, Perelman Sch Med, Div Neurol, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Univ Penn, Perelman Sch Med, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Univ Penn, Perelman Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Cohen, Andakiva S.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. RP Xiong, GX (reprint author), Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. EM xiong@email.chop.edu FU NICHD NIH HHS [R37 HD059288]; NINDS NIH HHS [R01 NS069629] NR 13 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 1541-2016 EI 1533-4058 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD MAR PY 2017 VL 25 IS 3 BP 221 EP 224 PG 4 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA EN3VR UT WOS:000395936500013 PM 26509907 ER PT J AU Nixon, RDV Sloan, DM AF Nixon, Reginald D. V. Sloan, Denise M. TI Treating PTSD: Innovations and Understanding Processes of Change SO BEHAVIOR THERAPY LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE THERAPY; PSYCHOLOGICAL TREATMENTS; PROLONGED EXPOSURE; CLINICAL-TRIAL; SYMPTOM CHANGE; METAANALYSIS; PSYCHOTHERAPY; DEPRESSION C1 [Nixon, Reginald D. V.] Flinders Univ S Australia, Adelaide, SA, Australia. [Sloan, Denise M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Sloan, Denise M.] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Nixon, RDV (reprint author), Flinders Univ S Australia, Sch Psychol, GPO Box 2100, Adelaide, SA 5001, Australia. EM reg.nixon@flinders.edu.au NR 34 TC 0 Z9 0 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 143 EP 146 PG 4 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700001 PM 28270325 ER PT J AU Kumpula, MJ Pentel, KZ Foa, EB LeBlanc, NJ Bui, E McSweeney, LB Knowles, K Bosley, H Simon, NM Rauch, SAM AF Kumpula, Mandy J. Pentel, Kimberly Z. Foa, Edna B. LeBlanc, Nicole J. Bui, Eric McSweeney, Lauren B. Knowles, Kelly Bosley, Hannah Simon, Naomi M. Rauch, Sheila A. M. TI Temporal Sequencing of Change in Posttraumatic Cognitions and PTSD Symptom Reduction During Prolonged Exposure Therapy SO BEHAVIOR THERAPY LA English DT Article DE posttraumatic stress disorder; treatment; cognitions; exposure therapy; trauma ID TRAUMA-RELATED COGNITIONS; STRESS-DISORDER SYMPTOMS; INVENTORY PTCI; NEGATIVE COGNITIONS; PROCESSING THERAPY; ASSAULT VICTIMS; PSYCHOMETRIC PROPERTIES; IMAGINAL EXPOSURE; CLINICAL-TRIAL; VALIDATION AB Prolonged exposure (PE) effectively reduces negative cognitions about self, world, and self-blame associated with posttraumatic stress disorder (PTSD), with changes in posttraumatic cognitions being associated with reductions in PTSD symptoms (Foa & Rauch, 2004). Further, recent research has demonstrated that cognitive change is a likely mechanism for PTSD symptom reduction in PE (Zalta et al., 2014). The present study examines temporal sequencing of change in three domains of posttraumatic cognitions (i.e., negative cognitions about the self, negative cognitions about the world, and self-blame) and PTSD symptoms during the course of PE. Adult outpatients meeting diagnostic criteria for PTSD were recruited at 4 sites. Participants (N = 46) received 8 sessions of PE over 4 to 6 weeks. PTSD symptoms and posttraumatic cognitions were assessed at pretreatment and Sessions 2, 4, 6, and 8. PTSD symptom severity and negative cognitions about the self and the world each decreased significantly from pre- to posttreatment, while self-blame cognitions were unchanged. Examination of temporal sequencing of changes during the course of PE via time-lagged mixed effects regression modeling revealed that preceding levels of negative cognitions about the world drove successive severity levels of PTSD symptoms, whereas preceding PTSD symptom severity did not drive subsequent negative cognitions about the world. Reductions in negative cognitions about the self led to subsequent improvement in PTSD. Improvement in PTSD symptoms in prior sessions was related to later reduction in negative cognitions about the self, though the impact of negative cognitions in influencing subsequent symptom change demonstrated a stronger effect. Results support that reductions in negative cognitions about the self and world are mechanisms of change in PE, which may have valuable implications for maximizing treatment effectiveness. C1 [Kumpula, Mandy J.] Milwaukee Med Coll Wisconsin, Clement J Zablocki VA Med Ctr, Milwaukee, WI USA. [Pentel, Kimberly Z.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Foa, Edna B.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [LeBlanc, Nicole J.] Harvard Univ, Cambridge, MA 02138 USA. [Bui, Eric; Simon, Naomi M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McSweeney, Lauren B.] Eastern Michigan Univ, VA Ann Arbor Healthcare Syst, Ypsilanti, MI 48197 USA. [Knowles, Kelly; Rauch, Sheila A. M.] Univ Michigan, VA Ann Arbor Healthcare Syst, Ann Arbor, MI 48109 USA. [Bosley, Hannah] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Rauch, SAM (reprint author), Emory Sch Med, 12 Execut Pk Dr,3rd Floor, Atlanta, GA 30329 USA. EM sheila.a.m.rauch@emory.edu FU GlaxoSmithKline; VA Ann Arbor Healthcare System FX This study was supported by an investigator initiated Collaborative Research Trial grant from GlaxoSmithKline. Dr. Rauch's effort was partially supported by VA Ann Arbor Healthcare System. NR 50 TC 2 Z9 2 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 156 EP 165 PG 10 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700003 PM 28270327 ER PT J AU Farmer, CC Mitchell, KS Parker-Guilbert, K Galovski, TE AF Farmer, Courtney C. Mitchell, Karen S. Parker-Guilbert, Kelly Galovski, Tara E. TI Fidelity to the Cognitive Processing Therapy Protocol: Evaluation of Critical Elements SO BEHAVIOR THERAPY LA English DT Article DE trauma recovery; Cognitive Processing Therapy; PTSD; critical elements ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CLINICAL-TRIAL; TREATMENT INTEGRITY; SYMPTOM CHANGE; PTSD; DEPRESSION; VETERANS; VICTIMS; TRAUMA; METAANALYSIS AB The contributions of individual therapy elements to the overall efficacy of evidence-based practices for the treatment of posttraumatic stress disorder (PTSD) are not well-understood. This study first examined the extent to which theoretically important treatment components of Cognitive Processing Therapy (CPT; i.e., skill in Socratic questioning; prioritizing assimilation; attention to practice assignments; emphasis on expression of natural affect) were successfully administered across the course of therapy for 68 PTSD-positive survivors of interpersonal trauma. Therapist fidelity in the administration of these four elements was evaluated in 533 taped CPT sessions of study participants included in one of two randomized controlled CPT treatment trials. Second, we examined therapist fidelity to these components as a predictor of session-to-session PTSD and depression symptom change. Third, follow-up analyses examined the influence of high therapist competence for these four components across an entire course of therapy on symptom change from pre- to posttreatment. Results showed consistently high adherence and more variable competence for these four treatment components. There were no significant effects of therapist fidelity on session-to-session symptom change. However, results showed that overall high therapist competence for "skill in Socratic questioning" and "prioritizing assimilation before overaccommodation" were related to greater client improvement in PTSD severity, but "attention to practice assignments" and "emphasis on expression of natural affect" were not. Overall competence ratings for the four components were not significantly associated with improvement in depressive symptoms. Findings contribute to increased understanding of the relationship between the key treatment components of CPT and symptom change. C1 [Farmer, Courtney C.; Galovski, Tara E.] Univ Missouri St Louis, Ctr Trauma Recovery, St Louis, MO USA. [Mitchell, Karen S.; Parker-Guilbert, Kelly] Boston Univ, VA Boston Healthcare Syst, Natl Ctr PTSD, Sch Med, Boston, MA 02215 USA. [Farmer, Courtney C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Galovski, Tara E.] VA Boston Healthcare System, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. RP Farmer, CC (reprint author), Adult Psychosocial Treatment Clin, Dept Psychiat & Behav Sci, 401 Quarry Rd, Palo Alto, CA 94304 USA. EM CourtneyCFarmer@gmail.com NR 46 TC 1 Z9 1 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 195 EP 206 PG 12 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700006 PM 28270330 ER PT J AU Au, TM Sauer-Zavala, S King, MW Petrocchi, N Barlow, DH Litz, BT AF Au, Teresa M. Sauer-Zavala, Shannon King, Matthew W. Petrocchi, Nicola Barlow, David H. Litz, Brett T. TI Compassion-Based Therapy for Trauma-Related Shame and Posttraumatic Stress: Initial Evaluation Using a Multiple Baseline Design SO BEHAVIOR THERAPY LA English DT Article DE trauma; posttraumatic stress disorder; shame; compassion; single-case experimental design ID RANDOMIZED CONTROLLED-TRIAL; PTSD SYMPTOM SEVERITY; SELF-COMPASSION; DISORDER; QUESTIONNAIRE; EXPOSURE; ABUSE; PSYCHOTHERAPY; VALIDATION; EVENTS AB Accumulating research suggests that shame can strongly contribute to the development and maintenance of post traumatic stress disorder (PTSD). Interventions that promote self-compassion have shown promise for reducing shame related to various clinical problems, but this approach has not been systematically evaluated for traumatized individuals. The aim of this study was to develop a brief compassion-based therapy and assess its efficacy for reducing trauma-related shame and PTSD symptoms. Using a multiple baseline experimental design, the intervention was evaluated in a community sample of trauma-exposed adults (N = 10) with elevated trauma-related shame and PTSD symptoms. Participants completed weekly assessments during a 2-, 4-, or 6-week baseline phase and a 6-week treatment phase, and at 2 and 4 weeks after the intervention. By the end of treatment, 9 of 10 participants demonstrated reliable decreases in PTSD symptom severity, while 8 of 10 participants showed reliable reductions in shame. These improvements were maintained at 2- and 4-week follow-up. The intervention was also associated with improvements in self-compassion and self-blame. Participants reported high levels of satisfaction with the intervention. Results suggest that the intervention may be useful as either a stand-alone treatment or as a supplement to other treatments. C1 [Au, Teresa M.] Boston Univ, Ctr Anxiety & Related Disorders, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Sauer-Zavala, Shannon; Petrocchi, Nicola; Barlow, David H.] Boston Univ, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. [King, Matthew W.] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Petrocchi, Nicola] John Cabot Univ, Rome, Italy. [Litz, Brett T.] Boston Univ, VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Sch Med, Boston, MA 02215 USA. RP Au, TM (reprint author), Boston Univ, 648 Beacon St,6th Fl, Boston, MA 02215 USA. EM tau@bu.edu FU Clara Mayo Memorial Fellowship Award FX The authors wish to acknowledge Dr. Frank Dibert for providing clinical supervision; Dr. Lizabeth Roemer for providing consultation on study design and feedback on a previous version of the manuscript; and Rebecca Lubin, Carol Hundert, and Mia Tankersley for assisting with adherence ratings. This study was supported by a Clara Mayo Memorial Fellowship Award to T. M. Au. NR 50 TC 0 Z9 0 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 207 EP 221 PG 15 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700007 PM 28270331 ER PT J AU Campbell, SB Renshaw, KD Kashdan, TB Curby, TW Carter, SP AF Campbell, Sarah B. Renshaw, Keith D. Kashdan, Todd B. Curby, Timothy W. Carter, Sarah P. TI A Daily Diary Study of Posttraumatic Stress Symptoms and Romantic Partner Accommodation SO BEHAVIOR THERAPY LA English DT Article DE PTSD; romantic relationships; accommodation; maintenance ID SOCIAL SUPPORT; DISORDER; PTSD; VETERANS; EXPOSURE; OUTCOMES; THERAPY; COMBAT; SCALE; COMMUNICATION AB Little is known about the role of romantic partner symptom accommodation in PTSD symptom maintenance. To explore the bidirectional associations of posttraumatic stress disorder (PTSD) symptoms and romantic partner symptom accommodation over time, military servicemen (n = 64) with symptoms of PTSD and their cohabiting heterosexual civilian romantic partners (n = 64) completed a 2-week daily diary study. Cross-lagged, autoregressive models assessed the stability of men's PTSD symptoms and partners' accommodation, as well as the prospective associations of earlier PTSD symptoms with later accommodation and vice versa. Analyses used Bayesian estimation to provide point estimates (b) and Credible Intervals (CIs). In all models, PTSD symptoms (total and individual clusters) were highly stable (b = 0.91; CI: 0.88-0.95), and accommodation was moderately stable (b = 0.48; CI: 0.40-0.54). In all models, earlier PTSD symptoms (total and clusters) were significantly, positively associated with later accommodation (b = 0.04; CI: 0.02-0.07). In contrast, earlier accommodation was significantly associated only with later situational avoidance (b = 0.02; CI: 0.00-0.07). Thus, PTSD symptoms may lead to subsequent accommodating behaviors in romantic partners, but partner accommodation seems to contribute only to survivors' future situational avoidance symptoms. The findings reinforce the notion that PTSD symptoms have an impact on relationship behaviors, and that accommodation from partners may sustain avoidant behaviors in particular. Clinicians should attend to romantic partners' accommodating behaviors when working with survivors. C1 [Campbell, Sarah B.; Renshaw, Keith D.; Kashdan, Todd B.; Curby, Timothy W.; Carter, Sarah P.] George Mason Univ, Fairfax, VA 22030 USA. RP Campbell, SB (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div, 1660 S Columbian Way,116MHC, Seattle, WA 98108 USA. EM scampbep@gmu.edu FU National Institute of Mental Health under Ruth L. Kirschstein National Research Service Award [1F31MH098581-01A1]; International Society of Traumatic Stress Studies; American Psychological Foundation FX This research was supported in part by grants from the National Institute of Mental Health under Ruth L. Kirschstein National Research Service Award number 1F31MH098581-01A1, the International Society of Traumatic Stress Studies, and the American Psychological Foundation awarded to Sarah B. Campbell, M.A. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 0 Z9 0 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 222 EP 234 PG 13 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700008 PM 28270332 ER PT J AU Fredman, SJ Beck, JG Shnaider, P Le, YY Pukay-Martin, ND Pentel, KZ Monson, CM Simon, NM Marques, L AF Fredman, Steffany J. Beck, J. Gayle Shnaider, Philippe Le, Yunying Pukay-Martin, Nicole D. Pentel, Kimberly Z. Monson, Candice M. Simon, Naomi M. Marques, Luana TI Longitudinal Associations Between PTSD Symptoms and Dyadic Conflict Communication Following a Severe Vehicle Accident SO BEHAVIOR THERAPY LA English DT Article DE PTSD; PTSD symptom clusters; motor vehicle accident; couple; communication ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; INTIMATE-RELATIONSHIPS; RELATIONSHIP DISTRESS; PERCEIVED CRITICISM; EXPRESSED EMOTION; VIETNAM VETERANS; SOCIAL SUPPORT; IRAQ WAR; PARTNERS AB There are well-documented associations between posttraumatic stress disorder (PTSD) symptoms and intimate relationship impairments, including dysfunctional communication at times of relationship conflict. To date, the extant research on the associations between PTSD symptom severity and conflict communication has been cross-sectional and focused on military and veteran couples. No published work has evaluated the extent to which PTSD symptom severity and communication at times of relationship conflict influence each other over time or in civilian samples. The current study examined the prospective bidirectional associations between PTSD symptom severity and dyadic conflict communication in a sample of 114 severe motor vehicle accident (MVA) survivors in a committed intimate relationship at the time of the accident. PTSD symptom severity and dyadic conflict communication were assessed at 4 and 16 weeks post-MVA, and prospective associations were examined using path analysis. Total PTSD symptom severity at 4 weeks prospectively predicted greater dysfunctional communication at 16 weeks post-MVA but not vice versa. Examination at the level of PTSD symptom clusters revealed that effortful avoidance at 4 weeks prospectively predicted greater dysfunctional communication at 16 weeks, whereas dysfunctional communication 4 weeks after the MVA predicted more severe emotional numbing at 16 weeks. Findings highlight the role of PTSD symptoms in contributing to dysfunctional communication and the importance of considering PTSD symptom clusters separately when investigating the dynamic interplay between PTSD symptoms and relationship functioning over time, particularly during the early posttrauma period. Clinical implications for the prevention of chronic PTSD and associated relationship problems are discussed. C1 [Fredman, Steffany J.; Le, Yunying] Penn State Univ, University Pk, PA 16802 USA. [Beck, J. Gayle] Univ Memphis, Memphis, TN 38152 USA. [Shnaider, Philippe; Monson, Candice M.] Ryerson Univ, Toronto, ON, Canada. [Pukay-Martin, Nicole D.] Cincinnati VA Med Ctr, Trauma Recovery Ctr, Cincinnati, OH USA. [Pentel, Kimberly Z.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Simon, Naomi M.; Marques, Luana] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Simon, Naomi M.; Marques, Luana] Harvard Med Sch, Boston, MA USA. RP Fredman, SJ (reprint author), Penn State Univ, Dept Human Dev & Family Studies, 119 Hlth & Human Dev Bldg, University Pk, PA 16802 USA. EM sjf23@psu.edu FU National Institute of Mental Health [R36 MH075383, K23 MH096029-01A1]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000127]; start-up funds FX This research was supported in part by grants from the National Institute of Mental Health to Luana Marques (R36 MH075383 and K23 MH096029-01A1), a grant from the National Center for Advancing Translational Sciences, National Institutes of Health to the Pennsylvania State University (UL1 TR000127), and start-up funds to Steffany J. Fredman at The Pennsylvania State University. We gratefully acknowledge Timothy Brick, Gregory Fosco, Thomas Rodebaugh, and Jeremiah Schumm for their guidance regarding data analysis. NR 54 TC 1 Z9 1 U1 0 U2 0 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 235 EP 246 PG 12 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700009 PM 28270333 ER PT J AU Knobloch-Fedders, LM Caska-Wallace, C Smith, TW Renshaw, K AF Knobloch-Fedders, Lynne M. Caska-Wallace, Catherine Smith, Timothy W. Renshaw, Keith TI Battling on the Home Front: Posttraumatic Stress Disorder and Conflict Behavior Among Military Couples SO BEHAVIOR THERAPY LA English DT Article DE couples; PTSD; military; interpersonal behavior; Structural Analysis of Social Behavior ID ADMINISTERED PTSD SCALE; RELATIONSHIP QUALITY; COMBAT VETERANS; STRUCTURAL-ANALYSIS; INTIMATE PARTNERS; DEPRESSION; SYMPTOMS; DISTRESS; IMPACT; QUESTIONNAIRE AB This study evaluated interpersonal behavior differences among male military service members with and without PTSD and their female partners. Couples (N= 64) completed a 17-minute videotaped conflict discussion, and their interaction behavior was coded using the circumplex-based Structural Analysis of Social Behavior model (SASB; Benjamin, 1979, 1987, 2000). Within couples, the behavior of partners was very similar. Compared to military couples without PTSD, couples with PTSD displayed more interpersonal hostility and control. Couples with PTSD also exhibited more sulking, blaming, and controlling behavior, and less affirming and connecting behavior, than couples without PTSD. Results advance our understanding of the relational impacts of PTSD on military service members and their partners, and underscore the value of couple-based interventions for PTSD in the context of relationship distress. C1 [Knobloch-Fedders, Lynne M.] Northwestern Univ, Family Inst, Evanston, IL 60208 USA. [Caska-Wallace, Catherine] Univ Washington, VA Puget Sound Hlth Care Syst, Mental Hlth Serv, Seattle Div, Seattle, WA 98195 USA. [Smith, Timothy W.] Univ Utah, Salt Lake City, UT 84112 USA. [Renshaw, Keith] George Mason Univ, Fairfax, VA 22030 USA. RP Knobloch-Fedders, LM (reprint author), Northwestern Univ, Family Inst, Bette D Harris Ctr, 618 Lib Pl, Evanston, IL USA. EM l-knobloch@northwestern.edu FU American Psychological Association's Division 19 (Society for Military Psychology) Member / Affiliate Member Research Grant Award; National Institute of Mental Health grant [1F31MH091915-01A1] FX This study was funded in part by the 2014 American Psychological Association's Division 19 (Society for Military Psychology) Member / Affiliate Member Research Grant Award, and by National Institute of Mental Health grant 1F31MH091915-01A1. NR 65 TC 0 Z9 0 U1 1 U2 1 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2017 VL 48 IS 2 BP 247 EP 261 PG 15 WC Psychology, Clinical SC Psychology GA EO6KA UT WOS:000396799700010 PM 28270334 ER PT J AU Askenazi, DJ Heung, M Connor, MJ Basu, RK Cerda, J Doi, K Koyner, JL Bihorac, A Golestaneh, L Vijayan, A Okusa, MD Faubel, S AF Askenazi, D. J. Heung, Michael Connor, Michael J., Jr. Basu, Rajit K. Cerda, Jorge Doi, Kent Koyner, Jay L. Bihorac, Azra Golestaneh, Ladan Vijayan, Anitha Okusa, Mark D. Faubel, Sarah CA Amer Soc Nephrology Acute Kidney Injury Adv TI Optimal Role of the Nephrologist in the Intensive Care Unit SO BLOOD PURIFICATION LA English DT Article DE Critical care nephrology; Quality Improvement; Acute kidney injury; Education; Renal replacement therapy ID ACUTE KIDNEY INJURY; RENAL-REPLACEMENT THERAPY; CRITICALLY-ILL PATIENTS; CYCLE ARREST BIOMARKERS; FUROSEMIDE STRESS TEST; DIALYSIS FACILITY; MEDICAL DIRECTOR; MORTALITY; AKI; SURGERY AB As advances in Critical Care Medicine continue, critically ill patients are surviving despite the severity of their illness. The incidence of acute kidney injury (AKI) has increased, and its impact on clinical outcomes as well as medical expenditures has been established. The role, indications and technological advancements of renal replacement therapy (RRT) have evolved, allowing more effective therapies with less complications. With these changes, Critical Care Nephrology has become an established specialty, and ongoing collaborations between critical care physicians and nephrologist have improved education of multi-disciplinary team members and patient care in the ICU. Multidisciplinary programs to support these changes have been stablished in some hospitals to maximize the delivery of care, while other programs have continue to struggle in their ability to acquire the necessary resources to maximize outcomes, educate their staff, and develop quality initiatives to evaluate and drive improvements. Clearly, the role of the nephrologist in the ICU has evolved, and varies widely among institutions. This special article will provide insights that will hopefully optimize the role of the nephrologist as the leader of the acute care nephrology program, as clinician for critically ill patients, and as teacher for all members of the health care team. (C) 2016 S. Karger AG, Basel C1 [Askenazi, D. J.] Univ Alabama Birmingham, Dept Pediat, Div Pediat Nephrol, ACC 516,1600 7th Ave South, Birmingham, AL 35233 USA. [Heung, Michael] Univ Michigan, Dept Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Connor, Michael J., Jr.] Emory Univ, Dept Med, Div Renal Med, Atlanta, GA 30322 USA. [Basu, Rajit K.] Cincinnati Childrens Hosp Ctr, Ctr Acute Care Nephrol, Cincinnati, OH USA. [Cerda, Jorge] Albany Med Coll, Dept Med, Albany, NY 12208 USA. [Koyner, Jay L.] Univ Chicago, Dept Med, Nephrol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Bihorac, Azra] Univ Florida, Dept Anesthesiol, Gainesville, FL USA. [Golestaneh, Ladan] Albert Einstein Coll Med, Dept Clin Med, Div Nephrol, Bronx, NY 10467 USA. [Vijayan, Anitha] Washington Univ, Div Nephrol, St Louis, MO USA. [Okusa, Mark D.] Univ Virginia Hlth Syst, Div Nephrol, Charlottesville, VA USA. [Faubel, Sarah] Univ Colorado, Dept Med, Denver, CO USA. [Faubel, Sarah] Denver VA Med Ctr, Denver, CO USA. [Doi, Kent] Tokyo Univ Hosp, Dept Emergency & Crit Care Med, Bunkyo Ku, Tokyo, Japan. RP Askenazi, DJ (reprint author), Univ Alabama Birmingham, Dept Pediat, Div Pediat Nephrol, ACC 516,1600 7th Ave South, Birmingham, AL 35233 USA. EM daskenazi@peds.uab.edu OI Bihorac, Azra/0000-0002-5745-2863 FU NCATS NIH HHS [UL1 TR001417]; NIDDK NIH HHS [R01 DK103608]; NIGMS NIH HHS [P50 GM111152, R01 GM110240] NR 55 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0253-5068 EI 1421-9735 J9 BLOOD PURIFICAT JI Blood Purif. PD MAR PY 2017 VL 43 IS 1-3 BP 68 EP 77 DI 10.1159/000452317 PG 10 WC Hematology; Urology & Nephrology SC Hematology; Urology & Nephrology GA EN4AA UT WOS:000395948100009 PM 27923227 ER PT J AU D'Sa, S Kersten, MJ Castillo, JJ Dimopoulos, M Kastritis, E Laane, E Leblond, V Merlini, G Treon, SP Vos, JM Lunn, MP AF D'Sa, Shirley Kersten, Marie Jose Castillo, Jorge J. Dimopoulos, Meletios Kastritis, Efstathios Laane, Edward Leblond, Veronique Merlini, Giampaolo Treon, Steven P. Vos, Josephine M. Lunn, Michael P. TI Investigation and management of IgM and Waldenstrom-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE IgM; paraproteinaemic neuropathy; Waldenstrom macroglobulinaemia ID MYELIN-ASSOCIATED GLYCOPROTEIN; NERVOUS-SYSTEM INVOLVEMENT; ANTI-MAG NEUROPATHY; REFRACTORY MULTIPLE-MYELOMA; RANDOMIZED CONTROLLED-TRIAL; SENSORY ATAXIC NEUROPATHY; PLACEBO-CONTROLLED TRIAL; LIGHT-CHAIN AMYLOIDOSIS; BING-NEEL SYNDROME; MONOCLONAL GAMMOPATHY AB Paraproteinaemic neuropathies are a heterogeneous group of disorders most frequently associated with IgM monoclonal gammopathies including Waldenstrom macroglobulinaemia (WM). Their consequences are significant for affected patients, and their management challenging for their physicians. The variability in clinical presentation and time course hamper classification and management. The indications for invasive investigations such as cerebrospinal fluid analysis, nerve conduction tests and sensory nerve biopsies are unclear, and the optimum way to measure clinical response to treatment unknown. When to intervene and and how to treat, also present challenges to physicians. As part of its latest deliberations at the International Workshops on WM (IWWM) in London, UK (August 2014), the IWWM8 panel have proposed a consensus approach to the diagnosis and management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM. Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions. C1 [D'Sa, Shirley] Univ Coll London Hosp NHS Fdn Trust, Canc Div, Waldenstrom Clin, London, England. [Kersten, Marie Jose; Vos, Josephine M.] Acad Med Ctr, Dept Haematol, Amsterdam, Netherlands. [Castillo, Jorge J.; Treon, Steven P.] Harvard Med Sch, Dana Farber Canc Inst, Bing Ctr Waldenstrom Macroglobulinemia, Boston, MA USA. [Dimopoulos, Meletios; Kastritis, Efstathios] Univ Athens, Dept Clin Therapeut, Athens, Greece. [Laane, Edward] North Estonia Med Ctr, Dept Haematol, Tallinn, Estonia. [Leblond, Veronique] UPMC Univ Paris 6, Hop Pitie Salpetriere, AP HP, GRC 11, Paris, France. [Merlini, Giampaolo] Univ Pavia, Ctr Res & Treatment Syst Amyloidosis, Pavia, Italy. [Vos, Josephine M.] Sint Antonius Ziekenhuis, Ctr Canc, Nieuwegein, Netherlands. [Lunn, Michael P.] Natl Hosp Neurol & Neurosurg, Ctr Neuromuscular Dis, London, England. RP D'Sa, S (reprint author), Univ Coll Hosp, Dept Haematol, 3rd Floor West,250 Euston Rd, London NW1 2PG, England. EM shirley.dsa@uclh.nhs.uk NR 105 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 176 IS 5 BP 728 EP 742 DI 10.1111/bjh.14492 PG 15 WC Hematology SC Hematology GA EM3CG UT WOS:000395191500007 PM 28198999 ER PT J AU Raje, NS Moreau, P Terpos, E Benboubker, L Grzasko, N Holstein, SA Oriol, A Huang, SY Beksac, M Kuliczkowski, K Tai, DF Wooldridge, JE Conti, I Kaiser, CJ Nguyen, TS Cronier, DM Palumbo, A AF Raje, Noopur S. Moreau, Philippe Terpos, Evangelos Benboubker, Lotfi Grzasko, Norbert Holstein, Sarah A. Oriol, Albert Huang, Shang-Yi Beksac, Meral Kuliczkowski, Kazimierz Tai, Datchen F. Wooldridge, James E. Conti, Ilaria Kaiser, Christopher J. Nguyen, Tuan S. Cronier, Damien M. Palumbo, Antonio TI Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE multiple myeloma; treatment; tabalumab; bortezomib; B-cell activating factor (BAFF) ID MONOCLONAL-ANTIBODY; MATURATION ANTIGEN; THERAPY; APRIL; BAFF; LENALIDOMIDE; PANOBINOSTAT; CARFILZOMIB; COMBINATION; ELOTUZUMAB AB In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N=72), tabalumab 100mg (N=74), or tabalumab 300mg (N=74), each in combination with dexamethasone 20mg and subcutaneous bortezomib 13mg/m(2) on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 66, 75 and 76months for the tabalumab 100, 300mg and placebo groups, respectively (tabalumab 100mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)]=113 [080-159], P=0480; tabalumab 300mg vs. placebo HR [95% CI]=103 [072-145], P=0884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n=162) had significantly longer mPFS than those with high BAFF expression (n=55), using the 75th percentile cut-off point (mPFS [95% CI]=83 [70-93] months vs. 58 [37-66] months; HR [95% CI]=159 [111-229], P=0015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300mg tabalumab did not improve efficacy compared to the 100mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma. C1 [Raje, Noopur S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moreau, Philippe] Univ Hosp Hotel Dieu, Nantes, France. [Terpos, Evangelos] Univ Athens, Sch Med, Athens, Greece. [Benboubker, Lotfi] CHRU, Hop Bretonneau, Tours, France. [Grzasko, Norbert] Med Univ Lublin, Lublin, Poland. [Grzasko, Norbert] St Johns Canc Ctr, Dept Haematol, Lublin, Poland. [Holstein, Sarah A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Oriol, Albert] Hosp Badalona Germans Trias & Pujol, ICO, Badalona, Spain. [Oriol, Albert] Hosp Badalona Germans Trias & Pujol, Inst Recerca Leucemia Josep Carreras IJC, Badalona, Spain. [Huang, Shang-Yi] Natl Taiwan Univ, Med Coll & Hosp, Taipei, Taiwan. [Beksac, Meral] Ankara Univ, Ibn Sina Hosp, Ankara, Turkey. [Kuliczkowski, Kazimierz] Wroclaw Med Univ, Wroclaw, Poland. [Tai, Datchen F.; Wooldridge, James E.; Conti, Ilaria; Kaiser, Christopher J.; Nguyen, Tuan S.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Cronier, Damien M.] Eli Lilly & Co Ltd, Windlesham, Surrey, Uruguay. [Palumbo, Antonio] Univ Torino, Myeloma Unit, Azienda Osped Univ Citta Salute & Sci Torino, Div Haematol, Turin, Italy. [Nguyen, Tuan S.] Gilead Sci, Foster City, CA USA. RP Raje, NS (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, 55 Fruit St, Boston, MA 02114 USA. EM NRAJE@mgh.harvard.edu FU Eli Lilly and Company FX This work was funded by Eli Lilly and Company. NR 49 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 176 IS 5 BP 783 EP 795 DI 10.1111/bjh.14483 PG 13 WC Hematology SC Hematology GA EM3CG UT WOS:000395191500012 PM 28005265 ER PT J AU Gustine, J Meid, K Xu, L Hunter, ZR Castillo, JJ Treon, SP AF Gustine, Joshua Meid, Kirsten Xu, Lian Hunter, Zachary R. Castillo, Jorge J. Treon, Steven P. TI To select or not to select? The role of B-cell selection in determining the MYD88 mutation status in Waldenstrom Macroglobulinaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE Waldenstrom Macroglobulinaemia; MYD88 ID L265P SOMATIC MUTATION; MONOCLONAL GAMMOPATHY C1 [Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532; Hunter, Zachary/0000-0002-1689-1691 FU International Waldenstrom Macroglobulinaemia Foundation; D'Amato Family Fund for Genomic Discovery in WM; Peter S. Bing, M.D. FX Supported by Peter S. Bing, M.D., the International Waldenstrom Macroglobulinaemia Foundation, and the D'Amato Family Fund for Genomic Discovery in WM. NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 MAR PY 2017 VL 176 IS 5 BP 822 EP 824 DI 10.1111/bjh.13996 PG 3 WC Hematology SC Hematology GA EM3CG UT WOS:000395191500016 PM 26936399 ER PT J AU Kamycheva, E Goto, T Camargo, CA AF Kamycheva, Elena Goto, Tadahiro Camargo, Carlos A., Jr. TI Celiac disease autoimmunity is associated with leukocyte telomere shortening in older adults: The US National Health and Nutrition Examination Survey SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Celiac disease; Leukocyte telomere length; Tissue transglutaminase IgA; NHANES ID IDIOPATHIC STEATORRHEA; LENGTH; CANCER; RISK; METAANALYSIS; HERITABILITY; MALIGNANCY; DIAGNOSIS; SURVIVAL; ANEMIA AB Purpose: Telomeres are nucleotide sequences, and their function is to maintain cell surveillance. Exaggeration of the attrition rate of leukocyte telomere length (LTL) may result in genomic instability and tumorigenesis. Celiac disease (CD), an autoimmune inflammation of small intestine, has increasing prevalence in the elderly and may lead to lymphomas and gastrointestinal malignancies. We used nationally-representative datasets from the U.S. National Health and Nutrition Examination Survey (NHANES) to investigate if CD autoimmunity in older adults (age >= 50 years) is associated with shorter LTL Results: Our study included 3939 subjects, where 25 subjects (mean age 65 years) were CD seropositive and 3914 (mean age 64 years) were CD seronegative. CD seropositive subjects had shorter LTL than CD seronegative subjects (P < 0.001). In the linear regression model, CD seropositivity was significantly associated with 0.25 kb pairs decrease in LTL length (P < 0.001), adjusted for age, sex, race/ethnicity, serum ferritin and folate, and ratio of family income to poverty. Conclusions: In a nationally-representative population of adults age >= 50 years, CD seropositivity is significantly associated with shorter LTL, independently of age, sex, race/ethnicity, serum ferritin and folate, and socioeconomic status. This supports the enhanced telomere attrition in of CD seropositive adults. (C) 2017 Elsevier Inc. All rights reserved. C1 [Kamycheva, Elena; Goto, Tadahiro; Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. [Kamycheva, Elena] Univ Hosp North Norway, Dept Geriatr, Med Clin, Sykehusveien 38, N-9038 Tromso, Norway. [Kamycheva, Elena] UiT Arctic Univ Norway, Dept Clin Med, Endocrine Res Grp, Fac Hlth Sci, Hansine Hansen Veg 18, N-9017 Tromso, Norway. [Goto, Tadahiro; Camargo, Carlos A., Jr.] Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. RP Kamycheva, E (reprint author), Univ Hosp North Norway, Dept Geriatr, Med Clin, Sykehusveien 38, N-9038 Tromso, Norway. EM elena.kamycheva@unn.no; qq_gto@yahoo.co.jp; ccamargo@partners.org FU Department of Geriatrics, Medical Clinic, University Hospital of North Norway, Sykehusveien, Tromsoe, Norway FX Elena Kamycheva was financially supported by the Department of Geriatrics, Medical Clinic, University Hospital of North Norway, Sykehusveien 38, 9038 Tromsoe, Norway. NR 31 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 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD MAR PY 2017 VL 89 BP 64 EP 68 DI 10.1016/j.exger.2017.01.003 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EN2ML UT WOS:000395844500009 PM 28104447 ER PT J AU Wenande, E Olesen, UH Nielsen, MMB Janfelt, C Hansen, SH Anderson, RR Haedersdal, M AF Wenande, Emily Olesen, Uffe H. Nielsen, Mette M. B. Janfelt, Christian Hansen, Steen Honore Anderson, R. Rox Haedersdal, Merete TI Fractional laser-assisted topical delivery leads to enhanced, accelerated and deeper cutaneous 5-fluorouracil uptake SO EXPERT OPINION ON DRUG DELIVERY LA English DT Article DE 5-Fluorouracil; fractional ablative CO2 laser; Franz skin permeability diffusion cells; high performance liquid chromatography; laser-assisted drug delivery; matrix-assisted laser desorption ionization mass spectrometry imaging; non-melanoma skin cancer ID BASAL-CELL CARCINOMA; DRUG-DELIVERY; TRANSDERMAL DELIVERY; IN-VIVO; ACTINIC KERATOSIS; SKIN-CANCER; PHOTODYNAMIC THERAPY; PRECURSOR LESIONS; BOWENS-DISEASE; FLUOROURACIL AB Background: Topical 5-Fluorouracil (5-FU) exhibits suboptimal efficacy for non-melanoma skin cancer, attributed to insufficient intracutaneous penetration. This study investigates the impact of ablative fractional laser (AFXL) at different laser-channel depths on cutaneous 5-FU pharmacokinetics and biodistribution. Methods: In vitro porcine skin underwent AFXL-exposure using a fractional 10,600 nm CO2-laser, generating microscopic ablation zones (MAZ) reaching the dermoepidermal junction (MAZ-ED), superficial-( MAZ-DS), or mid-dermis(MAZ-DM). 5-FU in AFXL-exposed and control skin was measured in Franz diffusion cells at 4 and 24 hours (n = 55). HPLC quantified 5-FU in full-thickness skin, specific skin depths of 100 mu m-1500 mu m, and transcutaneous receiver-compartments. Qualitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) visualized 5-FU in selected samples. Results: Overall, AFXL enhanced and accelerated 5-FU uptake versus unexposed controls, with increased accumulation in deep skin layers (p < 0.01). While total, 24-hour 5-FU uptake in control skin was 0.096 mg/cm(3) (0.19% of applied concentration), AFXL delivered up to 4.707 mg/cm(3) (MAZ-DM; 9.41% uptake, 49-fold enhancement) (p = 0.002; 24 hours). Indicating accelerated delivery, 5-FU in laser-exposed samples at 4 hours was at least 10-fold that of 24-hour controls (p = 0.002). Deeper laser-channels increased delivery throughout the skin (MAZ-ED vs. MAZ-DM; p<0.01). MALDI-MSI confirmed enhanced, accelerated, deeper and more uniform 5-FU distribution after AFXL versus controls. Conclusions: AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers. C1 [Wenande, Emily; Olesen, Uffe H.; Haedersdal, Merete] Univ Copenhagen, Bispebjerg Hosp, Dept Dermatol, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. [Nielsen, Mette M. B.] Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark. [Janfelt, Christian; Hansen, Steen Honore] Univ Copenhagen, Dept Pharm, Copenhagen, Denmark. [Anderson, R. Rox; Haedersdal, Merete] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. RP Wenande, E (reprint author), Univ Copenhagen, Bispebjerg Hosp, Dept Dermatol, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. EM emilycathrinew@hotmail.com FU Capital Region of Denmark's Foundation for Health Research; Novo Nordisk Foundation [NNF - 13OC0007917]; Danish Council for Independent Research \ Medical Sciences [DFF - 4002-00391] FX This work was supported by the Capital Region of Denmark's Foundation for Health Research, Novo Nordisk Foundation [Grant number NNF - 13OC0007917]), and the Danish Council for Independent Research vertical bar Medical Sciences [Grant number DFF - 4002-00391]. NR 62 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 14 IS 3 BP 307 EP 317 DI 10.1080/17425247.2017.1260119 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EM3GB UT WOS:000395201400003 PM 27835937 ER PT J AU Kwon, JY Gonzalez, T Riedel, MD Nazarian, A Ghorbanhoseini, M AF Kwon, John Y. Gonzalez, Tyler Riedel, Matthew D. Nazarian, Ara Ghorbanhoseini, Mohammad TI Proximity of the Lateral Calcaneal Artery With a Modified Extensile Lateral Approach Compared to Standard Extensile Approach SO FOOT & ANKLE INTERNATIONAL LA English DT Article DE lateral calcaneal artery; extensile lateral approach; modified extensile lateral approach; calcaneus fracture; operative technique; wound complications ID INTRAARTICULAR FRACTURES; ORIF AB Background: The extensile lateral approach (EL) has been associated with increased wound complications such as apical necrosis which may be due partially from violation of the lateral calcaneal artery (LCA). Traditionally, the vertical limb has been placed half-way between the fibula and Achilles tendon, which may be suboptimal given the proximity to the LCA. We hypothesized that placing the vertical limb further posterior (ie, modified EL [MEL]) would increase the distance from the LCA. The purposes of this study were to quantify the location of the LCA in relation to the vertical limb of the traditional EL approach and to determine if utilizing the MEL approach endangered the LCA to a lesser extent. Methods: 20 cadavers were used. For the EL approach, the fibula and Achilles tendon were palpated and a line parallel to the plantar foot was drawn between the two. A vertical line (VL), representing the vertical limb of the approach, was drawn at the midway point as a perpendicular extending proximally from the junction of the glabrous/non-glabrous skin (JGNG). For the MEL approach, the anterior border of the Achilles tendon was palpated and a similar vertical line (MVL) was drawn 0.75 cm anterior. Dissection was performed and if the LCA was identified crossing the line VL/MVL, the distance from the JGNG was documented. Results: For the EL approach, the LCA was identified in 17/20 (85%) cadavers at an average distance of 5.0 cm (range 3-7 cm, SD = 1.3 cm) from JGNG. For the ML approach, the LCA was identified in 4/20 (20%) cadavers at an average distance of 5.9 cm (range 3-6.5 cm, SD = 1.7 cm) from the JGNG (P < .001). Conclusions: The LCA was encountered 4 times more often during the EL approach as compared to the MEL approach. Clinical Relevance: A modification of the EL approach may decrease iatrogenic injury to the LCA and may decrease wound complications. C1 [Kwon, John Y.; Nazarian, Ara; Ghorbanhoseini, Mohammad] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Gonzalez, Tyler; Riedel, Matthew D.] Harvard Combined Orthopaed Surg Residency Program, Boston, MA USA. RP Ghorbanhoseini, M (reprint author), Harvard Med Sch, BIDMC, Carl J Shapiro Dept Orthopaed, 330 Brookline Ave, Boston, MA 02215 USA. EM mghorban@bidmc.harvard.edu NR 24 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 1071-1007 EI 1944-7876 J9 FOOT ANKLE INT JI Foot Ankle Int. PD MAR PY 2017 VL 38 IS 3 BP 318 EP 323 DI 10.1177/1071100716674695 PG 6 WC Orthopedics SC Orthopedics GA EM5XO UT WOS:000395387500014 PM 27923213 ER PT J AU Counter, SA Buchanan, LH Ortega, F Jacobs, AB Laurell, G AF Counter, S. Allen Buchanan, Leo H. Ortega, Fernando Jacobs, Anthony B. Laurell, Goran TI Assessment of the Brainstem- Mediated Stapedius Muscle Reflex in Andean Children Living at High Altitudes SO HIGH ALTITUDE MEDICINE & BIOLOGY LA English DT Article DE altitude; Andean; auditory; brainstem; children; hearing; hypoxia; stapedius reflex ID AUDITORY REACTION-TIME; P300 LATENCY; HYPOXIA; EAR; ADAPTATION AB This study examined the physiological thresholds, amplitude growth, and contraction duration of the acoustic stapedius reflex (ASR) in Andean children aged 2-17 years living at altitudes of 2850m (Altitude I Group) and 3973m (Altitude II Group) as part of a general medical assessment of the health status of the children. The brainstem-mediated ASR reveals the integrity of the neuronal components of the auditory reflex arc, including the cochlea receptors, eight cranial nerves, and brainstem neural projections to the cochlear nuclei, bilateral superior olivary nuclei, facial nerve nuclei, and facial nerve and its stapedius branch. Uncrossed (ipsilateral) and crossed (contralateral) ASR thresholds (ASRT), ASR amplitude growth (ASRG) function, and ASR muscle contraction duration (decay/ fatigue) (ASRD) were measured noninvasively with 500, 1000 Hz and broadband (bandwidth = 125-4000 Hz) noise stimulus activators using a middle ear immittance system. Oxygen saturation (SaO(2)) level and heart rate were measured in a subsample of the study group. Statistical analyses revealed that the Altitude I and Altitude II groups had ASRT, ASRG function, and ASRD rates comparable to children at sea level and that the two groups were not significantly different for any of the ASR measures. No significant association was found between SaO(2) or heart rate and ASRT, growth, and muscle fatigue rate. In conclusion, the assessment of the ASR in children in the high-altitude groups revealed normal function. Furthermore, the results indicate no adverse oto-physiological effects of altitude on the brainstem-mediated ASR at elevations between 2850 and 4000m and suggest normal middle ear and auditory brainstem function. C1 [Counter, S. Allen] Harvard Med Sch, Biol Labs, Dept Neurol, 16 Divin Ave, Cambridge, MA 02138 USA. [Counter, S. Allen] Massachusetts Gen Hosp, Dept Neurophysiol, Boston, MA 02114 USA. [Buchanan, Leo H.] Harvard Univ Hlth Serv, Audiol Clin, Dept Otolaryngol, Cambridge, MA USA. [Ortega, Fernando] Univ San Francisco Quito, Galapagos Inst Arts & Sci GAIAS, Colegio Ciencias Salud, Escuela Salud Publ, Quito, Ecuador. [Jacobs, Anthony B.] Harvard Biol Labs, Cambridge, MA USA. [Laurell, Goran] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. RP Counter, SA (reprint author), Harvard Med Sch, Biol Labs, Dept Neurol, 16 Divin Ave, Cambridge, MA 02138 USA. EM allen_counter@harvard.edu NR 30 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1527-0297 EI 1557-8682 J9 HIGH ALT MED BIOL JI High Alt. Med. Biol. PD MAR PY 2017 VL 18 IS 1 BP 37 EP 45 DI 10.1089/ham.2016.0082 PG 9 WC Biophysics; Public, Environmental & Occupational Health; Sport Sciences SC Biophysics; Public, Environmental & Occupational Health; Sport Sciences GA EP7PZ UT WOS:000397571000005 PM 27860516 ER PT J AU Zanni, MV Fitch, K Rivard, C Sanchez, L Douglas, PS Grinspoon, S Smeaton, L Currier, JS Looby, SE AF Zanni, Markella V. Fitch, Kathleen Rivard, Corinne Sanchez, Laura Douglas, Pamela S. Grinspoon, Steven Smeaton, Laura Currier, Judith S. Looby, Sara E. TI Follow YOUR Heart: development of an evidence-based campaign empowering older women with HIV to participate in a large-scale cardiovascular disease prevention trial SO HIV CLINICAL TRIALS LA English DT Article DE Women; Sex differences; Research participation; HIV-associated cardiovascular disease; Clinical trials; Community-based research; REPRIEVE ID CLINICAL-TRIALS; ENROLLMENT; RISK AB Background: Women's under-representation in HIV and cardiovascular disease (CVD) research suggests a need for novel strategies to ensure robust representation of women in HIV-associated CVD research. Objective: To elicit perspectives on CVD research participation among a community-sample of women with or at risk for HIV, and to apply acquired insights toward the development of an evidence-based campaign empowering older women with HIV to participate in a large-scale CVD prevention trial. Methods: In a community-based setting, we surveyed 40 women with or at risk for HIV about factors which might facilitate or impede engagement in CVD research. We applied insights derived from these surveys into the development of the Follow YOUR Heart campaign, educating women about HIV-associated CVD and empowering them to learn more about a multi-site HIV-associated CVD prevention trial: REPRIEVE. Results: Endorsed best methods for learning about a CVD research study included peer-to-peer communication (54%), provider communication (46%) and video-based communication (39%). Top endorsed non-monetary reasons for participating in research related to gaining information (63%) and helping others (47%). Top endorsed reasons for not participating related to lack of knowledge about studies (29%) and lack of request to participate (29%). Based on survey results, the REPRIEVE Follow YOUR Heart campaign was developed. Interwoven campaign components (print materials, video, web presence) offer provider-based information/knowledge, peer-to-peer communication, and empowerment to learn more. Campaign components reflect women's self-identified motivations for research participation - education and altruism. Conclusions: Investigation of factors influencing women's participation in HIV-associated CVD research may be usefully applied to develop evidence-based strategies for enhancing women's enrollment in disease-specific large-scale trials. If proven efficacious, such strategies may enhance conduct of large-scale research studies across disciplines. C1 [Zanni, Markella V.; Fitch, Kathleen; Rivard, Corinne; Sanchez, Laura; Grinspoon, Steven; Looby, Sara E.] Mass Gen Hosp, Program Nutr Metab, Boston, MA USA. [Zanni, Markella V.; Fitch, Kathleen; Rivard, Corinne; Sanchez, Laura; Grinspoon, Steven; Looby, Sara E.] Harvard Med Sch, Boston, MA USA. [Douglas, Pamela S.] Duke Univ, Sch Med, Duke Univ Hosp, Cardiol Div, Durham, NC USA. [Douglas, Pamela S.] Duke Univ, Sch Med, Duke Univ Hosp, Duke Clin Res Inst, Durham, NC USA. [Smeaton, Laura] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Currier, Judith S.] Univ Calif Los Angeles, Los Angeles CARE Hosp, Div Infect Dis, Los Angeles, CA USA. [Currier, Judith S.] Univ Calif Los Angeles, Los Angeles Med Sch, Los Angeles, CA USA. [Looby, Sara E.] Mass Gen Hosp, Yvonne L Munn Ctr Nursing Res, Boston, MA USA. RP Looby, SE (reprint author), Massachusetts Gen Hosp, Longfellow Pl Suite 207,55 Fruit St, Boston, MA 02114 USA. EM slooby@mgh.harvard.edu FU NIH/NIAID [1R01AI123001-01]; MGH Executive Committee on Research; The Claflin Distinguished Scholar Award; Munn Center for Nursing Research; Connell Extension Grant FX This work was supported by NIH/NIAID: MZ and SL [grant number 1R01AI123001-01]; MGH Executive Committee on Research; MZ and SL [The Claflin Distinguished Scholar Award]; William F. Connell Family and the Yvonne L. Munn Center for Nursing Research; SL [Connell Extension Grant]. NR 21 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1528-4336 EI 1945-5771 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD MAR PY 2017 VL 18 IS 2 BP 83 EP 91 DI 10.1080/15284336.2017.1297551 PG 9 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA EN5GI UT WOS:000396033200006 PM 28277924 ER PT J AU Rajaram, R Perkins, JM Joe, W Subramanian, SV AF Rajaram, Ramaprasad Perkins, Jessica M. Joe, William Subramanian, S. V. TI Individual and community levels of maternal autonomy and child undernutrition in India SO INTERNATIONAL JOURNAL OF PUBLIC HEALTH LA English DT Article DE Maternal autonomy; Child undernutrition; Empowerment; Stunting; Multilevel; India ID WOMENS EMPOWERMENT; NUTRITIONAL-STATUS; RURAL INDIA; MORTALITY; HEIGHT AB Objectives Investigate the relationship between maternal autonomy at multiple levels and the risk of child stunting, underweight, and wasting in India. Methods Data were from a 2005-2006 nationally representative, cross-sectional sample of 51,555 children under 5 years from 29 states in India. Multilevel, multivariable, logistic regression analyses were used to estimate the odds of child stunting, underweight, and wasting in relation to maternal autonomy in healthcare, movement, and money at the individual level and community level, while adjusting for several child, maternal, and household factors. Results When only adjusting for child age and sex, children in communities with a high proportion of women with autonomy in healthcare, or movement, or money, separately, had a lower risk of being stunted, underweight, or wasted, separately. However, adjusting for other explanatory factors attenuated these relationships and made them statistically insignificant. Individual maternal autonomy in any of the three domains was not associated with any of the outcomes. Conclusions The results suggest that caution should be taken when interpreting the direct relevance of maternal autonomy at both individual and community levels to measures of child undernutrition. C1 [Rajaram, Ramaprasad] Athena Infon, Madras, Tamil Nadu, India. [Perkins, Jessica M.; Subramanian, S. V.] Harvard Ctr Populat & Dev Studies, 9 Bow St, Cambridge, MA 02138 USA. [Perkins, Jessica M.; Subramanian, S. V.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Perkins, Jessica M.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Joe, William] Univ Delhi Enclave, IEG, North Campus, Delhi 110007, India. RP Rajaram, R (reprint author), Athena Infon, Madras, Tamil Nadu, India. EM ramaprasad.r@athenainfonomics.in; jessica.perkins@post.harvard.edu; william@iegindia.org; svsubram@hsph.harvard.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1661-8556 EI 1661-8564 J9 INT J PUBLIC HEALTH JI Int. J. Public Health PD MAR PY 2017 VL 62 IS 2 SI SI BP 327 EP 335 DI 10.1007/s00038-016-0850-8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EM0AN UT WOS:000394981300017 PM 27392731 ER PT J AU Garrido, MM Prigerson, HG Neupane, S Penrod, JD Johnson, CE Boockvar, KS AF Garrido, Melissa M. Prigerson, Holly G. Neupane, Suvam Penrod, Joan D. Johnson, Christopher E. Boockvar, Kenneth S. TI Mental Illness and Mental Healthcare Receipt among Hospitalized Veterans with Serious Physical Illnesses SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article DE depression; hospitalized; mental health; veterans ID OBSESSIVE-COMPULSIVE DISORDER; POSTTRAUMATIC-STRESS-DISORDER; ADMINISTRATIVE DATA; PHARMACOLOGICAL-TREATMENT; PSYCHIATRIC COMORBIDITY; ANXIETY DISORDERS; PALLIATIVE CARE; ADVANCED CANCER; HEART-FAILURE; DEPRESSION AB Background: Psychosocial distress among patients with limited life expectancy influences treatment decisions, treatment adherence, and physical health. Veterans may be at elevated risk of psychosocial distress at the end of life, and understanding their mental healthcare needs may help identify hospitalized patients to whom psychiatric services should be targeted. Objective: To examine mental illness prevalence and mental health treatment rates among a national sample of hospitalized veterans with serious physical illnesses. Design, Subjects, and Measurements: This was a retrospective study of 11,286 veterans hospitalized in a Veterans Health Administration acute care facility in fiscal year 2011 with diagnoses of advanced cancer, congestive heart failure, chronic obstructive pulmonary disease, and/or advanced HIV/AIDS. Prevalent and incident mental illness diagnoses during and before hospitalization and rates of psychotherapy and psychotropic use among patients with incident depression and anxiety were measured. Results: At least one-quarter of the patients in our sample had a mental illness or substance use disorder. The most common diagnoses at hospitalization were depression (11.4%), followed by alcohol abuse or dependence (5.5%), and post-traumatic stress disorder (4.9%). Of the 831 patients with incident past-year depression and 258 with incident past-year anxiety, nearly two-thirds received at least some psychotherapy or guideline-concordant medication within 90 days of diagnosis. Of 191 patients with incident depression and 47 with incident anxiety at time of hospitalization, fewer than half received mental healthcare before discharge. Conclusions: Many veterans hospitalized with serious physical illnesses have comorbid mental illnesses and may benefit from depression and anxiety treatment. C1 [Garrido, Melissa M.; Penrod, Joan D.; Boockvar, Kenneth S.] James J Peters VA Med Ctr, GRECC, Bronx, NY USA. [Garrido, Melissa M.; Neupane, Suvam; Penrod, Joan D.; Boockvar, Kenneth S.] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Prigerson, Holly G.] Weill Cornell Med Coll, Cornell Ctr Res End Life Care, New York, NY USA. [Johnson, Christopher E.] Univ Louisville, Dept Hlth Management & Syst Sci, Louisville, KY 40292 USA. [Boockvar, Kenneth S.] Jewish Home Lifecare, New York, NY USA. RP Garrido, MM (reprint author), James J Peters VA Med Ctr, GRECC 4A-17,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM melissa.garrido@mssm.edu FU VA HSRD [CDA 11-201/CDP 12-255]; NIH [CA197730, MH095378, MD007652]; American Federation for Aging Research FX Dr. M.M.G. is supported by a career development award from VA HSR&D (CDA 11-201/CDP 12-255). Dr. H.G.P. is supported by the following NIH Grant Nos.: CA197730, MH095378, and MD007652. Mr. S.N. is supported by the American Federation for Aging Research. NR 35 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 30 IS 3 BP 247 EP 252 DI 10.1089/jpm.2016.0261 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EM6FC UT WOS:000395407200010 ER PT J AU Zhang, HP Barysauskas, C Rickerson, E Catalano, P Jacobson, J Dalby, C Lindvall, C Selvaggi, K AF Zhang, Haipeng Barysauskas, Constance Rickerson, Elizabeth Catalano, Paul Jacobson, Joseph Dalby, Carol Lindvall, Charlotta Selvaggi, Kathy TI The Intensive Palliative Care Unit: Changing Outcomes for Hospitalized Cancer Patients in an Academic Medical Center SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article DE intensive palliative care unit; inpatient palliative care unit; IPCU ID INTERVENTIONS; PREFERENCES; DISTRESS AB Background: Patients with advanced cancer often require complex symptom management. At Dana-Farber/Brigham and Women's Cancer Center, the intensive palliative care unit (IPCU) admits symptomatic oncology patients with uncontrolled symptoms throughout the trajectory of illness. Patients are uniquely managed by an interdisciplinary team of clinicians who focus on symptom management and advance care planning. Objective: The purpose of our analysis was to investigate goals-of-care outcomes and healthcare utilization after admission to the IPCU. Design: We retrospectively reviewed 74 oncology patients admitted to the IPCU in August and September, 2013. Results: A total of 67 IPCU patients who were admitted received palliative intent treatment, whereas 7 patients received curative intent care. All patients were engaged in a goals-of-care discussion during admission. Of the palliative intent patients, 58% were transferred to the IPCU from medical oncology and 42% were directly admitted. Forty-eight percent of the patients were diagnosed with metastatic lung, genitourinary, or gastrointestinal cancer. Eighty-seven percent of patients reported pain as the chief complaint at admission. Twenty-five patients experienced a change in code status from Full Code to do-not-resuscitate/do-not-incubate. A total of eight patients died in the IPCU, and 50% experienced a code status change. Eighty-eight percent of patients were discharged alive. Of those, 49% were discharged to home hospice, general inpatient hospice, or an inpatient hospice facility. The risk of 30-day readmission was 4%. Conclusions: Among advanced cancer patients, our findings suggest that an inpatient palliative care unit helps clarify goals of care, aids in appropriate hospice referrals, and decreases hospital readmissions. C1 [Zhang, Haipeng; Rickerson, Elizabeth; Lindvall, Charlotta] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Barysauskas, Constance; Catalano, Paul] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Jacobson, Joseph] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dalby, Carol] Dana Farber Canc Inst, Dept Qual Improvement, Boston, MA 02115 USA. [Selvaggi, Kathy] Butler Hlth Syst, Dept Palliat Care, Butler, PA USA. RP Zhang, HP (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,DA 2016A, Boston, MA 02215 USA. EM hzhang37@partners.org NR 15 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 30 IS 3 BP 285 EP 289 DI 10.1089/jpm.2016.0225 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EM6FC UT WOS:000395407200016 ER PT J AU Zehm, A Kamdar, M AF Zehm, April Kamdar, Mihir TI Palliative Uses of Botulinum Neurotoxin #324 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID PLACEBO-CONTROLLED TRIAL; TOXIN TYPE-A; DOUBLE-BLIND; PAIN; ONABOTULINUMTOXINA; SIALORRHEA; DEPRESSION; RADIATION; NEURALGIA; SAFETY C1 [Zehm, April] Massachusetts Gen Hosp, Div Palliat Care, 55 Fruit St,Founders 600, Boston, MA 02114 USA. RP Zehm, A (reprint author), Massachusetts Gen Hosp, Div Palliat Care, 55 Fruit St,Founders 600, Boston, MA 02114 USA. EM AZehm@partners.org NR 24 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 30 IS 3 BP 300 EP 302 DI 10.1089/jpm.2016.0498 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EM6FC UT WOS:000395407200020 ER PT J AU Shiozawa, A Szabo, SM Bolzani, A Cheung, A Choi, HK AF Shiozawa, Aki Szabo, Shelagh M. Bolzani, Anna Cheung, Antoinette Choi, Hyon K. TI Serum Uric Acid and the Risk of Incident and Recurrent Gout: A Systematic Review SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE GOUT; URIC ACID; HYPERURICEMIA ID RANDOMIZED CONTROLLED-TRIALS; QUALITY-OF-LIFE; HYPERURICEMIA; MANAGEMENT; HEALTH; URATE; EPIDEMIOLOGY; IMPACT; LEVEL; POPULATION AB Objective. Lowering serum uric acid (SUA) levels can essentially cure gout; however, this is not widely practiced. To summarize epidemiologic evidence related to this causal link, we conducted a systematic review of the published literature reporting the association between SUA level and incident and recurrent gout (i.e., gout flares). Methods. We systematically searched Medline, EMBASE, and the Cochrane Database of Systematic Reviews using separate search strategies for incident gout and recurrent gout. We screened 646 abstracts to identify 8 eligible articles reporting gout incidence and 913 abstracts to identify 18 articles reporting recurrent Results. For both gout incidence and recurrence, a graded trend was observed where the risk was increased with higher SUA levels. Gout incidence rates per 1000 person-years from population-based studies ranged from 0.8 (SUA <= 6 mg/ dl) to 70.2 cases (SUA >= 10 mg/ dl). Recurrent gout risk in clinical cohorts ranged from 12% (SUA <= 6 mg/ dl) to 61% (SUA >= 9 mg/ dl) among those receiving urate-lowering therapy (ULT), and 3.7% (SUA 6-7 mg/ dl) to 61% (SUA > 9.3 mg/ dl) after successful ULT. Retrospective database studies also showed a graded relationship, although the strength of the association was weaker. Studies reporting mean flares or time-to-flare according to SUA showed similar findings. Conclusion. This systematic review confirms that higher SUA levels are associated with increased risk of incident and recurrent gout in a graded manner. Although few prospective cohorts have evaluated incident and recurrent gout according to SUA, the existing evidence underscores the need to treat to SUA targets, as recommended by the American College of Rheumatology and the European League Against Rheumatism. C1 Takeda Pharmaceut Int Inc, Deerfield, IL USA. Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA USA. Redwood Outcomes, Vancouver, BC, Canada. RP Szabo, SM (reprint author), 301-343 Railway St, Vancouver, BC V6A 1A4, Canada. EM sszabo@broadstreetheor.com FU Takeda Pharmaceuticals International Inc. FX Funded by Takeda Pharmaceuticals International Inc. NR 45 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD MAR PY 2017 VL 44 IS 3 BP 388 EP 396 DI 10.3899/jrheum.160452 PG 9 WC Rheumatology SC Rheumatology GA EN5FS UT WOS:000396031600019 PM 28148699 ER PT J AU Wierda, WG Zelenetz, AD Gordon, LI Abramson, JS Advani, RH Andreadis, CB Bartlett, N Byrd, JC Caimi, P Fayad, LE Fisher, RI Glenn, MJ Habermann, TM Harris, NL Hernandez-Ilizaliturri, F Hoppe, RT Horwitz, SM Kaminski, MS Kelsey, CR Kim, YH Krivacic, S LaCasce, AS Martin, MG Nademanee, A Porcu, P Press, O Rabinovitch, R Reddy, N Reid, E Roberts, K Saad, AA Snyder, ED Sokol, L Swinnen, LJ Vose, JM Yahalom, J Dwyer, MA Sundar, H AF Wierda, William G. Zelenetz, Andrew D. Gordon, Leo I. Abramson, Jeremy S. Advani, Ranjana H. Andreadis, C. Babis Bartlett, Nancy Byrd, John C. Caimi, Paolo Fayad, Luis E. Fisher, Richard I. Glenn, Martha J. Habermann, Thomas M. Harris, Nancy Lee Hernandez-Ilizaliturri, Francisco Hoppe, Richard T. Horwitz, Steven M. Kaminski, Mark S. Kelsey, Christopher R. Kim, Youn H. Krivacic, Susan LaCasce, Ann S. Martin, Michael G. Nademanee, Auayporn Porcu, Pierluigi Press, Oliver Rabinovitch, Rachel Reddy, Nishitha Reid, Erin Roberts, Kenneth Saad, Ayman A. Snyder, Erin D. Sokol, Lubomir Swinnen, Lode J. Vose, Julie M. Yahalom, Joachim Dwyer, Mary A. Sundar, Hema TI NCCN Guidelines (R) Insights Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia, Version 1.2017 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID PREVIOUSLY UNTREATED PATIENTS; SINGLE-AGENT IBRUTINIB; PHASE-II TRIAL; OPEN-LABEL; 1ST-LINE TREATMENT; COMPLEX KARYOTYPE; PLUS CHLORAMBUCIL; ELDERLY-PATIENTS; INITIAL THERAPY; 17P DELETION AB Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmuno-therapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL. C1 [Wierda, William G.; Fayad, Luis E.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77004 USA. [Zelenetz, Andrew D.; Horwitz, Steven M.; Yahalom, Joachim] Memorial Sloan Kettering Canc Ctr, New York, NY 10022 USA. [Gordon, Leo I.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Abramson, Jeremy S.; Harris, Nancy Lee] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Advani, Ranjana H.; Kim, Youn H.] Stanford Canc Inst, Stanford, CA USA. [Andreadis, C. Babis] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bartlett, Nancy] Barnes Jewish Hosp, Site man Canc Ctr, St Louis, MO USA. [Bartlett, Nancy] Washington Univ, Sch Med, Washington, DC USA. [Byrd, John C.] Ohio State Univ, James Canc Hosp, Ctr Comprehens Canc, Columbus, OH USA. [Byrd, John C.] Ohio State Univ, Solove Res Inst, Columbus, OH USA. [Caimi, Paolo] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Caimi, Paolo] Univ Hosp Seidman Canc Ctr, Cleveland Clin Taussig Canc Inst, Cleveland, OH 44106 USA. [Fisher, Richard I.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Glenn, Martha J.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Habermann, Thomas M.] Mayo Clin Canc Ctr, Rochester, MN 55905 USA. [Hernandez-Ilizaliturri, Francisco] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kelsey, Christopher R.] Duke Canc Inst, Durham, NC USA. [LaCasce, Ann S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02215 USA. [Martin, Michael G.] Univ Tennessee, St Jude Childrens Res Hosp, Hlth Sci Ctr, Knoxville, TN USA. [Nademanee, Auayporn] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Press, Oliver] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. [Rabinovitch, Rachel] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Reddy, Nishitha] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Reid, Erin] UC San Diego Moores Canc Ctr, San Diego, CA USA. [Roberts, Kenneth] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT USA. [Saad, Ayman A.; Snyder, Erin D.] Univ Alabama, Birmingham Comprehens Canc Ctr, Tuscaloosa, AL 35487 USA. [Sokol, Lubomir] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Vose, Julie M.] Fred Pamela Buffett Canc Ctr, Omaha, NE USA. [Dwyer, Mary A.; Sundar, Hema] Nat Comprehens Canc Network, Ft Washington, MD 19034 USA. RP Wierda, WG (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77004 USA.; Zelenetz, AD (reprint author), Memorial Sloan Kettering Canc Ctr, New York, NY 10022 USA.; Gordon, LI (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA.; Habermann, TM (reprint author), Mayo Clin Canc Ctr, Rochester, MN 55905 USA.; Dwyer, MA; Sundar, H (reprint author), Nat Comprehens Canc Network, Ft Washington, MD 19034 USA. NR 55 TC 0 Z9 0 U1 0 U2 0 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 MAR 1 PY 2017 VL 15 IS 3 BP 293 EP 311 PG 19 WC Oncology SC Oncology GA EN3DN UT WOS:000395889300004 PM 28275031 ER PT J AU Armstrong, K AF Armstrong, Katrina TI Equity in Precision Medicine: Is It Within Our Reach? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material ID RACIAL-DIFFERENCES; DISPARITIES; CANCER; BREAST; WOMEN C1 [Armstrong, Katrina] Harvard Med Sch, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Armstrong, K (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 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 MAR 1 PY 2017 VL 15 IS 3 BP 421 EP 423 PG 3 WC Oncology SC Oncology GA EN3DN UT WOS:000395889300013 PM 28275040 ER PT J AU Shatzel, JJ Taylor, JA AF Shatzel, Joseph J. Taylor, Jason A. TI Syndromes of Thrombotic Microangiopathy SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Article DE Thrombotic thrombocytopenic purpura (TTP); Hemolytic uremic syndrome (HUS); Microangiopathic hemolytic anemia (MAHA); Atypical hemolytic uremic syndrome (aHUS); Pregnancy induced microangiopathic hemolytic anemia; Transplant induced microangiopathic hemolytic anemia ID HEMOLYTIC-UREMIC SYNDROME; VON-WILLEBRAND-FACTOR; BONE-MARROW-TRANSPLANTATION; FACTOR-CLEAVING PROTEASE; THERAPEUTIC PLASMA-EXCHANGE; STEM-CELL TRANSPLANTATION; ACUTE FATTY LIVER; SINGLE-CENTER EXPERIENCE; SERUM LACTATE-DEHYDROGENASE; THROMBOCYTOPENIC PURPURA AB Thrombotic thrombocytopenia purpura (TTP) and the hemolytic uremic syndrome (HUS) are rare thrombotic microangiopathies that can be rapidly fatal. Although the acquired versions of TTP and HUS are generally highest on this broad differential, multiple rarer entities can produce a clinical picture similar to TTP/HUS, including microangiopathic hemolysis, renal failure, and neurologic compromise. More recent analysis has discovered a host of genetic factors that can produce microangiopathic hemolytic syndromes. This article discusses the current understanding of thrombotic microangiopathy and outlines the pathophysiology and causative agents associated with each distinct syndrome as well as the most accepted treatments. C1 [Shatzel, Joseph J.] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol & Med Oncol, 3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. [Taylor, Jason A.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Hemophilia Ctr, Knight Canc Inst,Div Hematol & Med Oncol, 3181 Southwest Sam Jackson Pk Road,L586, Portland, OR 97239 USA. RP Taylor, JA (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Hemophilia Ctr, Knight Canc Inst,Div Hematol & Med Oncol, 3181 Southwest Sam Jackson Pk Road,L586, Portland, OR 97239 USA. EM taylojas@ohsu.edu NR 183 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 0025-7125 EI 1557-9859 J9 MED CLIN N AM JI Med. Clin. N. Am. PD MAR PY 2017 VL 101 IS 2 BP 395 EP + DI 10.1016/j.mcna.2016.09.010 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA EN7KD UT WOS:000396180800011 ER PT J AU Garbayo, L Stahl, J AF Garbayo, Luciana Stahl, James TI Simulation as an ethical imperative and epistemic responsibility for the implementation of medical guidelines in health care SO MEDICINE HEALTH CARE AND PHILOSOPHY LA English DT Article DE Medical guideline implementation; Ethical imperative; Epistemic responsibility; Medical simulation; Moral luck; Learning health systems ID RECOMMENDATIONS; CONSEQUENCES; SCIENCE AB Guidelines orient best practices in medicine, yet, in health care, many real world constraints limit their optimal realization. Since guideline implementation problems are not systematically anticipated, they will be discovered only post facto, in a learning curve period, while the already implemented guideline is tweaked, debugged and adapted. This learning process comes with costs to human health and quality of life. Despite such predictable hazard, the study and modeling of medical guideline implementation is still seldom pursued. In this article we argue that to systematically identify, predict and prevent medical guideline implementation errors is both an epistemic responsibility and an ethical imperative in health care, in order to properly provide beneficence, minimize or avoid harm, show respect for persons, and administer justice. Furthermore, we suggest that implementation knowledge is best achieved technically by providing simulation modeling studies to anticipate the realization of medical guidelines, in multiple contexts, with system and scenario analysis, in its alignment with the emerging field of implementation science and in recognition of learning health systems. It follows from both claims that it is an ethical imperative and an epistemic responsibility to simulate medical guidelines in context to minimize (avoidable) harm in health care, before guideline implementation. C1 [Garbayo, Luciana] Univ Cent Florida, Dept Philosophy, Coll Arts & Humanities & Med Educ, Coll Med, 4000 Cent Florida Blvd, Orlando, FL 32816 USA. [Stahl, James] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Garbayo, Luciana; Stahl, James] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Garbayo, L (reprint author), Univ Cent Florida, Dept Philosophy, Coll Arts & Humanities & Med Educ, Coll Med, 4000 Cent Florida Blvd, Orlando, FL 32816 USA.; Garbayo, L (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. EM luciana.garbayo@ucf.edu FU ITA/MGH, Hastings Center & UT El Paso Research Grant FX Profs. Garbayo and Stahl wrote the bulk of this paper while collaborating doing research at the Massachusetts General Hospital - Institute for Technology Assessment 101 Merrimac St, 10th Floor Boston, MA 02114. The authors would like to acknowledge the helpful feedback of Prof. Dan Wickler (Harvard School of Public Health) on the discussion of moral responsibility and luck in health care, and of Prof. Mildred Solomon (Hastings Center/Harvard Medical School) on the overall ethics challenges pertaining to learning health systems. Prof. Garbayo was a visiting scholar at MGH-ITA, and at the Hastings Center, where this work was first presented and discussed. She received support from ITA/MGH, Hastings Center & UT El Paso Research Grant. She would like to thank ITA/MGH, Hastings Center and UT El Paso for their gracious support. NR 30 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-7423 EI 1572-8633 J9 MED HEALTH CARE PHIL JI Med. Health Care Philos. PD MAR PY 2017 VL 20 IS 1 BP 37 EP 42 DI 10.1007/s11019-016-9719-0 PG 6 WC Ethics; History & Philosophy Of Science SC Social Sciences - Other Topics; History & Philosophy of Science GA EM0AK UT WOS:000394981000005 PM 27497698 ER PT J AU Church, LWP Chopra, A Judson, MA AF Church, L. W. Preston Chopra, Amit Judson, Marc A. TI Paradoxical Reactions and the Immune Reconstitution Inflammatory Syndrome SO MICROBIOLOGY SPECTRUM LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; MYCOBACTERIUM-AVIUM COMPLEX; HIV-INFECTED PATIENTS; KIDNEY-TRANSPLANT RECIPIENT; OF-THE-LITERATURE; PULMONARY SARCOIDOSIS; ACQUIRED-IMMUNODEFICIENCY; MILIARY TUBERCULOSIS; INTERFERON-GAMMA AB In HIV-infected individuals, paradoxical reactions after the initiation of antiretroviral therapy (ART) are associated with a variety of underlying infections and have been called the immune reconstitution inflammatory syndrome (IRIS). In cases of IRIS associated with tuberculosis (TB), two distinct patterns of disease are recognized: (i) the progression of subclinical TB to clinical disease after the initiation of ART, referred to as unmasking, and (ii) the progression or appearance of new clinical and/or radiographic disease in patients with previously recognized TB after the initiation of ART, the classic or "paradoxical" TB-IRIS. IRIS can potentially occur in all granulomatous diseases, not just infectious ones. All granulomatous diseases are thought to result from interplay of inflammatory cells and mediators. One of the inflammatory cells thought to be integral to the development of the granuloma is the CD4 T lymphocyte. Therefore, HIV-infected patients with noninfectious granulomatous diseases such as sarcoidosis may also develop IRIS reactions. Here, we describe IRIS in HIV-infected patients with TB and sarcoidosis and review the basic clinical and immunological aspects of these phenomena. C1 [Church, L. W. Preston] Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Chopra, Amit; Judson, Marc A.] Albany Med Coll, Div Pulm & Crit Care Med, Albany, NY 12208 USA. RP Judson, MA (reprint author), Albany Med Coll, Div Pulm & Crit Care Med, Albany, NY 12208 USA. EM judsonm@mail.amc.edu NR 113 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD MAR PY 2017 VL 5 IS 2 AR UNSP TNMI7-0033-2016 DI 10.1128/microbiolspec.TNMI7-0033-2016 PG 15 WC Microbiology SC Microbiology GA EP3IE UT WOS:000397275200004 ER PT J AU Frydenlund, N Leone, D Yang, S Hoang, MP Deng, A Hernandez-Perez, M Singh, R Biswas, A Yaar, R Mahalingam, M AF Frydenlund, Noah Leone, Dominick Yang, Shi Hoang, Mai P. Deng, April Hernandez-Perez, Marier Singh, Rajendra Biswas, Asok Yaar, Ron Mahalingam, Meera TI Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant SO MODERN PATHOLOGY LA English DT Article ID MALIGNANT-MELANOMA; NEUROTROPHIN RECEPTORS; UNTREATED MELANOMA; PROMOTER MUTATIONS; IPILIMUMAB; NIVOLUMAB; SURVIVAL; CANCER; RESISTANCE; BLOCKADE AB Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with >= 5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness 44 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range = 3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range = 2.04 mm for PD-L1 negatives, P = 0.0002) and was linearly associated with increasing depth of invasion (P = 0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P = 0.0047). The presence of CD8+ lymphocytes correlated significantly with depth of invasion > 1mm (P = 0.022). On multivariate analysis, PD-L1 was 6.14 x more likely to be expressed in mixed DM than pure DM (P = 0.0131), CD8+ staining was 6.22 x more likely in PD-L1 positive cases than in PD-L1 negative (P = 0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR = 1.61, P = 0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy. C1 [Frydenlund, Noah] Univ Iowa Carver Coll Med, Iowa City, IA 52242 USA. [Leone, Dominick] Boston Univ Sch Publ Hlth, Boston, MA USA. [Leone, Dominick] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Yang, Shi] Boston Univ Sch Med, Dept Pathol, Boston, MA USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Deng, April] Univ Massachusetts Med Sch, Dept Pathol, Worcester, MA USA. [Hernandez-Perez, Marier] Miraca Life Sci, Newton, MA USA. [Singh, Rajendra] Icahn Sch Med, Dept Pathol, New York, NY USA. [Biswas, Asok] Western Gen Hosp, Dept Pathol, Edinburgh, Midlothian, Scotland. [Yaar, Ron] Aurora Diagnost GPA Labs, Greensboro, NC USA. [Mahalingam, Meera] Dermatopathol Sect, Dept Pathol & Lab Med 113, VA Integrated Serv Networks VISN1, West Roxbury, MA 02132 USA. RP Mahalingam, M (reprint author), Dermatopathol Sect, Dept Pathol & Lab Med 113, VA Integrated Serv Networks VISN1, West Roxbury, MA 02132 USA. EM me@meeramahalingam.com NR 36 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 MAR PY 2017 VL 30 IS 3 BP 357 EP 369 DI 10.1038/modpathol.2016.210 PG 13 WC Pathology SC Pathology GA EN1WI UT WOS:000395800600005 PM 28084337 ER PT J AU Adar, T Rodgers, LH Shannon, KM Yoshida, M Ma, T Mattia, A Lauwers, GY Iafrate, AJ Chung, DC AF Adar, Tomer Rodgers, Linda H. Shannon, Kristen M. Yoshida, Makoto Ma, Tianle Mattia, Anthony Lauwers, Gregory Y. Iafrate, Anthony J. Chung, Daniel C. TI A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome SO MODERN PATHOLOGY LA English DT Article ID COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; SYNDROME HNPCC; MANAGEMENT; GUIDELINES; SOCIETY; TUMORS AB To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients >= 70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P < 0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wildtype cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs. C1 [Adar, Tomer; Yoshida, Makoto; Ma, Tianle; Chung, Daniel C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA USA. [Rodgers, Linda H.; Shannon, Kristen M.; Chung, Daniel C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA USA. [Mattia, Anthony; Lauwers, Gregory Y.; Iafrate, Anthony J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Mattia, Anthony] North Shore Med Ctr, Dept Pathol, Danvers, MA USA. RP Chung, DC (reprint author), Massachusetts Gen Hosp, Dept Gastroenterol, GRJ 704,50 Blossom St, Boston, MA 02114 USA. EM Chung.Daniel@mgh.harvard.edu FU American Physicians Fellowship for Medicine in Israel [Israel Cancer Association] FX The authors would like to acknowledge Dr Hui Zheng of the the Massachusetts General Hospital Biostatistics Center and Harvard Catalyst (The Harvard Clinical and Translational Science Center) for his statistical support. TA is a recipient of a fellowship grant from The American Physicians Fellowship for Medicine in Israel and from Israel Cancer Association. NR 23 TC 0 Z9 0 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 MAR PY 2017 VL 30 IS 3 BP 440 EP 447 DI 10.1038/modpathol.2016.211 PG 8 WC Pathology SC Pathology GA EN1WI UT WOS:000395800600012 PM 28059100 ER PT J AU Watkins, JC Howitt, BE Horowitz, NS Ritterhouse, LL Dong, F MacConaill, LE Garcia, E Lindeman, NI Lee, LJ Berkowitz, RS Nucci, MR Crum, CP AF Watkins, Jaclyn C. Howitt, Brooke E. Horowitz, Neil S. Ritterhouse, Lauren L. Dong, Fei MacConaill, Laura E. Garcia, Elizabeth Lindeman, Neal I. Lee, Larissa J. Berkowitz, Ross S. Nucci, Marisa R. Crum, Christopher P. TI Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA SO MODERN PATHOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; LICHEN-SCLEROSUS; NEOPLASIA; PRECURSOR; PATHOLOGY; CANCER; TRENDS; WOMEN AB Human papillomavirus-negative keratinizing vulvar cancers typically harbor TP53 mutations as do their precursors, differentiated vulvar intraepithelial neoplasia. However, atypical verruciform proliferations are also associated with these malignancies and their pathogenesis is poorly understood. This study compared 11 atypical verruciform lesions, including atypical verruciform hyperplasia, vulvar acanthosis with altered differentiation, and verruciform lichen simplex chronicus, with 14 human papillomavirus-negative keratinizing squamous cell carcinomas. Extracted tissue DNA was subjected to targeted massively parallel sequencing of the exonic regions of 300 genes. Eight (73%) and six (55%) of eleven atypical verruciform lesions contained mutations in PIK3CA and ARID2, respectively. No TP53 mutations were identified. Eleven (79%) and five (36%) of fourteen keratinizing squamous cell carcinomas tested contained TP53 and CDKN2A mutations, respectively. Keratinizing squamous cell carcinomas displayed the majority of copy number variations with some variations (7p gain and 8p loss) shared by some cases in both groups. One patient developed atypical verruciform lesions with PIK3CA mutations followed by a keratinizing carcinoma with mutations in both PIK3CA and TP53. This study, for the first time segregates atypical verruciform lesions by virtue of a unique genotype (PIK3CA mutant/TP53 wild type) illustrating an example of progression to a TP53-mutated keratinizing carcinoma. The findings indicate that although PIK3CA mutations are found in < 10% of vulvar squamous cell carcinomas, they may be specific for a particular pathway involving atypical verruciform lesions, which could function as either a direct precursor or a risk factor for vulvar squamous cell carcinoma. Given the presence of a molecular signature, we propose the term 'differentiated exophytic vulvar intraepithelial lesion' for this group. Whether they function as direct precursors to a less common form of squamous cell carcinoma will require further study, but carcinomas associated with these lesions might warrant testing for PIK3CA mutations to address this question. C1 [Watkins, Jaclyn C.; Howitt, Brooke E.; Ritterhouse, Lauren L.; Dong, Fei; Garcia, Elizabeth; Lindeman, Neal I.; Nucci, Marisa R.; Crum, Christopher P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Horowitz, Neil S.; Berkowitz, Ross S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. [MacConaill, Laura E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Lee, Larissa J.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Crum, CP (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St Amory 3, Boston, MA 02115 USA. EM ccrum@partners.org FU Advanced Molecular Diagnostics at Brigham and Women's Hospital; Dana-Farber Cancer Institute FX Portions of this study were presented in poster format at the United States and Canadian Academy of Pathology 2016 Annual Meeting, held in Seattle, Washington on March 12, 2016. We are grateful to the Division of Gynecologic Oncology (Michael Muto, Colleen Feltmate, and Donald Goldstein) and to Dr Jerome Federschneider for their support and contribution of this case material in this study. We also acknowledge the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital and the Dana-Farber Cancer Institute for their support. NR 23 TC 0 Z9 0 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 MAR PY 2017 VL 30 IS 3 BP 448 EP 458 DI 10.1038/modpathol.2016.187 PG 11 WC Pathology SC Pathology GA EN1WI UT WOS:000395800600013 PM 27834349 ER PT J AU Richardson, PG Moreau, P Laubach, JP Maglio, ME Lonial, S San-Miguel, J AF Richardson, Paul G. Moreau, Philippe Laubach, Jacob P. Maglio, Michelle E. Lonial, Sagar San-Miguel, Jesus TI Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Multiple myeloma; Histone deacetylase inhibitors; Epigenetic modification ID PANOBINOSTAT PLUS BORTEZOMIB; DEXAMETHASONE; COMBINATION; LENALIDOMIDE; MULTICENTER; TRIAL; VORINOSTAT; MECHANISM; THERAPY; PLACEBO AB Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received >= 2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM. (C) 2016 Published by Elsevier Ltd. C1 [Richardson, Paul G.; Laubach, Jacob P.; Maglio, Michelle E.] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Moreau, Philippe] Univ Hosp Nantes, 1 Pl Alexis Ricordeau, F-44093 Nantes 1, France. [Lonial, Sagar] Emory Univ, Winship Canc Inst, 1365-C Clifton Rd, Atlanta, GA 30322 USA. [San-Miguel, Jesus] Univ Navarra, Univ Navarra Clin, CIMA, IDISNA, Av Pio XII 36, Pamplona 31008, Navarra, Spain. RP Richardson, PG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Paul_Richardson@dfci.harvard.edu; philippe.moreau@chu-nantes.fr; JacobP_Laubach@dfci.harvard.edu; Michelle_Maglio@dfci.harvard.edu; sloni01@emory.edu; sanmiguel@unav.es FU Novartis Pharmaceuticals Corporation FX Medical editorial assistance was funded by Novartis Pharmaceuticals Corporation. NR 42 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAR PY 2017 VL 117 BP 185 EP 191 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EN2MQ UT WOS:000395845000019 PM 27884726 ER PT J AU Sabbath, EL Boden, LI Williams, JAR Hashimoto, D Hopcia, K Sorensen, G AF Sabbath, Erika L. Boden, Leslie I. Williams, Jessica A. R. Hashimoto, Dean Hopcia, Karen Sorensen, Glorian TI Obscured by administrative data? Racial disparities in occupational injury SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE healthcare worker; health disparity; health inequality; injury data; minority worker; occupational health; race; workplace injury ID PATIENT-CARE WORKERS; HEALTH DISPARITIES; MUSCULOSKELETAL DISORDERS; BLOOD-PRESSURE; DISCRIMINATION; SURVEILLANCE; SYSTEM; EXPERIENCES; CHALLENGES; AMERICANS AB Objectives Underreporting of occupational injuries is well documented, but underreporting patterns may vary by worker characteristics, obscuring disparities. We tested for racial and ethnic differences in injury reporting patterns by comparing injuries reported via research survey and administrative injury database in the same group of healthcare workers in the US. Methods We used data from a cohort of 1568 hospital patient-care workers who were asked via survey whether they had been injured at work during the year prior (self-reported injury; N=244). Using the hospital's injury database, we determined whether the same workers had reported injuries to the hospital's occupational health service during that year (administratively reported injury; N=126). We compared data sources to test for racial and ethnic differences in injury reporting practices. Results In logistic regression models adjusted for demographic and occupational characteristics, black workers' odds of injury as measured by self-report data were 1.91 [95% confidence interval (95% CI) 1.04-3.49] compared with white workers. The same black workers' odds of injury as measured by administrative data were 1.22 (95% CI 0.54-2.77) compared with white workers. Conclusions The undercount of occupational injuries in administrative versus self-report data may be greater among black compared to white workers, leading to underestimates of racial disparities in workplace injury. C1 [Sabbath, Erika L.] Boston Coll, Sch Social Work, McGuinn 202,140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. [Boden, Leslie I.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Williams, Jessica A. R.] Univ Kansas, Sch Med, Kansas City, KS USA. [Hashimoto, Dean; Hopcia, Karen] Partners HealthCare, Occupat Hlth Serv, Boston, MA USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Sorensen, Glorian] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Sabbath, EL (reprint author), Boston Coll, Sch Social Work, McGuinn 202,140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. EM erika.sabbath@bc.edu FU US Centers for Disease Control and Prevention [7K01 OH010673-02, 5U19 OH008861-07] FX The US Centers for Disease Control and Prevention provided funding for this project: 7K01 OH010673-02 (PI: Sabbath) and 5U19 OH008861-07 (PI: Sorensen). The funders had no role in the design or analysis of data. NR 32 TC 0 Z9 0 U1 0 U2 0 PU SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 EI 1795-990X J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD MAR PY 2017 VL 43 IS 2 BP 155 EP 162 DI 10.5271/sjweh.3611 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN2OG UT WOS:000395849200008 PM 27942733 ER PT J AU Bauman, WA Krassioukov, A Biering-Sorensen, F AF Bauman, W. A. Krassioukov, A. Biering-Sorensen, F. TI Version 2.0 of the international spinal cord injury endocrinology and metabolic function basic data set SO SPINAL CORD LA English DT Letter C1 [Bauman, W. A.] James J Peters Vet Affairs Med Ctr, Natl Ctr Med Consequences Spinal Cord Injury, Bronx, NY 10468 USA. [Krassioukov, A.] Univ British Columbia, Int Collaborat Repair Discoveries ICORD, Div Phys Med & Rehabil,Auton Res Unit,Dept Med, Spinal Cord Program,GF Strong Rehabil Ctr, Vancouver, BC, Canada. [Krassioukov, A.] Univ Western Ontario, London, ON, Canada. [Biering-Sorensen, F.] Univ Copenhagen, Clin Spinal Cord Injuries, Rigshosp, Copenhagen, Denmark. RP Bauman, WA (reprint author), James J Peters Vet Affairs Med Ctr, Natl Ctr Med Consequences Spinal Cord Injury, Bronx, NY 10468 USA. EM William.Bauman@va.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 EI 1476-5624 J9 SPINAL CORD JI Spinal Cord PD MAR PY 2017 VL 55 IS 3 BP 327 EP 328 DI 10.1038/sc.2016.105 PG 2 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA EN3RA UT WOS:000395924400020 PM 27401128 ER PT J AU White, MC Longstaff, L Lai, PS AF White, Michelle C. Longstaff, Lydia Lai, Peggy S. TI Effect of Pre-operative Anaemia on Post-operative Complications in Low-Resource Settings SO WORLD JOURNAL OF SURGERY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SURGICAL SITE INFECTION; NONCARDIAC SURGERY; INTRAVENOUS IRON; RISK-FACTORS; OUTCOMES; COUNTRIES; PROTOCOL; COHORT; IMPACT AB In high-resource settings, even mild anaemia is associated with an increased risk of post-operative complications. Whether this is true in low-resource settings is unclear. We aimed to evaluate the effect of anaemia on surgical outcomes in the Republic of Congo and Madagascar. It is a retrospective chart review of 2064 non-pregnant patients undergoing elective surgery with Mercy Ships. Logistic regression was used to determine the association between pre-operative anaemia and pre-defined surgical complications, adjusted for age, gender, surgical specialty, and country. The average age of patients was 27.2 years; 56.7% were male. Sixty-two percent of patients were not anaemic, and 22.7, 13.9 and 1.4% met sex-related criteria for mild, moderate and severe anaemia, respectively. In adjusted analyses, the severe anaemia group had an 8.58 [3.65, 19.49] higher odds of experiencing any surgical complication (p < 0.001) compared to non-anaemic patients. Analysis of each complication showed a 33.13 [9.57, 110.39] higher odds of unexpected ICU admission (p < 0.001); a 7.29 [1.98, 21.45] higher odds of surgical site infection (p < 0.001); and 7.48 [1.79, 25.78] higher odds of requiring hospital readmission (p < 0.001). Evaluating other anaemia categories, only those with moderate anaemia had a higher risk of requiring ICU admission (odds ratio 2.75 [1.00, 7.04], p = 0.04) compared to those without anaemia. Our results indicate that in low-income settings, severe anaemia is associated with an increased risk of post-operative complications including unexpected ICU admission, surgical site infection and hospital readmission, whereas mild anaemia was not associated with increased post-operative complications. C1 [White, Michelle C.; Longstaff, Lydia] Mercy Ships, MV Africa Mercy, Port Au Toamasina, Toamasina, Madagascar. [Lai, Peggy S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP White, MC (reprint author), Mercy Ships, MV Africa Mercy, Port Au Toamasina, Toamasina, Madagascar. EM doctormcw@gmail.com FU US National Institutes of Health [NIH-NIEHS K23ES023700] FX There is no direct funding for this work. PSL reports salary support from the US National Institutes of Health (NIH-NIEHS K23ES023700). NR 27 TC 0 Z9 0 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 MAR PY 2017 VL 41 IS 3 BP 644 EP 649 DI 10.1007/s00268-016-3785-6 PG 6 WC Surgery SC Surgery GA EM2YY UT WOS:000395182900002 PM 27837236 ER PT J AU Johnson, TJ Winger, DG Hickey, RW Switzer, GE Miller, E Nguyen, MB Saladino, RA Hausmann, LRM AF Johnson, Tiffani J. Winger, Daniel G. Hickey, Robert W. Switzer, Galen E. Miller, Elizabeth Nguyen, Margaret B. Saladino, Richard A. Hausmann, Leslie R. M. TI Comparison of Physician Implicit Racial Bias Toward Adults Versus Children SO ACADEMIC PEDIATRICS LA English DT Article DE implicit bias; pediatric health care disparities; physician implicit attitudes; racial bias; racial disparities ID ASSOCIATION TEST; ACHIEVEMENT GAP; EXPLICIT ATTITUDES; AFRICAN-AMERICANS; UNCONSCIOUS RACE; MEDICAL-STUDENTS; DECISION-MAKING; HEALTH-CARE; BLACK; STEREOTYPES AB BACKGROUND AND OBJECTIVES: The general population and most physicians have implicit racial bias against black adults. Pediatricians also have implicit bias against black adults, albeit less than other specialties. There is no published research on the implicit racial attitudes of pediatricians or other physicians toward children. Our objectives were to compare implicit racial bias toward adults versus children among resident physicians working in a pediatric emergency department, and to assess whether bias varied by specialty (pediatrics, emergency medicine, or other), gender, race, age, and year of training. METHODS: We measured implicit racial bias of residents before a pediatric emergency department shift using the Adult and Child Race Implicit Association Tests (IATs). Generalized linear models compared Adult and Child IAT scores and determined the association of participant demographics with Adult and Child IAT scores. RESULTS: Among 91 residents, we found moderate pro-white/anti-black bias on both the Adult (mean = 0.49, standard deviation = 0.34) and Child Race IAT (mean = 0.55, standard deviation = 0.37). There was no significant difference between Adult and Child Race IAT scores (difference = 0.06, P = .15). Implicit bias was not associated with resident demographic characteristics, including specialty. CONCLUSIONS: This is the first study demonstrating that resident physicians have implicit racial bias against black children, similar to levels of bias against black adults. Bias in our study did not vary by resident demographic characteristics, including specialty, suggesting that pediatric residents are as susceptible as other physicians to implicit bias. Future studies are needed to explore how physicians' implicit attitudes toward parents and children may impact inequities in pediatric health care. C1 [Johnson, Tiffani J.; Hickey, Robert W.; Nguyen, Margaret B.; Saladino, Richard A.] Univ Pittsburgh, Div Pediat Emergency Med, Pittsburgh, PA USA. [Miller, Elizabeth] Univ Pittsburgh, Div Adolescent & Young Adult Med, Pittsburgh, PA USA. [Winger, Daniel G.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Clin & Translat Sci Inst, Pittsburgh, PA USA. [Switzer, Galen E.; Hausmann, Leslie R. M.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Switzer, Galen E.; Hausmann, Leslie R. M.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. RP Johnson, TJ (reprint author), Childrens Hosp Philadelphia, PolicyLab, 3535 Market St,Room 1425, Philadelphia, PA 19104 USA. EM johnsont6@email.chop.edu FU RWJF [AMFDP 72430]; National Institutes of Health [UL 1-TR-000005]; [T32 HS 017587]; [K12 HL109009] FX We thank Dennis Durbin, MD, MSCE, Children's Hospital of Philadelphia, for his critical review of the manuscript. Supported in part by grants T32 HS 017587, K12 HL109009, and RWJF AMFDP 72430 (to TJJ); and by the National Institutes of Health through grant UL 1-TR-000005 to the University of Pittsburgh Clinical and Translational Science Institute. The sponsoring agencies had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the sponsoring agency. NR 41 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 1876-2859 EI 1876-2867 J9 ACAD PEDIATR JI Acad. Pediatr. PD MAR PY 2017 VL 17 IS 2 BP 120 EP 126 PG 7 WC Pediatrics SC Pediatrics GA EM9GB UT WOS:000395618700004 PM 27620844 ER PT J AU Harris, E McNamara, P Durso, R AF Harris, Erica McNamara, Patrick Durso, Raymon TI Possible selves in patients with right- versus left-onset Parkinson's disease SO AGING NEUROPSYCHOLOGY AND COGNITION LA English DT Article DE Parkinson's disease; possible selves; goal-directed behavior; self-regulation; psychological well-being ID ALZHEIMERS-DISEASE; NOVELTY SEEKING; SELF-REGULATION; OLDER-ADULTS; ASYMMETRY; AVOIDANCE; INDIVIDUALS; DEPRESSION; LATERALITY; FUTURE AB Possible selves can be used to self-regulate and guide behavior towards what is desired to be achieved or avoided in life. Previous work suggests laterality effects exist within the brain regarding approach and avoidance systems to achieve self-regulation. A modified version of the possible selves task was administered to 45 patients with PD (22 right-onset and 23 left-onset) and 25 community dwelling control subjects (CS). Only 11.1% of patients exhibited balance among their hoped-for and feared possible selves versus 28% of CS. More right-onset patients used a promotion strategy whereas more left-onset patients used a prevention strategy. Patients with left-onset PD thought more about their feared selves, exhibiting reduced goal-directed behavior. Findings among the left-onset group indicate relative dependence of self-regulation on right-sided avoidance brain systems. This may point to an inability to move away from negative outcomes and to work towards rewarding outcomes, which could affect psychological health. C1 [Harris, Erica; McNamara, Patrick; Durso, Raymon] VA Boston Healthcare Syst, Dept Neurol, Boston, MA USA. [McNamara, Patrick; Durso, Raymon] Boston Univ, Sch Med, Boston, MA 02118 USA. [McNamara, Patrick] Northcent Univ, Grad Sch, Prescott Valley, AZ USA. RP Harris, E (reprint author), VA Boston Healthcare Syst, Dept Neurol, Boston, MA USA. EM uva2bu@gmail.com FU John Templeton Foundation [29245]; Federal [NIDCD, 5R01DC007956-03] FX This work was supported by the John Templeton Foundation: [grant number 29245] and Federal grant no. NIDCD Grant no. 5R01DC007956-03 to PM. NR 44 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1382-5585 EI 1744-4128 J9 AGING NEUROPSYCHOL C JI Aging Neuropsychol. Cogn. PD MAR PY 2017 VL 24 IS 2 BP 198 EP 215 DI 10.1080/13825585.2016.1178211 PG 18 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA EM0WF UT WOS:000395037700005 ER PT J AU Conway, G Velonias, G Andrews, E Garber, JJ Yajnik, V Ananthakrishnan, AN AF Conway, G. Velonias, G. Andrews, E. Garber, J. J. Yajnik, V. Ananthakrishnan, A. N. TI The impact of co-existing immune-mediated diseases on phenotype and outcomes in inflammatory bowel diseases SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID QUALITY-OF-LIFE; PRIMARY SCLEROSING CHOLANGITIS; ULCERATIVE-COLITIS; CROHNS-DISEASE; AUTOIMMUNE-DISEASES; CELIAC-DISEASE; UNITED-STATES; RHEUMATOID-ARTHRITIS; ASSOCIATION; POPULATION AB Background Inflammatory bowel diseases lead to progressive bowel damage and need for surgery. While the increase in prevalence of other immune-mediated diseases in IBD is well recognised, the impact of this on the natural history of IBD is unknown. Aim To determine the impact of concomitant immune-mediated diseases on phenotypes and outcomes in IBD. Methods Patients with IBD enrolled in a prospective registry were queried about the presence of other immune-mediated diseases, defined as those where immune dysregulation plays a role in pathogenesis. Demographics and disease-related information were obtained. Subjects also completed measures of quality of life. Multivariable regression models compared disease phenotype and outcomes of IBD patients with and without other immune-mediated diseases. Results The cohort included 2145 IBD patients among whom 458 (21%) had another immune-mediated disease. There was no difference in CD phenotype between the two groups. UC patients were more likely to have pancolitis in the presence of another immune-mediated disease (62%) compared to those without (52%, P = 0.02). IBD patients with another immune-mediated disease had higher rates of needing anti-TNF biologics [Odds ratio (OR) 1.31, 95% CI 1.05-1.63] and surgery (OR 1.26, 95% CI 0.99-1.61). The presence of another immune-mediated disease was also associated with lower diseasespecific and general physical quality of life. Conclusions The presence of another immune-mediated disease in IBD patients was associated with higher likelihood of pancolonic involvement in UC, and a modest increase in need for IBD-related surgery and anti-TNF biological therapy. Such patients also experienced worse quality of life. C1 [Conway, G.; Velonias, G.; Andrews, E.; Garber, J. J.; Yajnik, V.; Ananthakrishnan, A. N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Garber, J. J.; Yajnik, V.; Ananthakrishnan, A. N.] Harvard Med Sch, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU National Institutes of Health (NIH) [P30DK043351]; Center for Study of Inflammatory Bowel Diseases; National Institutes of Health [K23 DK097142] FX This work was supported by the National Institutes of Health (NIH) (P30DK043351) to the Center for Study of Inflammatory Bowel Diseases. Ananthakrishnan was supported in part by a grant from the National Institutes of Health (K23 DK097142). NR 51 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR PY 2017 VL 45 IS 6 BP 814 EP 823 DI 10.1111/apt.13940 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EL5XK UT WOS:000394694600005 PM 28105709 ER PT J AU Siddiqi, HK Luminais, SN Montgomery, D Bossone, E Dietz, H Evangelista, A Isselbacher, E LeMaire, S Manfredini, R Milewicz, D Nienaber, CA Roman, M Sechtem, U Silberbach, M Eagle, KA Pyeritz, RE AF Siddiqi, Hasan K. Luminais, Steven N. Montgomery, Dan Bossone, Eduardo Dietz, Harry Evangelista, Arturo Isselbacher, Eric LeMaire, Scott Manfredini, Roberto Milewicz, Dianna Nienaber, Christoph A. Roman, Mary Sechtem, Udo Silberbach, Michael Eagle, Kim A. Pyeritz, Reed E. CA GenTAC IRAD Invest TI Chronobiology of Acute Aortic Dissection in the Marfan Syndrome (from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions and the International Registry of Acute Aortic Dissection) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; SUDDEN CARDIAC DEATH; CIRCADIAN VARIATION; METAANALYSIS; HEART; DISEASE; MORTALITY; INSIGHTS; CORONARY; RUPTURE AB Marfan syndrome (MFS) is an autosomal dominant connective tissue disease associated with acute aortic dissection (AAD). We used 2 large registries that include patients with MFS to investigate possible trends-in the chronobiology of AAD in MFS. We queried the International Registry of Acute Aortic Dissection (IRAD) and the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry to extract data on all patients with MFS who had suffered an AAD. The group included 257 patients with MFS who suffered an AAD from 1980 to 2012. The chi-square tests were used for statistical testing. Mean subject age at time of AAD was 38 years, and 61% of subjects were men. AAD was more likely in the winter/spring season (November to April) than the other half of the year (57% vs 43%, p = 0.05). Dissections were significantly more likely to occur during the' daytime hours, with 65% of dissections occurring from 6 A.M. to 6 P.M. (p = 0.001). Men were more likely to dissect during the daytime hours (6 A.M. to 6 P.M.) than women (74% vs 51%, p = 0.01). These insights offer a glimpse of the times of greatest vulnerability for patients with MFS who suffer from.this catastrophic event. In conclusion, the chronobiology of AAD in MFS reflects that of AAD in the general population. (C) 2016 Elsevier Inc. All rights reserved. C1 [Siddiqi, Hasan K.; Luminais, Steven N.; Pyeritz, Reed E.] Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. [Montgomery, Dan; Eagle, Kim A.] Univ Michigan, Dept Cardiol, Ann Arbor, MI 48109 USA. [Bossone, Eduardo] Univ Hosp Salerno, Scuola Med Salernitana, Div Cardiol, Salerno, Italy. [Dietz, Harry] Johns Hopkins Univ, Dept Pediat, Dept Med, Baltimore, MD USA. [Dietz, Harry] Johns Hopkins Univ, Dept Mol Biol & Genet, Baltimore, MD USA. [Evangelista, Arturo] Hosp Univ Vall Hebron, Cardiac Imaging Dept, Barcelona, Spain. [Isselbacher, Eric] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [LeMaire, Scott] Baylor Coll Med, Div Cardiothorac Surg, Houston, TX 77030 USA. [Manfredini, Roberto] Univ Ferrara, Dept Internal Med, I-44100 Ferrara, Italy. [Milewicz, Dianna] Univ Texas Houston, Dept Internal Med, Houston, TX USA. [Nienaber, Christoph A.] Univ Rostock, Div Cardiol & Vasc Med, D-18055 Rostock, Germany. [Roman, Mary] Cornell Univ, Div Cardiol, New York, NY 10021 USA. [Sechtem, Udo] Robert Bosch Krankenhaus, Dept Cardiol, Stuttgart, Germany. [Silberbach, Michael] Oregon Hlth & Sci Univ, Dept Pediat Cardiol, Portland, OR 97201 USA. RP Siddiqi, HK (reprint author), Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. EM hasansiddiqi@gmail.com FU US Federal Government from the National Heart, Lung, and Blood Institute [HHSN268200648199C, HHSN268201000048C]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (Bethesda, Maryland); W.L. Gore & Associates, Inc. (Flagstaff, Arizona); Medtronic (Minneapolis, Minnesota); Varbedian Aortic Research Fund (Ann Arbor, Michigan); Hewlett Foundation (Menlo Park, California); Mardigian Foundation (Ann Arbor, Michigan); University of Michigan Faculty Group Practice (Ann Arbor, Michigan); Terumo (Tokyo, Japan); Ann and Bob Aikens (Ann Arbor, Michigan) FX The GenTAC Registry has been supported by US Federal Government contracts HHSN268200648199C and HHSN268201000048C from the National Heart, Lung, and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Bethesda, Maryland). IRAD is supported by grants and generous contributions by W.L. Gore & Associates, Inc. (Flagstaff, Arizona), Medtronic (Minneapolis, Minnesota), the Varbedian Aortic Research Fund (Ann Arbor, Michigan), the Hewlett Foundation (Menlo Park, California), the Mardigian Foundation (Ann Arbor, Michigan), University of Michigan Faculty Group Practice (Ann Arbor, Michigan), Terumo (Tokyo, Japan), and Ann and Bob Aikens (Ann Arbor, Michigan). NR 30 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 1 PY 2017 VL 119 IS 5 BP 785 EP 789 DI 10.1016/j.amjcard.2016.11.021 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0JE UT WOS:000396383300015 PM 28065489 ER PT J AU Jain, CC Chang, YC Kabrhel, C Giri, J Channick, R Rodriguez-Lopez, J Rosovsky, RP Fogerty, A Rosenfield, K Jaff, MR Weinberg, I AF Jain, C. Charles Chang, Yuchiao Kabrhel, Christopher Giri, Jay Channick, Richard Rodriguez-Lopez, Josanna Rosovsky, Rachel P. Fogerty, Annemarie Rosenfield, Kenneth Jaff, Michael R. Weinberg, Ido TI Impact of Pulmonary Arterial Clot Location on Pulmonary Embolism Treatment and Outcomes (90 Days) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RIGHT-VENTRICULAR DYSFUNCTION; VENOUS THROMBOEMBOLISM; MULTICENTER REGISTRY; COMPUTED-TOMOGRAPHY; PROGNOSTIC ROLE; MANAGEMENT; CT; ECHOCARDIOGRAPHY; EPIDEMIOLOGY; METAANALYSIS AB Pulmonary embolism (PE) is common and management is based on risk stratification. The significance of clot location in submassive and massive PE is unclear. Data from a prospectively gathered database of submassive and massive PE were used for analysis. Available data included patient presentation, diagnostics, treatment, and outcome. Comparisons were made according to clot location: central or peripheral. A multivariable model. as used for composite outcome of death or right ventricular (RV) strain at 90 days. Among 269 patients, there were no significant demographic differences between patients with peripheral and central PE. Peripheral PE was more likely to present with hypotension (46.4% vs 32.6%; p = 0.02), but central PE was more likely to have RV strain on echocardiography (76.7% vs 57.7%, p <0.001) and computed- tomography (58.1% vs 32.0%, p <0.0001). Peripheral PE was more likely to receive anticoagulation as the only form of therapy (69.1% vs 55.8%; p = 0.03), and central PE was more likely to receive catheter-directed therapies (18.3% vs 3.3%; p <0.001). Nonetheless, peripheral PE had higher 30- and 90-day all-cause mortality (18.5% vs 9.3%; p = 0.03; 25.9% vs 13.5%; p = 0.02, respectively). In a multivariable analysis, the only independent predictor of death or RV strain at 90 days was increased age (odds radio 1.35, CI 1.06 to 1.72 per 10 years). Specifically, neither clot location nor treatment was associated with patient outcomes. In conclusion, in this cohort of patients with submassive and massive PE, clot location was associated with treatment patterns but not patient outcomes to 90 days. Reevaluation of practice is thus warranted. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jain, C. Charles; Chang, Yuchiao] Massachusetts Gen Hosp, Dept Med, Boston, MA 19104 USA. [Kabrhel, Christopher] Massachusetts Gen Hosp, Ctr Vasc Emergencies, Dept Emergency Med, Boston, MA 19104 USA. [Channick, Richard; Rodriguez-Lopez, Josanna] Massachusetts Gen Hosp, Pulmonol Div, Boston, MA 19104 USA. [Rosovsky, Rachel P.; Fogerty, Annemarie] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA USA. [Rosenfield, Kenneth; Jaff, Michael R.; Weinberg, Ido] Massachusetts Gen Hosp, Fireman Vasc Ctr, Div Cardiol, Boston, MA USA. [Giri, Jay] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. RP Jain, CC (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 19104 USA. EM cjain@partners.org OI Rosovsky, Rachel/0000-0002-2392-7365 FU Diagnostica Stago, Parsippany, New Jersey; Janssen, Beerse, Belgium; Siemens Healthcare, Erlangen, Germany; Boehringer-Ingelheim, Ingelheim am Rhein, Germany; Actelion Pharmaceuticals, Allschwil, Switzerland; Cardinal Health, Dublin, Ohio; Novella/Bi02 Data and Safety Monitoring Board, Morrisville, North Carolina; AngioDynamics Incorprorated, Latham, New York FX Dr. Kabrhel has received grants from Diagnostica Stago, Parsippany, New Jersey, Janssen, Beerse, Belgium, Siemens Healthcare, Erlangen, Germany, Boehringer-Ingelheim, Ingelheim am Rhein, Germany and has also served as a consultant for Diagnostica Stago, Parsippany, New Jersey, Janssen, Beerse, Belgium and Siemens Healthcare, Erlangen, Germany. Dr. Giri has served as a compensated advisor for AngioDynamics Incorprorated, Latham, New York. Dr. Channick has no relevant disclosures. Dr. Rodriguez-Lopez has served as a consultant for Gilead Pharmaceuticals, Foster City, California and has received research support from Actelion Pharmaceuticals, Allschwil, Switzerland. Dr. Rosenfield has served as an advisor for Abbott Vascular, Abbot Park, Illinois, Cardinal Health, Dublin, Ohio, Inari Medical, Irvine, California, InspireMD, Boston, Massachusetts, Surmodics, Eden Prane, Minnesota, Volcano/Philips, San Diego, California and Proteon, Waltham, Massachusetts; he is an investor for Access Vascular, Herriman, Utah, CardioMEMS, - Atlanta, Georgia, Contego, CRUZAR Systems, Brooklyn, New York, Embolitech, Austin, Texas, Icon, Dublin, Ireland, Jana Care, Boston, Massachusetts, MD Insider, Santa Monica, California, Primacea, Boston, Massachusetts, PQ Bypass, Sunnyvale, California and Vortex, Middleton, Wisconsin; and he is also a consultant with equity options for Capture Vascular, Telluride, Colorado, Contego, Brooklyn, New York, CRUZAR Systems, Braintree, Massachusetts, Endospan, Herzliya, Israel, Austin, Texas, Eximo, Rehovot, HaMerkaz, MD Insider, Santa Monica, California, Micell, Raleigh, North Carolina, Shockwave, Fremont, California, Silk Road Medical, Sunnyvale, California and Valcare, Herzliya, Israel. Dr. Rosenfield provides research support for Abbott Vascular, Abbot Park, Illinois, Atrium, New York, New York, NIH, Bethesda, Maryland and Lutonix Bard, Murray Hill, New Jersey; he is also a board member for VIVA Physicians. Dr. Jaff is a noncompensated advisor for Abbott Vascular, Abbot Park, Illinois, Boston Scientific, Marlborough, Massachusetts, Cordis Corporation, Hialeah, Florida and Medtronic, Dublin, Ireland; he is a compensated advisor for Cardinal Health, Dublin, Ohio and Novella/Bi02 Data and Safety Monitoring Board, Morrisville, North Carolina; he is an equity investor in Embolitech, Austin, Texas and Valiant Medical, Woodbury, New York; and he is also a board member in VIVA Physicians and the Society for Cardiovascular Angiography and Interventions, San Jose, California. The other authors have no conflicts of interest to disclose. NR 21 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 1 PY 2017 VL 119 IS 5 BP 802 EP 807 DI 10.1016/j.amjcard.2016.11.018 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO0JE UT WOS:000396383300018 PM 28153347 ER PT J AU Byers, AL Lai, AX Bruce, ML AF Byers, Amy L. Lai, Amy X. Bruce, Martha L. TI Timing of Mental Health Services Use: Reducing the Risk of Late-life Suicidal Behavior SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Byers, Amy L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Byers, Amy L.; Lai, Amy X.] San Francisco VA Med Ctr, San Francisco, CA USA. [Bruce, Martha L.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. FU NIH [MD007019] FX This work is supported by a NIH R01 grant (MD007019) that is administered by the Northern California Institute for Research and Education through resources from the San Francisco Veterans Affairs Medical Center. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA NR 21 BP S135 EP S136 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000133 ER PT J AU Gebara, MA DiNapoli, E Kho, T Karp, J Gildengers, A Butters, MA Albert, S Reynoldsiii, CF AF Gebara, Marie Anne DiNapoli, Elizabeth Kho, Terry Karp, Jordan Gildengers, Ariel Butters, Meryl A. Albert, Stven Reynoldsiii, Charles F. TI Depression Prevention in Older Adults: Changes in Mood and Sleep SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Gebara, Marie Anne; DiNapoli, Elizabeth] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. [Gebara, Marie Anne; Kho, Terry; Karp, Jordan; Gildengers, Ariel; Butters, Meryl A.; Albert, Stven; Reynoldsiii, Charles F.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA EI 3 BP S64 EP S65 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000061 ER PT J AU Jimenez, D Reynolds, CF Alegria, M Harvey, PS Bartels, SJ AF Jimenez, Daniel Reynolds, Charles F., III Alegria, Margarita Harvey, Philip S. Bartels, Stephen J. TI Preventing Anxiety in Depression in Older Latinos: The Happy Older Latinos are Active (HOLA) Health Promotion Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Jimenez, Daniel; Harvey, Philip S.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Reynolds, Charles F., III] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Alegria, Margarita] Massachusettes Gen Hosp, Boston, MA USA. [Bartels, Stephen J.] Geisel Sch Med Dartmouth, Lebanon, NH USA. FU National Institute of Mental Health [K23 MH098025] FX This research was funded by: This research is supported by grant K23 MH098025 from the National Institute of Mental Health. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA NR 9 BP S124 EP S124 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000121 ER PT J AU Kasckow, J Reynolds, CF Karp, J Chickering, S Morse, J AF Kasckow, John Reynolds, Charles F., III Karp, Jordan Chickering, Sunita Morse, Jennifer TI Problem Solving Therapy Improves Social Problem Solving Skills in Older Adults with Depression and Low Back Pain SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Kasckow, John; Reynolds, Charles F., III; Karp, Jordan; Chickering, Sunita] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Kasckow, John; Karp, Jordan] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Morse, Jennifer] Chatham Univ, Pittsburgh, PA USA. FU [AG033575]; [MH101371] FX This research was funded by: AG033575 and MH101371. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA NR 2 BP S116 EP S117 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000114 ER PT J AU Kasckow, J Gebara, MA Mulsant, BH Lenze, E AF Kasckow, John Gebara, Marie Anne Mulsant, Benoit H. Lenze, Eric TI ADVANCES IN PHARMACOTHERAPY OF LATE-LIFE DEPRESSION SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Kasckow, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Gebara, Marie Anne] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Mulsant, Benoit H.; Lenze, Eric] Univ Toronto, Toronto, ON, Canada. FU Bristol-Myers Squibb; Eli Lilli; NIH; CAMH Foundation; Lundbeck; Takeda FX Bristol-Myers Squibb-Medications for a NIH-funded clinical trial; Eli Lilli-Medications for a NIH-funded clinical trial; Pfizer-Medications for a NIH-funded clinical trial; Capital Solution Design LLC-Software used in study funded by CAMH Foundation; Lundbeck-co-funding for IISR; Takeda-co-funding for IISR NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA 107 BP S7 EP S7 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000009 ER PT J AU Radue, RM Boyle, LL Welch, L Eastman, A Schroeder, R Hermann, C Barczi, S AF Radue, Rebecca M. Boyle, Lisa L. Welch, Lauren Eastman, Alexis Schroeder, Rebecca Hermann, Carol Barczi, Steve TI Interprofessional Learners' Performance in a Late Life Depression Simulated-Patient Assessment: Preliminary Results From the GEAR-UP Project SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Radue, Rebecca M.; Boyle, Lisa L.; Barczi, Steve] Univ Wisconsin, Madison, WI USA. [Boyle, Lisa L.; Welch, Lauren; Eastman, Alexis; Schroeder, Rebecca; Hermann, Carol; Barczi, Steve] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. FU William S. Middleton Veterans Administration (VA) Geriatric Research, Education and Clinical Center (GRECC) & University ofWisconsin (UW) Department of Medicine, Madison, WI; Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) [U1QHP28712] FX This research was funded by: William S. Middleton Veterans Administration (VA) Geriatric Research, Education and Clinical Center (GRECC) & University ofWisconsin (UW) Department of Medicine, Madison, WI-This project was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant U1QHP28712 (Geriatrics Workforce Enhancement Program). The information or content and conclusions contained herein are those of the authors 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. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA EI 56 BP S113 EP S115 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000111 ER PT J AU Renn, BN Ali, AA Thielke, S Catic, A Martini, SR Mitchell, BG Kunik, M AF Renn, Brenna N. Ali, Ali Asghar Thielke, Stephen Catic, Angela Martini, Sharyl R. Mitchell, Brian G. Kunik, Mark TI A Review of Cholinesterase Inhibitor Discontinuation in Alzheimer's Disease: Should Clinicians Ever Stop Treatment? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Renn, Brenna N.; Thielke, Stephen] Univ Washington, Seattle, WA 98195 USA. [Ali, Ali Asghar; Martini, Sharyl R.; Mitchell, Brian G.; Kunik, Mark] Baylor Coll Med, Houston, TX 77030 USA. [Ali, Ali Asghar; Catic, Angela; Mitchell, Brian G.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Thielke, Stephen] VA Puget Sound Healthcare Syst, Seattle, WA USA. [Kunik, Mark] VA HSR&D Houston Ctr Innovat, Houston, TX USA. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA EI 19 BP S80 EP S81 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000077 ER PT J AU Wilkins, J AF Wilkins, James TI Narrative interest standard: a novel approach to surrogate decision-making for individuals with dementia. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) on Integrated Geriatric Mental Health Care Through Innovation CY MAR 24-27, 2017 CL Dallas, TX SP Amer Assoc Geriatr Psychiat C1 [Wilkins, James] McLean Hosp, Massachusetts Gen Hosp, Psychiat, Boston, MA USA. NR 0 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2017 VL 25 IS 3 SU S MA EI 1 BP S63 EP S63 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EP1IG UT WOS:000397138000059 ER PT J AU Kageleiry, A Samuelson, D Duh, MS Lefebvre, P Campbell, J Skotko, BG AF Kageleiry, Andrew Samuelson, David Duh, Mei Sheng Lefebvre, Patrick Campbell, John Skotko, Brian G. TI Out-of-pocket Medical Costs and Third-party Healthcare Costs for Children with Down Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Down syndrome; children; out-of-pocket costs; third-party payers ID POPULATION; DEFECTS; IMPACT; RISK AB Prior analyses have estimated the lifetime total societal costs of a person with Down syndrome (DS); however, no studies capture the expected medical costs that patients with DS can expect to incur during childhood. The study utilized the OptumHealth Reporting and Insights administrative claims database from 1999 to 2013. Children with a diagnosis of DS were identified, and their time was divided into clinically relevant age categories. Patients with DS in each age category were matched to controls without chromosomal conditions. Out-of-pocket medical costs and third-party expenditures were compared between the patient-age cohorts with DS and matched controls. Patients with DS had significantly higher mean annual out-of-pocket costs than their matched controls within each age and cost category. Total annual incremental out-of-pocket costs associated with DS were highest among individuals from birth to age 1 ($1,907, P<0.001). The main drivers of the incremental out-of-pocket costs associated with DS were inpatient costs in the 1st year of life ($925, P<0.001) and outpatient costs in later years (ranging $183-$623, all P<0.001). Overall, patients with DS incurred incremental out-of-pocket medical costs of $18,248 between birth and age 18 years; third-party payers incurred incremental costs of $230,043 during the same period. Across all age categories, mean total out-of-pocket annual costs were greater for individuals with DS than those of matched controls. On average, parents of children with DS pay an additional $84 per month for out-of-pocket medical expenses when costs are amortized over 18 years. (C) 2016 Wiley Periodicals, Inc. C1 [Kageleiry, Andrew; Samuelson, David; Duh, Mei Sheng] Anal Grp Inc, Boston, MA USA. [Lefebvre, Patrick] Grp Anal Montreal, Montreal, PQ, Canada. [Campbell, John] Harvard Univ, Dept Econ, Cambridge, MA USA. [Skotko, Brian G.] Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Boston, MA USA. [Skotko, Brian G.] Harvard Med Sch, Boston, MA USA. RP Skotko, BG (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,Room 2222, Boston, MA 02114 USA. EM bskotko@mgh.harvard.edu NR 29 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2017 VL 173 IS 3 BP 627 EP 637 DI 10.1002/ajmg.a.38050 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EL8XN UT WOS:000394903800008 PM 27966292 ER PT J AU Riklin, E Talaei-Kheoi, M Merker, VL Sheridan, MR Jordan, JT Plotkin, SR Vranceanu, AM AF Riklin, Eric Talaei-Kheoi, Mojtaba Merker, Vanessa L. Sheridan, Monica R. Jordan, Justin T. Plotkin, Scott R. Vranceanu, Ana-Maria TI First Report of Factors Associated with Satisfaction in Patients With Neurofibromatosis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurofibromatosis; health literacy; patient satisfaction; medical visits ID HEALTH LITERACY; COMMUNICATION; OUTCOMES; QUALITY; DEPRESSION; PROMIS; GENDER; CARE; PAIN AB Patient satisfaction is an integral part of quality health care. We assessed whether health literacy and psychosocial factors are associated with patient satisfaction among adults with neurofibromatosis. Eighty adults (mean age=44 years; 55% female, 87% white) with NF (50% NF1, 41% NF2, and 9% schwannomatosis) completed an adapted Functional, Communicative, and Critical Health Literacy Questionnaire (FCCHL), the Health Literacy Assessment, a series of Patient Reported Outcome Measures Information System (PROMIS) psychosocial tests, and demographics before the medical visit. After, participants completed two measures of satisfaction: the Medical Interview Satisfaction Scale (MISS) to assess satisfaction with the medical visit, and an adapted version of the Consumer Assessment of Healthcare Providers and Systems Health Literacy Item Set (CAHPS-HL) to assess satisfaction with communication with the provider. Although higher FCCHL health literacy (r=0.319, P=0.002), male gender (t=2.045, P=0.044) and better psychosocial functioning (r=-0.257 to 0.409, P < 0.05) were associated with higher satisfaction with the medical visit in bivariate correlations, only male gender and higher health literacy remained as significant predictors in multivariable analyses. Higher FCCHL health literacy, less pain interference, fewer pain behaviors, and higher satisfaction with social roles and social discretionary activities (r=-0.231 to 0.331, P < 0.05) were associated with higher satisfaction with the communication with the provider in bivariate analyses. Results support the use of psychosocial and health literacy measures in clinical practice. Referrals to psychosocial treatments in addition to brief interventions focused on increasing health literacy may also be beneficial. (C) 2017 Wiley Periodicals, Inc. C1 [Riklin, Eric] Harvard Med Sch, Dept Psychiat, Benson Henry Inst Mind Body Med, Massachusetts Gen Hosp, Boston, MA USA. [Talaei-Kheoi, Mojtaba] Harvard Med Sch, Hand & Upper Extrem Serv, Massachusetts Gen Hosp, Boston, MA USA. [Merker, Vanessa L.; Sheridan, Monica R.; Jordan, Justin T.; Plotkin, Scott R.] Harvard Med Sch, Dept Neurol, Massachusetts Gen Hosp, Boston, MA USA. [Merker, Vanessa L.; Sheridan, Monica R.; Jordan, Justin T.; Plotkin, Scott R.] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Boston, MA USA. [Vranceanu, Ana-Maria] Harvard Med Sch, Dept Psychiat, Behav Med Serv, Massachusetts Gen Hosp, Boston, MA USA. RP Vranceanu, AM (reprint author), Behav Med Serv, Dept Psychiat, One Bowdoin Sq,7th Floor,Suite 758, Boston, MA 02114 USA. EM avranceanu@partners.org NR 32 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2017 VL 173 IS 3 BP 671 EP 677 DI 10.1002/ajmg.a.38079 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EL8XN UT WOS:000394903800014 PM 28211981 ER PT J AU Brown, DN Lum, D AF Brown, D. N. Lum, D. TI Clinical characteristics and outcomes of patients undergoing contained extracorporeal manual tissue extraction SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons (SGS) CY MAR 26-29, 2017 CL San Antonio, TX SP Soc Gynecol Surg C1 [Brown, D. N.] Harvard Med Sch, Massachusetts Gen Hosp, Obstet & Gynecol, Boston, MA USA. [Lum, D.] Stanford Univ, Med Ctr, Obstet & Gynecol, Palo Alto, CA 94304 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2017 VL 216 IS 3 SU S MA 73 BP S616 EP S617 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO9ZP UT WOS:000397046900095 ER PT J AU Ahmad, I Zelnick, LR Robinson, NR Hung, AM Kestenbaum, B Utzschneider, KM Kahn, SE de Boer, IH AF Ahmad, Iram Zelnick, Leila R. Robinson, Nicole R. Hung, Adriana M. Kestenbaum, Bryan Utzschneider, Kristina M. Kahn, Steven E. de Boer, Ian. H. TI Chronic kidney disease and obesity bias surrogate estimates of insulin sensitivity compared with the hyperinsulinemic euglycemic clamp SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article ID GLUCOSE-TOLERANCE TEST; RENAL-DISEASE; FATTY-ACIDS; RESISTANCE; CLEARANCE; INDEX; HOMEOSTASIS; SECRETION; VALIDATION; METABOLISM AB Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross-sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) , 60 ml.min(-1.)1.73 m(2)] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8-38% lower in participants with vs. without CKD and 13-59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD (P = 0.09) and 36% lower in participants with vs. without obesity (P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD (P = 0.02) and 46% lower in participants with vs. without obesity (P = 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin. C1 [Ahmad, Iram; Utzschneider, Kristina M.; Kahn, Steven E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Ahmad, Iram; Zelnick, Leila R.; Robinson, Nicole R.; Kestenbaum, Bryan; de Boer, Ian. H.] Univ Washington, Dept Med, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA. [Hung, Adriana M.] Vanderbilt Univ, Sch Med, Div Nephrol & Hypertens, Nashville, TN 37212 USA. [Utzschneider, Kristina M.; Kahn, Steven E.; de Boer, Ian. H.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Ahmad, I (reprint author), Kidney Res Inst, 325 9th Ave,Box 359606, Seattle, WA 98104 USA. EM iram@uw.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-087726]; Department of Veterans Affairs; National Institutes of Health Grants [UL1-TR-000423, P01-DK-017047, P30-DK-035816, R01-DK-088762, R01-DK-099199, T32-DK-007247]; unrestricted fund from the Northwest Kidney Center FX The SUGAR study was funded primarily by Grant no. R01-DK-087726 from the National Institute of Diabetes and Digestive and Kidney Diseases. Additional support came from the Department of Veterans Affairs, National Institutes of Health Grants UL1-TR-000423, P01-DK-017047, P30-DK-035816, R01-DK-088762, R01-DK-099199, and T32-DK-007247, and an unrestricted fund from the Northwest Kidney Center. NR 37 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2017 VL 312 IS 3 BP E175 EP E182 DI 10.1152/ajpendo.00394.2016 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA EN1YD UT WOS:000395805500005 PM 28073780 ER PT J AU Eisenberg, JD Reisner, AT Binder, WD Zaheer, A Gunn, ML Linnau, KF Miller, CM Tramontano, AC Herring, MS Dowling, EC Halpern, EF Donelan, K Gazelle, GS Pandharipande, PV AF Eisenberg, Jonathan D. Reisner, Andrew T. Binder, William D. Zaheer, Atif Gunn, Martin L. Linnau, Ken F. Miller, Chad M. Tramontano, Angela C. Herring, Maurice S. Dowling, Emily C. Halpern, Elkan F. Donelan, Karen Gazelle, G. Scott Pandharipande, Pari V. TI Role of CT in the Diagnosis of Nonspecific Abdominal Pain: A Multicenter Analysis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE abdominal pain; CT; emergency radiology; utilization AB OBJECTIVE. The objective of our study was to determine whether specific patient and physician factors--known before CT--are associated with a diagnosis of nonspecific abdominal pain (NSAP) after CT in the emergency department (ED). MATERIALS AND METHODS. We analyzed data originally collected in a prospective multicenter study. In the parent study, we identified ED patients referred to CT for evaluation of abdominal pain. We surveyed their physicians before and after CT to identify changes in leading diagnoses, diagnostic confidence, and admission decisions. In the current study, we conducted a multiple regression analysis to identify whether the following were associated with a post-CT diagnosis of NSAP: patient age; patient sex; physicians' years of experience; physicians' pre-CT diagnostic confidence; and physicians' pre-CT admission decision if CT had not been available. We analyzed patients with and those without a pre-CT diagnosis of NSAP separately. For the sensitivity analysis, we excluded patients with different physicians before and after CT. RESULTS. In total, 544 patients were included: 10% (52/544) with a pre-CT diagnosis of NSAP and 90% (492/544) with a pre-CT diagnosis other than NSAP. The leading diagnoses changed after CT in a large proportion of patients with a pre-CT diagnosis of NSAP (38%, 20/52). In regression analysis, we found that physicians' pre-CT diagnostic confidence was inversely associated with a post-CT diagnosis of NSAP in patients with a pre- CT diagnosis other than NSAP (p = 0.0001). No other associations were significant in both primary and sensitivity analyses. CONCLUSION. With the exception of physicians' pre-CT diagnostic confidence, the factors evaluated were not associated with a post-CT diagnosis of NSAP. C1 [Eisenberg, Jonathan D.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Eisenberg, Jonathan D.; Tramontano, Angela C.; Herring, Maurice S.; Dowling, Emily C.; Halpern, Elkan F.; Gazelle, G. Scott; Pandharipande, Pari V.] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Fl, Boston, MA 02114 USA. [Eisenberg, Jonathan D.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Reisner, Andrew T.; Binder, William D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Binder, William D.] Brown Univ, Dept Emergency Med, Providence, RI 02912 USA. [Zaheer, Atif] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Gunn, Martin L.; Linnau, Ken F.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Miller, Chad M.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Tramontano, Angela C.; Dowling, Emily C.; Halpern, Elkan F.; Gazelle, G. Scott; Pandharipande, Pari V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Herring, Maurice S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Herring, Maurice S.] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA. [Donelan, Karen] Massachusetts Gen Hosp, Dept Med, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Fl, Boston, MA 02114 USA.; Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM pari@mgh-ita.org RI Miller, Chad/A-2536-2017 OI Miller, Chad/0000-0002-9896-470X FU National Electrical Manufacturers Association (NEMA) FX This research was supported by a grant from the National Electrical Manufacturers Association (NEMA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NEMA or Medical Imaging and Technology Alliance, a division of the NEMA. The following were at the sole discretion of the authors and not the NEMA: the design and conduct of the study; collection, storage, management, analysis, and interpretation of the data; preparation and approval of the manuscript; and decision to submit the manuscript for publication. The NEMA had the opportunity to review the manuscript, and incorporation of the NEMA's comments on the research was at the sole discretion of the authors. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAR PY 2017 VL 208 IS 3 BP 570 EP 576 DI 10.2214/AJR.16.16669 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4MT UT WOS:000394596000027 PM 28075619 ER PT J AU Abujudeh, H Kaewlai, R Shaqdan, K Bruno, MA AF Abujudeh, Hani Kaewlai, Rathachai Shaqdan, Khalid Bruno, Michael A. TI Key Principles in Quality and Safety in Radiology SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE change management; Hawthorne effect; key quality concepts; quality and safety; quality improvement ID HEALTH-CARE; IMPROVEMENT; CULTURE; TOOLS AB OBJECTIVE. The purpose of this article is to introduce the reader to basic concepts of quality and safety in radiology. CONCLUSION. Concepts are introduced that are keys to identifying, understanding, and utilizing certain quality tools with the aim of making process improvements. Challenges, opportunities, and change drivers can be mapped from the radiology quality perspective. Best practices, informatics, and benchmarks can profoundly affect the outcome of the quality improvement initiative we all aim to achieve. C1 [Abujudeh, Hani] Cooper Univ Hosp, One Cooper Plaza, Camden, NJ 08103 USA. [Kaewlai, Rathachai] Bumrungrad Hosp, Dept Radiol, Bangkok, Thailand. [Shaqdan, Khalid] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Bruno, Michael A.] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. RP Abujudeh, H (reprint author), Cooper Univ Hosp, One Cooper Plaza, Camden, NJ 08103 USA. EM Abujudeh-hani@cooperhealth.edu NR 31 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAR PY 2017 VL 208 IS 3 BP W101 EP W109 DI 10.2214/AJR.16.16951 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4MT UT WOS:000394596000006 PM 28075621 ER PT J AU Jaconis, M Ana, EJS Killeen, TK Badour, CL Back, SE AF Jaconis, Maryanne Ana, Elizabeth J. Santa Killeen, Therese K. Badour, Christal L. Back, Sudie E. TI Case-Series: Concurrent Treatment of PTSD and Alcohol Use Disorder via Telehealth in a Female Iraq Veteran SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PROLONGED EXPOSURE THERAPY; DEPENDENCE AB Background and Objectives: A growing literature provides evidence for the use of integrated treatments (e.g., Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; COPE); however, no known studies have applied COPE via telehealth. Method: COPE was delivered via telehealth to treat one black female veteran with combat trauma and alcohol use disorder. Results: The patient demonstrated significant reductions in alcohol consumption and PTSD and depressive symptoms. Conclusions and Scientific Significance: Although preliminary, findings demonstrate that integrated treatment via telehealth is feasible and effective, and may be useful for female veterans reluctant to seek services at male-dominated VAMCs. C1 [Jaconis, Maryanne; Ana, Elizabeth J. Santa; Killeen, Therese K.; Back, Sudie E.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Addict Sci Div, Charleston, SC USA. [Jaconis, Maryanne] Univ Wyoming, Dept Psychol, Laramie, WY 82071 USA. [Jaconis, Maryanne] VA Portland Hlth Care Syst, 3710 SW US Vet Hosp Rd,P3MHN, Portland, OR 97202 USA. [Ana, Elizabeth J. Santa; Killeen, Therese K.; Back, Sudie E.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Badour, Christal L.] Univ Kentucky, Dept Psychol, Lexington, KY 40506 USA. RP Jaconis, M (reprint author), VA Portland Hlth Care Syst, 3710 SW US Vet Hosp Rd,P3MHN, Portland, OR 97202 USA. EM maryanne.jaconis@va.gov FU NIDA [T32 DA007288] FX This publication was supported by NIDA grant T32 DA007288 (Jaconis). NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD MAR PY 2017 VL 26 IS 2 BP 112 EP 114 DI 10.1111/ajad.12481 PG 3 WC Substance Abuse SC Substance Abuse GA EP3QK UT WOS:000397296600002 PM 28118514 ER PT J AU Capurso, NA AF Capurso, Noah A. TI Case-Series: Naltrexone for the Treatment of Comorbid Tobacco and Pornography Addiction SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID SMOKING-CESSATION; CONTROLLED-TRIAL; ALCOHOL; AUGMENTATION; DISORDER; BEHAVIOR AB Background and Objectives: Co-occurring addictive disorders are common, however treatment strategies for this population have not been extensively studied. This is especially the case for behavioral addictions. Methods: We present a patient (N = 1) with tobacco use disorder and problematic pornography use treated with naltrexone. Results: Naltrexone treatment resulted in a decrease in pornography viewing and cigarette smoking, however had the adverse effect of anhedonia. A lower dose modestly impacted pornography viewing but not smoking. Discussions and Conclusions: Relevant literature regarding co-occurring addictions as well as use of naltrexone is reviewed. Scientific Significance: This report represents the first case of tobacco and pornography co-addiction in the literature and supports the assertion that treatment of one addictive disorder can benefit another in the dually addicted patient. The efficacy of naltrexone for smoking is notable as previous studies of naltrexone in smoking have been disappointing. This case suggests future treatment strategies for comorbid addictions. C1 [Capurso, Noah A.] Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06520 USA. [Capurso, Noah A.] VA Connecticut Healthcare Syst, US Dept Vet Affairs, West Haven, CT USA. RP Capurso, NA (reprint author), Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06520 USA. EM noah.capurso@yale.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD MAR PY 2017 VL 26 IS 2 BP 115 EP 117 DI 10.1111/ajad.12501 PG 3 WC Substance Abuse SC Substance Abuse GA EP3QK UT WOS:000397296600003 PM 28106937 ER PT J AU Chen, XQ Feng, D Schwarzschild, MA Gao, X AF Chen, Xiqun Feng, Danielle Schwarzschild, Michael A. Gao, Xiang TI Red hair, MC1R variants, and risk for Parkinson's disease - a meta-analysis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID SKIN-CANCER; MELANOMA; NEUROMELANIN; EXPRESSION; RECEPTOR; SURFACE; CORE AB Several studies have been conducted with mixed results since our initial report of increased Parkinson's disease risk in individuals with red hair and/or red hair-associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta-analysis of six publications on red hair, MC1R, and Parkinson's disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson's disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson's disease. C1 [Chen, Xiqun; Feng, Danielle; Schwarzschild, Michael A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Chen, Xiqun] Tongji Univ, Sch Med, Shanghai Hosp 10, Shanghai, Peoples R China. [Gao, Xiang] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Gao, X (reprint author), Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA.; Chen, XQ (reprint author), Massachusetts Gen Hosp, Dept Neurol, 114 16th St, Charlestown, MA 02119 USA. EM xchen17@mgh.harvard.edu; xxg14@psu.edu FU Michael J. Fox Foundation [9908]; National Institute of Health [1R2 1NS090246-01A1, 5R21NS087235-02]; National Natural Science Foundation of China [81471293] FX The authors are supported by the Michael J. Fox Foundation (9908 to X. C.), National Institute of Health (1R2 1NS090246-01A1 to X. C., 5R21NS087235-02 to X. G.), National Natural Science Foundation of China (81471293 to X. C.). NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD MAR PY 2017 VL 4 IS 3 BP 212 EP 216 DI 10.1002/acn3.381 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP0YU UT WOS:000397113400006 PM 28275654 ER PT J AU Shields, RK Chen, L Cheng, SJ Chavda, KD Press, EG Snyder, A Pandey, R Doi, Y Kreiswirth, BN Nguyen, MH Clancy, CJ AF Shields, Ryan K. Chen, Liang Cheng, Shaoji Chavda, Kalyan D. Press, Ellen G. Snyder, Avin Pandey, Ruchi Doi, Yohei Kreiswirth, Barry N. Nguyen, M. Hong Clancy, Cornelius J. TI Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne bla(KPC-3) Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE ceftazidime-avibactam; resistance; carbapenem-resistant Enterobacteriaceae; Klebsiella pneumoniae; Klebsiella pneumoniae carbapenemase,sequence type 258 ID SEQUENCE TYPE 258; BETA-LACTAMASE; US HOSPITALS; ENTEROBACTERIACEAE; KPC; BACTEREMIA; MORTALITY; EVOLUTION; VARIANTS; THERAPY AB Ceftazidime-avibactam is a novel beta lactam/ beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Kleb-siella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidimeavibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Wholegenome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne bla(KPC-3), which were not present in baseline isolates. bla(KPC-3) mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli. In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs >= 4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced >= 4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of bla(KPC-3) encoding D179Y/T243M and D179Y variants was diminished compared to bla(KPC-3) expression in baseline isolates. In conclusion, the development of resistance-conferring bla(KPC-3) mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates. C1 [Shields, Ryan K.; Cheng, Shaoji; Press, Ellen G.; Snyder, Avin; Doi, Yohei; Nguyen, M. Hong; Clancy, Cornelius J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Shields, Ryan K.; Nguyen, M. Hong; Clancy, Cornelius J.] Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA 15260 USA. [Chen, Liang; Chavda, Kalyan D.; Pandey, Ruchi; Kreiswirth, Barry N.] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, TB Ctr, Newark, NJ USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Nguyen, MH (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA.; Nguyen, MH (reprint author), Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA 15260 USA. EM mhn5@pitt.edu FU National Institutes of Health [K08AI114883, R21AI117338, R01AI090155, UM1AI104681, R21AI111037] FX This work was funded, in part, by grants from the National Institutes of Health (K08AI114883 to R.K.S., R21AI117338 to L.C., R01AI090155 to B.N.K., UM1AI104681 to M.H.N., and R21AI111037 to C.J.C.). NR 41 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2017 VL 61 IS 3 AR e02097-16 DI 10.1128/AAC.02097-16 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EL4QM UT WOS:000394605900054 ER PT J AU Velasquez, GE Calderon, RI Mitnick, CD Becerra, MC Huang, CC Zhang, ZBA Contreras, CC Yataco, RM Galea, JT Lecca, LW Murray, MB AF Velasquez, Gustavo E. Calderon, Roger I. Mitnick, Carole D. Becerra, Mercedes C. Huang, Chuan-Chin Zhang, Zibiao Contreras, Carmen C. Yataco, Rosa M. Galea, Jerome T. Lecca, Leonid W. Murray, Megan B. TI Erratum for Velasquez et al., Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Correction C1 [Velasquez, Gustavo E.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Velasquez, Gustavo E.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Velasquez, Gustavo E.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Calderon, Roger I.; Mitnick, Carole D.; Becerra, Mercedes C.; Contreras, Carmen C.; Yataco, Rosa M.; Galea, Jerome T.; Lecca, Leonid W.; Murray, Megan B.] Partners Hlth, Boston, MA USA. [Calderon, Roger I.; Mitnick, Carole D.; Becerra, Mercedes C.; Contreras, Carmen C.; Yataco, Rosa M.; Galea, Jerome T.; Lecca, Leonid W.; Murray, Megan B.] Partners Hlth, Lima, Peru. [Mitnick, Carole D.; Becerra, Mercedes C.; Murray, Megan B.] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Mitnick, Carole D.; Becerra, Mercedes C.; Zhang, Zibiao; Murray, Megan B.] Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. [Huang, Chuan-Chin] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. [Murray, Megan B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Velasquez, GE (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA.; Velasquez, GE (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Velasquez, GE (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2017 VL 61 IS 3 AR e00069-17 DI 10.1128/AAC.00069-17 PG 1 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EL4QM UT WOS:000394605900066 ER PT J AU Locke, FL Pidala, J Storer, B Martin, PJ Pulsipher, MA Chauncey, TR Jacobsen, N Kroger, N Walker, I Light, S Shaw, BE Beato, F Laport, GG Nademanee, A Keating, A Socie, G Anasetti, C AF Locke, Frederick L. Pidala, Joseph Storer, Barry Martin, Paul J. Pulsipher, Michael A. Chauncey, Thomas R. Jacobsen, Niels Kroeger, Nicolaus Walker, Irwin Light, Susan Shaw, Bronwen E. Beato, Francisca Laport, Ginna G. Nademanee, Auayporn Keating, Armand Socie, Gerard Anasetti, Claudio TI CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Antitumor immunity; Daclizumab; Regulatory T cells ID BONE-MARROW-TRANSPLANTATION; STEROID-REFRACTORY ACUTE; PERIPHERAL-BLOOD; MONOCLONAL-ANTIBODY; IMPROVED SURVIVAL; UNRELATED DONORS; STEM-CELLS; DACLIZUMAB; IMMUNOTHERAPY; RECIPIENTS AB Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25(+)FOXP3(+) regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplas-, tic anemia. The risk of acute GVHD did not differ among the groups (P =.68). Long-terrri follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR]. 1.49; 95% confidence interval [CI], 1.0 to 2.3; P =.08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P =.05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P =.53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity. (C) 2017 Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Locke, Frederick L.; Pidala, Joseph; Beato, Francisca; Anasetti, Claudio] H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplantat Program, Tampa, FL USA. [Storer, Barry; Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Martin, Paul J.; Chauncey, Thomas R.] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. [Pulsipher, Michael A.] Univ Utah, Huntsman Canc Inst, Med Ctr, Blood & Marrow Transplant Program, Salt Lake City, UT 84112 USA. [Chauncey, Thomas R.] VA Puget Sound Hlth Care Syst, Canc Care Div, Seattle, WA USA. [Jacobsen, Niels] Rigshospitalet, Dept Hematol, Copenhagen, Denmark. [Kroeger, Nicolaus] Univ Med Ctr Hamburg Eppendorf, Ctr Oncol, Dept Stem Cell Transplantat, Hamburg, Germany. [Walker, Irwin] McMaster Univ, Dept Med, Hamilton, ON L8N 3Z5, Canada. [Light, Susan] Hoffman La Roche, Nutley, NJ USA. [Shaw, Bronwen E.] Royal Marsden Hosp, Haemato Oncol Unit, Downs Rd, Sutton SM2 5NG, Surrey, England. [Laport, Ginna G.] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Nademanee, Auayporn] Hematol Malignancies & Stem Cell Transplantat Ins, City Hope, Duarte, CA USA. [Keating, Armand] Princess Margaret Hosp, Blood & Marrow Transplant Ctr, Dept Hematol, Toronto, ON M4X 1K9, Canada. [Socie, Gerard] Hosp St Louis, Dept Hematol Transplantat, Paris, France. RP Anasetti, C (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplantat Program, Tampa, FL USA. EM claudio.anasetti@moffitt.org NR 46 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 MAR PY 2017 VL 23 IS 3 BP 405 EP 411 DI 10.1016/j.bbmt.2016.12.624 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EM5QL UT WOS:000395367300006 PM 28007665 ER PT J AU Stewart, IJ Sosnov, JA Snow, BD Batou, A Howard, JT Janak, JC Bollinger, M Chung, KK AF Stewart, Ian J. Sosnov, Jonathan A. Snow, Brian D. Batou, Augen Howard, Jeffrey T. Janak, Jud C. Bollinger, Mary Chung, Kevin K. TI Hypertension after injury among burned combat veterans: A retrospective cohort study SO BURNS LA English DT Article DE Burns; Hypertension; Acute kidney injury; War; Veterans ID CARDIOVASCULAR-DISEASE; CHILDREN; SYSTEM; PREVALENCE; SURVIVORS; RISK AB Background: The long-term health effects of burn are poorly understood. We sought to evaluate the relationship between burn and the subsequent development of hypertension. Methods: Retrospective cohort study of patients admitted to our burn center from 2003 to 2010. Data collected included demographic variables, burn size, injury severity score, presence of inhalation injury, serum creatinine, need for renal replacement therapy, as well as days spent in the hospital, in the intensive care unit and on mechanical ventilation. Data for the subsequent diagnosis of hypertension was obtained from medical records. Cox proportional hazard regression models were performed to determine what factors were associated with hypertension. Results: Of the 711 patients identified, 670 were included for analysis after exclusions. After adjustment, only age (HR 1.06 per one year increase, 95% confidence interval 1.03-1.08; p<0.001), percentage of total body surface area burned (HR 1.11 per 5% increase, 95% confidence interval 1.04-1.19; p=0.002) and acute kidney injury (HR 1.68, 95% confidence interval 1.05-2.69; p=0.03) were associated with hypertension. Conclusion: Burn size is independently associated with the subsequent risk of hypertension in combat casualties. Clinical support for primary prevention techniques to reduce the incidence of hypertension specific to burn patients may be warranted. Published by Elsevier Ltd. C1 [Stewart, Ian J.] David Grant USAF Med Ctr, Clin Invest Facil, 101 Bodin Circle, Travis AFB, CA 94535 USA. [Stewart, Ian J.; Sosnov, Jonathan A.; Chung, Kevin K.] Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Sosnov, Jonathan A.] San Antonio Mil Med Ctr, 3551 Roger Brooke Dr, Ft Sam Houston, TX 78219 USA. [Snow, Brian D.] Wright Patterson Med Ctr, 4881 Sugar Maple Dr, Wright Patterson AFB, OH 45433 USA. [Batou, Augen] Mike OCallaghan Fed Med Ctr, 4700 N Las Vegas Blvd, Nellis AFB, NV 89191 USA. [Howard, Jeffrey T.; Janak, Jud C.; Chung, Kevin K.] US Army, Inst Surg Res, 3698 Chambers Rd, Ft Sam Houston, TX 78234 USA. [Bollinger, Mary] South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. RP Stewart, IJ (reprint author), David Grant USAF Med Ctr, 101 Bodin Circle, Travis AFB, CA 94535 USA. EM ian.stewart@us.af.mil NR 29 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 0305-4179 EI 1879-1409 J9 BURNS JI Burns PD MAR PY 2017 VL 43 IS 2 BP 290 EP 296 DI 10.1016/j.burns.2016.10.005 PG 7 WC Critical Care Medicine; Dermatology; Surgery SC General & Internal Medicine; Dermatology; Surgery GA EN2LI UT WOS:000395841300006 PM 28029474 ER PT J AU Vopat, ML Vopat, BG Lubberts, B DiGiovanni, CW AF Vopat, Matthew L. Vopat, Bryan G. Lubberts, Bart DiGiovanni, Christopher W. TI Current trends in the diagnosis and management of syndesmotic injury SO CURRENT REVIEWS IN MUSCULOSKELETAL MEDICINE LA English DT Article DE Syndesmosis; Syndesmotic injury; Ankle fracture; High ankle sprain ID DISTAL TIBIOFIBULAR SYNDESMOSIS; NATIONAL FOOTBALL LEAGUE; ESSKA-AFAS CONSENSUS; HIGH ANKLE SPRAINS; CHRONIC INSTABILITY; SCREW FIXATION; COMPUTED-TOMOGRAPHY; FRACTURES; REDUCTION; STABILIZATION AB Ideal management of the various presentations of syndesmotic injury remains controversial to this day. High quality evidentiary science on this topic is rare, and numerous existing studies continue to contradict one another. The primary reasons for these discrepancies are that previous studies have failed to (1) properly distinguish between isolated (non-fractured) and non-isolated injuries, (2) accurately define stable from unstable injuries, and (3) sufficiently differentiate between acute and chronic injuries. The purpose of this review is to summarize today's body of literature regarding diagnosis and management of syndesmotic injury and discuss current trends and important future directions to optimize care of this very heterogeneous population. C1 [Vopat, Matthew L.] Univ Kansas, Dept Orthopaed, Sch Med Wichita, Via Christi Hlth,929 N St Francis,Room 4076, Wichita, KS 67214 USA. [Vopat, Bryan G.] Univ Kansas, Med Ctr, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Lubberts, Bart; DiGiovanni, Christopher W.] Harvard Univ, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. RP Vopat, ML (reprint author), Univ Kansas, Dept Orthopaed, Sch Med Wichita, Via Christi Hlth,929 N St Francis,Room 4076, Wichita, KS 67214 USA. EM mvopat@kumc.edu NR 80 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1935-973X EI 1935-9748 J9 CURR REV MUSCULOSKE JI Curr. Rev. Musculoskelet. Med. PD MAR PY 2017 VL 10 IS 1 BP 94 EP 103 DI 10.1007/s12178-017-9389-4 PG 10 WC Orthopedics SC Orthopedics GA EN8PE UT WOS:000396261500013 PM 28101828 ER PT J AU Knutsen, J Mandell, DS Frye, D AF Knutsen, John Mandell, David S. Frye, Douglas TI Children with autism are impaired in the understanding of teaching SO DEVELOPMENTAL SCIENCE LA English DT Article ID NATURAL COGNITIVE-ABILITY; SPECTRUM DISORDERS; EMOTION RECOGNITION; CENTRAL COHERENCE; EXECUTIVE FUNCTIONS; MENTAL-RETARDATION; TASK-PERFORMANCE; MIND; BELIEF; FACES AB Children learn novel information using various methods, and one of the most common is human pedagogical communication or teaching - the purposeful imparting of information from one person to another. Neuro-typically developing (TD) children gain the ability to recognize and understand teaching as a core method for acquiring knowledge from others. However, it is not known when children with Autism Spectrum Disorder (ASD) acquire the ability to recognize and understand teaching. This study (total N=70) examined whether children with ASD recognize the two central elements that define teaching: (1) that teaching is an intentional activity; and (2) that teaching requires a knowledge difference between teacher and learner. Theory of mind understanding was also tested. Compared to individually matched TD children, high cognitively functioning children with ASD were impaired in their comprehension of both components of teaching understanding, and their performance was correlated with theory of mind understanding. These findings could have broad implications for explaining learning in children with autism, and could help in designing more effective interventions, which could ultimately lead to improved learning outcomes for everyday life skills, school performance, health, and overall well-being. C1 [Knutsen, John] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Knutsen, John] Massachusetts Gen Hosp, Div Gen Acad Pediat, Boston, MA 02114 USA. [Mandell, David S.] Univ Penn, Ctr Mental Hlth Policy & Serv Res, Perelman Sch Med, Philadelphia, PA 19104 USA. [Frye, Douglas] Univ Penn, Grad Sch Educ, Div Appl Psychol & Human Dev, Philadelphia, PA 19104 USA. RP Knutsen, J (reprint author), Massachusettes Gen Hosp Children, 125 Nashua St,Suite 8438D, Boston, MA 02114 USA. EM jknutsen@mgh.harvard.edu FU Institute of Education Sciences, US Department of Education [R305B090015] FX The research reported here was supported by the Institute of Education Sciences, US Department of Education, through Grant #R305B090015 to the University of Pennsylvania. The opinions expressed are those of the authors and do not represent the views of the Institute or the US Department of Education. The authors would like to thank the Children's Hospital of Philadelphia Center for Autism research for assistance with data access and collection; Aimee Yuka-Kim for assistance with data collection; Henry May for assistance with data analysis; the School District of Philadelphia; Penn Children's Center; and especially the participating families and their children. NR 68 TC 2 Z9 2 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1363-755X EI 1467-7687 J9 DEVELOPMENTAL SCI JI Dev. Sci. PD MAR PY 2017 VL 20 IS 2 AR UNSP e12368 DI 10.1111/desc.12368 PG 15 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA EM1GQ UT WOS:000395066500008 ER PT J AU Shen, H Monto, A AF Shen, H. Monto, A. TI Identifying Drug-Induced Liver Illness (DILI) with Computerized Information Extraction: No More Dilly-Dallying SO DIGESTIVE DISEASES AND SCIENCES LA English DT Editorial Material C1 [Shen, H.; Monto, A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shen, H.; Monto, A.] San Francisco VA Med Ctr, Med 111A, 4150 Clement St, San Francisco, CA 94121 USA. RP Shen, H (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.; Shen, H (reprint author), San Francisco VA Med Ctr, Med 111A, 4150 Clement St, San Francisco, CA 94121 USA. EM Hui.Shen@ucsf.edu NR 9 TC 0 Z9 0 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 MAR PY 2017 VL 62 IS 3 BP 564 EP 566 DI 10.1007/s10620-016-4359-z PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL9YB UT WOS:000394974900002 PM 27943016 ER PT J AU Fuller, G Bolus, R Whitman, C Talley, J Erder, MH Joseph, A Silberg, DG Spiegel, B AF Fuller, Garth Bolus, Roger Whitman, Cynthia Talley, Jennifer Erder, M. Haim Joseph, Alain Silberg, Debra G. Spiegel, Brennan TI PRISM, a Patient-Reported Outcome Instrument, Accurately Measures Symptom Change in Refractory Gastroesophageal Reflux Disease SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Gastroesophageal reflux; Proton pump inhibitors; Patient-reported outcomes; Qualitative research; Psychometrics; Validation studies; US Food and Drug Administration ID INFORMATION-SYSTEM PROMIS; PUMP INHIBITOR THERAPY; PRIMARY-CARE; CLINICAL-TRIALS; QUESTIONNAIRE; RESPONDERS; PERSISTENT AB Most patients with gastroesophageal reflux disease (GERD) experience relief following treatment with proton pump inhibitors (PPIs) (Vakil et al. in Am J Gastroenterol 101:1900-1920, 2006; Everhart and Ruhl in Gastroenterology 136:376-386, 2009). As many as 17-44% of patients, however, exhibit only partial response to therapy. Most extant GERD patient-reported outcome (PRO) instruments fail to meet development best practices as described by the FDA (Talley and Wiklund in Qual Life Res 14:21-33, 2005; Van Pinxteren et al. in Cochrane Database Syst Rev 18:CD002095, 2004; El-Serag et al. in Aliment Pharmacol Ther 32:720-737, 2010). To develop and validate a PRO instrument for clinical trials involving patients with GERD who are PPI partial responders. We prepared a systematic literature review, held patient focus groups, convened an expert panel, and conducted cognitive interviews to establish content validity. Eligible participants took PPI therapy for at least 8 weeks, had undergone an upper endoscopy, and scored at least 8 points on the GerdQ [6]. Qualitative data guided development of 26 draft items. Items were reviewed by expert panels and debriefed with patients. The resulting 21-item instrument underwent psychometric evaluation during a Phase IIB trial. During the trial, confirmatory factor analysis (n = 220) resulted in a four-factor model displaying the highest goodness of fit. All domains had a high inter-item correlation (Cronbach's alpha > 0.8). Test-retest reliability and convergent validity were strong, with highly significant (p < 0.01) correlations between average weekly PRISM scores and severity anchors and significant (p < 0.05) correlations with anchor subscales. Cumulative distribution functions revealed significant differences between responders and non-responders. Analysis in a clinical trial setting demonstrated strong psychometric properties suggesting validity of PRISM. Developed in line with FDA guidance on PROs, PRISM represents an important new outcome measure for patients with GERD with a partial response to PPI therapy. C1 [Fuller, Garth; Bolus, Roger; Whitman, Cynthia; Talley, Jennifer; Spiegel, Brennan] CS CORE, 116 N Robertson Blvd Suite 400, Los Angeles, CA 90048 USA. [Bolus, Roger; Spiegel, Brennan] UCLA Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Erder, M. Haim; Silberg, Debra G.] MH Erder Hlth Econ Inc, Livingston, NJ USA. [Joseph, Alain] Shire, Zahlerweg 10, CH-6300 Zug, Switzerland. [Spiegel, Brennan] Cedars Sinai Med Ctr, Dept Med, Cedars Sinai Hlth Syst, Los Angeles, CA 90048 USA. [Spiegel, Brennan] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Bolus, Roger] 1016 Quail Gardens Ct, Encinitas, CA 92024 USA. [Whitman, Cynthia] 44 16th St, Hermosa Beach, CA 90254 USA. RP Spiegel, B (reprint author), CS CORE, 116 N Robertson Blvd Suite 400, Los Angeles, CA 90048 USA.; Spiegel, B (reprint author), UCLA Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA.; Spiegel, B (reprint author), Cedars Sinai Med Ctr, Dept Med, Cedars Sinai Hlth Syst, Los Angeles, CA 90048 USA.; Spiegel, B (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. EM garth.fuller@cshs.org; rbolus@netzero.net; cwhitman@psi.org; Jennifer.Soares@cshs.org; hmerder@gmail.com; ajoseph@shire.com; dsilberg@shire.com; brennan.spiegel@cshs.org FU Shire-Movetis NV FX Support for this study was provided by a research grant from Shire-Movetis NV. NR 23 TC 0 Z9 0 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 MAR PY 2017 VL 62 IS 3 BP 593 EP 606 DI 10.1007/s10620-016-4440-7 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL9YB UT WOS:000394974900008 PM 28116591 ER PT J AU Giordano, J Bikson, M Kappenman, ES Clark, VP Coslett, HB Hamblin, MR Hamilton, R Jankord, R Kozumbo, WJ McKinley, RA Nitsche, MA Reilly, JP Richardson, J Wurzman, R Calabrese, E AF Giordano, James Bikson, Marom Kappenman, Emily S. Clark, Vincent P. Coslett, H. Branch Hamblin, Michael R. Hamilton, Roy Jankord, Ryan Kozumbo, Walter J. McKinley, R. Andrew Nitsche, Michael A. Reilly, J. Patrick Richardson, Jessica Wurzman, Rachel Calabrese, Edward TI Mechanisms and Effects of Transcranial Direct Current Stimulation SO DOSE-RESPONSE LA English DT Article DE tDCS; hormesis; hormetic; dose-response; biphasic; electrical stimulation ID NONINVASIVE BRAIN-STIMULATION; HUMAN MOTOR CORTEX; DORSOLATERAL PREFRONTAL CORTEX; SPINAL-CORD-INJURY; ALTERNATING-CURRENT STIMULATION; HORMETIC DOSE RESPONSES; APPLIED ELECTRIC-FIELDS; INFRARED-LASER THERAPY; ACUTE STROKE TREATMENT; ACUTE ISCHEMIC-STROKE AB The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose-response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged. C1 [Giordano, James] Georgetown Univ, Med Ctr, Dept Neurol & Biochem, Neuroeth Studies Program,Pellegrino Ctr Clin Bioe, Washington, DC 20007 USA. [Bikson, Marom] CUNY City Coll, Biomed Engn, New York, NY 10031 USA. [Kappenman, Emily S.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Clark, Vincent P.] Univ New Mexico, Dept Psychol, Psychol Clin Neurosci Ctr, Albuquerque, NM 87131 USA. [Coslett, H. Branch; Hamilton, Roy; Wurzman, Rachel] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hamblin, Michael R.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Jankord, Ryan; McKinley, R. Andrew] US Air Force Res Lab, Wright Patterson AFB, OH USA. [Kozumbo, Walter J.] Univ Massachusetts, Hormesis Project, Amherst, MA 01003 USA. [Nitsche, Michael A.] Leibniz Res Ctr Working Environm & Human Factors, Dept Psychol & Neurosci, Dortmund, Germany. [Reilly, J. Patrick] Metatec Associates, Silver Spring, MD USA. [Richardson, Jessica] Univ New Mexico, Dept Speech & Hearing Sci, Albuquerque, NM 87131 USA. [Calabrese, Edward] Univ Massachusetts, Environm Hlth Sci, Amherst, MA 01003 USA. RP Calabrese, E (reprint author), Univ Massachusetts, Environm Hlth Sci, Amherst, MA 01003 USA. EM edwardc@schoolph.umass.edu FU United States Air Force; NIH [NIH-NIMH 1R01MH111896-01, NIH-NCI U54CA137788/U54CA132378, NIH-NINDA 1R01NS095123-01, NIH-NIMH 1R01MH109289-01]; DoD [FA8650-12-D-6280, FA9550-13-1-0073]; National Center for Advancing Translation Sciences (NCATS) [ULITR001409]; National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative; US NIH [R01A050875]; AFOSR; DARPA FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research activities of Calabrese and Kozumbo in the area of dose-response have been funded by the United States Air Force over several years. Bikson is supported by NIH (NIH-NIMH 1R01MH111896-01, NIH-NCI U54CA137788/U54CA132378, NIH-NINDA 1R01NS095123-01, NIH-NIMH 1R01MH109289-01) and the DoD (FA8650-12-D-6280, FA9550-13-1-0073). Giordano is funded, in part, by a grant from the National Center for Advancing Translation Sciences (NCATS, ULITR001409), National Institutes of Health, through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, "Re-Engineering the Clinical Research Enterprise.''Hamblin was funded by the US NIH grant R01A050875. McKinley has been funded by AFOSR and DARPA. NR 227 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 1559-3258 J9 DOSE-RESPONSE JI Dose-Response PD MAR PY 2017 VL 15 IS 1 DI 10.1177/1559325816685467 PG 22 WC Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging; Toxicology SC Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging; Toxicology GA EL5RL UT WOS:000394678400002 ER PT J AU Vergidis, P Ariza-Heredia, EJ Nellore, A Kotton, CN Kaul, DR Morris, MI Kelesidis, T Shah, H Park, SY Nguyen, MH Razonable, RR AF Vergidis, Pascalis Ariza-Heredia, Ella J. Nellore, Anoma Kotton, Camille N. Kaul, Daniel R. Morris, Michele I. Kelesidis, Theodoros Shah, Harshal Park, Seo Young Hong Nguyen, M. Razonable, Raymund R. TI Rhodococcus Infection in Solid Organ and Hematopoietic Stem Cell Transplant Recipients(1) SO EMERGING INFECTIOUS DISEASES LA English DT Article ID OF-THE-LITERATURE; EQUI INFECTION AB We conducted a case control study of 18 US transplant recipients with Rhodococcus infection and 36 matched controls. The predominant types of infection were pneumonia and bacteremia. Diabetes mellitus and recent opportunistic infection were independently associated with disease. Outcomes were penerally favorable except for 1 relapse and 1 death. C1 [Vergidis, Pascalis; Park, Seo Young; Hong Nguyen, M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Ariza-Heredia, Ella J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Nellore, Anoma] Univ Alabama Birmingham, Birmingham, AL USA. [Kotton, Camille N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kaul, Daniel R.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Morris, Michele I.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Kelesidis, Theodoros] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Shah, Harshal] Mayo Clin, Jacksonville, FL 32224 USA. [Razonable, Raymund R.] Mayo Clin, Rochester, MN USA. [Vergidis, Pascalis] Univ Manchester, Manchester, Lancs, England. RP Vergidis, P (reprint author), Univ Manchester, Manchester, Lancs, England.; Vergidis, P (reprint author), Univ Hosp South Manchester, Southmoor Rd, Manchester M23 9LT, Lancs, England. EM paschalis.vergidis@uhsm.nhs.uk FU National Center for Advancing Translational Sciences, National Institutes of Health [KL2TR000146] FX P.V. was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (grant KL2TR000146). NR 11 TC 0 Z9 0 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2017 VL 23 IS 3 BP 510 EP 512 DI 10.3201/eid2303.160633 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL7WB UT WOS:000394830900021 PM 28221102 ER PT J AU Everett, CJ Thompson, OM Dismuke, CE AF Everett, Charles J. Thompson, Olivia M. Dismuke, Clara E. TI Exposure to DDT and diabetic nephropathy among Mexican Americans in the 1999-2004 National Health and Nutrition Examination Survey SO ENVIRONMENTAL POLLUTION LA English DT Article DE DDT (dichlorodiphenyltrichloroethane); DDE (dichlorodiphenyldichloroethylene); Diabetes; Kidney disease ID CHRONIC KIDNEY-DISEASE; ORGANOCHLORINE PESTICIDES; BREAST-CANCER; ASSOCIATION; ACCULTURATION; POLYMORPHISM; PREVALENCE; HISPANICS; TRENDS; WOMEN AB Concentrations of the pesticide DDT (dichlorodiphenyltrichloroethane) and its metabolite DDE (dichlorodiphenyldichloroethylene), in the blood of Mexican Americans, were evaluated to determine their relationships with diabetes and diabetic nephropathy. The data were derived from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 (unweighted N = 1,411, population estimate = 13,760,609). The sample included teens, 12-19 years old, which accounted for 19.8% of the data. The time of the study overlapped the banning of DDT in Mexico in the year 2000, and those participants born in Mexico were exposed to DDT before they immigrated to the US. We sought to better understand the relationship of DDT with diabetes in a race/ethnicity group prone to develop diabetes and exposed to DDT. In this study, nephropathy was defined as urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria and macroalbuminuria, and total diabetes was defined as diagnosed and undiagnosed diabetes (glycohemoglobin, A1c >= 6.5%). The proportion with the isomer p,p'-DDT >0.086 ng/g (above the maximum limit of detection) was 13.3% for Mexican Americans born in the US, and 36.9% for those born in Mexico. Levels of p,p'-DDT >0.086 ng/g were associated with total diabetes with nephropathy (odds ratio = 4.42, 95% CI 2.23-8.76), and with total diabetes without nephropathy (odds ratio = 2.02, 95% CI 1.19-3.44). The third quartile of p,p'-DDE (2.99-7.67 ng/g) and the fourth quartile of p,p'-DDE (>= 7.68 ng/g) were associated with diabetic nephropathy and had odds ratios of 5.32 (95% CI 1.05-26.87) and 14.95 (95% CI 2.96-75.48) compared to less than the median, respectively, whereas p,p'-DDE was not associated with total diabetes without nephropathy. The findings of this study differ from those of a prior investigation of the general adult US population in that there were more associations found with the Mexican Americans sample. Published by Elsevier Ltd. C1 [Everett, Charles J.; Dismuke, Clara E.] US Dept Vet Affairs, Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Thompson, Olivia M.] Coll Charleston, Mayor Joseph P Riley Inst Livable Commun, Charleston, SC USA. [Everett, Charles J.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Everett, Charles J.; Dismuke, Clara E.] Ralph H Johnson VA Med Ctr, 109 Bee St,Mail Code 151, Charleston, SC 29401 USA. RP Everett, CJ; Thompson, OM; Dismuke, CE (reprint author), Ralph H Johnson VA Med Ctr, 109 Bee St,Mail Code 151, Charleston, SC 29401 USA. EM Charles.Everett@va.gov; thompsonom@cofc.edu; Clara.Dismuke@va.gov NR 30 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 0269-7491 EI 1873-6424 J9 ENVIRON POLLUT JI Environ. Pollut. PD MAR PY 2017 VL 222 BP 132 EP 137 DI 10.1016/j.envPol.2016.12.069 PG 6 WC Environmental Sciences SC Environmental Sciences & Ecology GA EM5OJ UT WOS:000395360900016 PM 28065571 ER PT J AU Shields, AE AF Shields, Alexandra E. TI Epigenetic signals of how social disadvantage "gets under the skin": a challenge to the public health community SO EPIGENOMICS LA English DT Editorial Material DE cohort studies; disparities; epigenetics; HPA axis; maternal health; methylation; psychosocial stress; resilience ID GLUCOCORTICOID-RECEPTOR GENE; RANDOMIZED CONTROLLED-TRIAL; POSTTRAUMATIC-STRESS-DISORDER; DNA METHYLATION; BREAST-CANCER; PRENATAL STRESS; BLOOD-PRESSURE; BIRTH-WEIGHT; EXPOSURE; DISEASE C1 [Shields, Alexandra E.] Massachusetts Gen Hosp, Harvard MGH Ctr Gen, Dept Med, Vulnerable Populat & Hlth Dispar, 50 Staniford St,Suite 901, Boston, MA 02114 USA. [Shields, Alexandra E.] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. [Shields, Alexandra E.] Massachusetts Gen Hosp, Natl Consortium Psychosocial Stress Spiritual & H, 50 Staniford St,Suite 901, Boston, MA 02114 USA. [Shields, Alexandra E.] Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA. RP Shields, AE (reprint author), Massachusetts Gen Hosp, Harvard MGH Ctr Gen, Dept Med, Vulnerable Populat & Hlth Dispar, 50 Staniford St,Suite 901, Boston, MA 02114 USA.; Shields, AE (reprint author), Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA.; Shields, AE (reprint author), Massachusetts Gen Hosp, Natl Consortium Psychosocial Stress Spiritual & H, 50 Staniford St,Suite 901, Boston, MA 02114 USA.; Shields, AE (reprint author), Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA. EM ashields1@partners.org FU John Templeton Foundation [48424] FX This work was financially supported by The John Templeton Foundation (grant #48424). The author has 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 61 TC 1 Z9 1 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 1750-1911 EI 1750-192X J9 EPIGENOMICS-UK JI Epigenomics PD MAR PY 2017 VL 9 IS 3 SI SI BP 223 EP 229 DI 10.2217/epi-2017-0013 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EN1ZC UT WOS:000395808100004 PM 28234017 ER PT J AU Kosova, EC Bonaca, MP Dellborg, M He, P Morais, J Oude Ophuis, T Scirica, BM Tendera, M Theroux, P Braunwald, E Morrow, DA AF Kosova, Ethan C. Bonaca, Marc P. Dellborg, Mikael He, Ping Morais, Joao Oude Ophuis, Ton Scirica, Benjamin M. Tendera, Michal Theroux, Pierre Braunwald, Eugene Morrow, David A. TI Vorapaxar in patients with coronary artery bypass grafting: Findings from the TRA 2 degrees P-TIMI 50 trial SO EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE LA English DT Article DE Vorapaxar; CABG; atherothrombosis; antiplatelet; bleeding ID ASPIRIN PLUS CLOPIDOGREL; SECONDARY PREVENTION; CARDIOPULMONARY BYPASS; PLATELET INHIBITION; HEART-ASSOCIATION; SURGERY; THROMBIN; DISEASE; EVENTS; OUTCOMES AB Background: Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for the reduction of cardiovascular death, myocardial infarction, and stroke in stable patients with prior atherothrombosis, who have not had a prior stroke or transient ischemic attack. The aims of this study were to investigate: 1) the role of vorapaxar in patients with severe coronary artery disease treated previously with coronary artery bypass grafting (CABG); and 2) safety in patients undergoing CABG while receiving vorapaxar. Methods: TRA 2 degrees P-TIMI 50 was a randomized, double-blinded, placebo-controlled trial of vorapaxar in 26,449 stable patients with prior atherothrombosis followed for a median of 30 months. We 1) investigated the efficacy of vorapaxar among patients with a history of CABG prior to randomization (n=2942); and 2) assessed the safety among 367 patients who underwent a new CABG during the trial. Results: Patients with a prior CABG were at higher risk for cardiovascular death, myocardial infarction, or stroke at three years compared with patients without a prior CABG (13.7% vs. 7.8%, p<0.001). Among patients with a prior CABG, vorapaxar significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke (11.9% vs. 15.6%, hazard ratio 0.71, 95% confidence interval 0.58-0.88, p=0.001; number-needed-to-treat = 27). In patients undergoing CABG while receiving vorapaxar, the rate of Thrombolysis in Myocardial Infarction CABG major bleeding was 6.3% vs. 4.1% with placebo (hazard ratio 1.53, 95% confidence interval 0.58-4.01, p=0.39). Conclusions: In patients with a prior CABG, vorapaxar significantly reduced the risk of recurrent major cardiovascular events. In patients undergoing CABG while receiving vorapaxar, bleeding risk appeared similar to that seen in the overall trial population. C1 [Kosova, Ethan C.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Bonaca, Marc P.; He, Ping; Scirica, Benjamin M.; Braunwald, Eugene; Morrow, David A.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Dellborg, Mikael] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. [Dellborg, Mikael] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Morais, Joao] Santo Andres Hosp, Leiria, Portugal. [Oude Ophuis, Ton] Canisius Willhelmina Hosp, Nijmegen, Netherlands. [Tendera, Michal] Med Univ Silesia, Div Cardiol 3, Katowice, Poland. [Theroux, Pierre] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. RP Morrow, DA (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org FU Merck Co. FX This work was supported by Merck & Co. NR 26 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 2048-8726 EI 2048-8734 J9 EUR HEART J-ACUTE CA JI Eur. Heart J.-Acute Cardiovasc. Care PD MAR PY 2017 VL 6 IS 2 BP 164 EP 172 DI 10.1177/2048872616644910 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP6PZ UT WOS:000397502700008 PM 27075924 ER PT J AU Chen, KT Izquierdo-Garcia, D Poynton, CB Chonde, DB Catana, C AF Chen, Kevin T. Izquierdo-Garcia, David Poynton, Clare B. Chonde, Daniel B. Catana, Ciprian TI On the accuracy and reproducibility of a novel probabilistic atlas-based generation for calculation of head attenuation maps on integrated PET/MR scanners SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Attenuation correction; Reproducibility; PET/MR; Probabilistic atlas ID ULTRASHORT ECHO TIME; CT IMAGES; BRAIN; SEGMENTATION; REGISTRATION; CLASSIFICATION; RECONSTRUCTION; OPTIMIZATION; COEFFICIENTS; ALGORITHM AB Purpose To propose an MR-based method for generating continuous-valued head attenuation maps and to assess its accuracy and reproducibility. Demonstrating that novel MR-based photon attenuation correction methods are both accurate and reproducible is essential prior to using them routinely in research and clinical studies on integrated PET/MR scanners. Methods Continuous-valued linear attenuation coefficient maps ("mu-maps") were generated by combining atlases that provided the prior probability of voxel positions belonging to a certain tissue class (air, soft tissue, or bone) and an MR intensity-based likelihood classifier to produce posterior probability maps of tissue classes. These probabilities were used as weights to generate the mu-maps. The accuracy of this probabilistic atlas-based continuous-valued mu-map ("PAC-map") generation method was assessed by calculating the voxel-wise absolute relative change (RC) between the MR-based and scaled CT-based attenuation-corrected PET images. To assess reproducibility, we performed pair-wise comparisons of the RC values obtained from the PET images reconstructed using the mu-maps generated from the data acquired at three time points. Results The proposed method produced continuous-valued mu-maps that qualitatively reflected the variable anatomy in patients with brain tumor and agreed well with the scaled CT-based mu-maps. The absolute RC comparing the resulting PET volumes was 1.76 +/- 2.33 %, quantitatively demonstrating that the method is accurate. Additionally, we also showed that the method is highly reproducible, the mean RC value for the PET images reconstructed using the mu-maps obtained at the three visits being 0.65 +/- 0.95 %. Conclusion Accurate and highly reproducible continuous valued head mu-maps can be generated from MR data using a probabilistic atlas-based approach. C1 [Chen, Kevin T.; Izquierdo-Garcia, David; Poynton, Clare B.; Chonde, Daniel B.; Catana, Ciprian] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Chen, Kevin T.; Izquierdo-Garcia, David; Poynton, Clare B.; Chonde, Daniel B.; Catana, Ciprian] Harvard Med Sch, Charlestown, MA 02129 USA. [Chen, Kevin T.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Poynton, Clare B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Poynton, Clare B.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Chonde, Daniel B.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. RP Catana, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Catana, C (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM ccatana@nmr.mgh.harvard.edu FU NIH [1R01EB014894-01A1]; U.S. Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program FX This work was funded by NIH grant 1R01EB014894-01A1 and by the U.S. Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program. NR 34 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD MAR PY 2017 VL 44 IS 3 BP 398 EP 407 DI 10.1007/s00259-016-3489-z PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM0BZ UT WOS:000394985100007 PM 27573639 ER PT J AU Winkelman, WD Huang, AJ Schembri, M Rogers, RG Richter, H Myers, DL Kraus, SR Johnson, KC Hess, R Gregory, T Bradley, CS Arya, L Brown, JS Subak, LL AF Winkelman, William D. Huang, Alison J. Schembri, Michael Rogers, Rebecca G. Richter, Holly Myers, Deborah L. Kraus, Stephen R. Johnson, Karen C. Hess, Rachel Gregory, Tomas Bradley, Catherine S. Arya, Lily Brown, Janette S. Subak, Leslee L. TI Modifiers of Response to Treatment With Fesoterodine for Urgency-Predominant Urinary Incontinence in a Randomized Controlled Trial SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article; Proceedings Paper CT Annual Scientific Meeting of the American-Urogynecologic-Society (AUGS) CY SEP 27-OCT 01, 2016 CL Denver, CO SP Amer Urogynecol Soc DE fesoterodine; predictors of treatment response; urgency urinary incontinence ID OVERACTIVE BLADDER; TOLERABILITY; EFFICACY; PLACEBO; SAFETY; PHARMACOKINETICS; TOLTERODINE; SOLIFENACIN; PREVALENCE; VALIDATION AB Objective: The aim of this studywas to identify clinical and demographic characteristics that moderate response to treatment with fesoterodine among women with a diagnosis of urgency-predominant urinary incontinence. Methods: A multicenter, double-blinded, 12-week randomized controlled trial of pharmacologic therapy for urgency-predominant urinary incontinence in community-dwelling women diagnosed by the 3-item Incontinence Questionnaire (3IQ) was previously performed. Participants (N = 645) were randomized to fesoterodine therapy (4-8 mg daily; n = 322) or placebo (n = 323). Urinary incontinence was assessed by 3-day voiding diaries. In this secondary analysis, a "responder" was defined as reduction of 50% or greater in overall incontinence episode frequency compared with baseline. Clinical and demographic characteristics that may moderate treatment response were assessed by testing for interaction between characteristics and intervention in logit models of responders, adjusting for clinical site. Results: Participants' ages were a mean of 56 (SD, 14) years, 68% were white race, and they had a mean of 3.9 (SD, 3.0) urgency incontinence episodes per day. There were no baseline differences in demographic, clinical, or incontinence characteristics between treatment and placebo groups or between responders and nonresponders. There was an increase in the proportion of responders to fesoterodine with increasing age (P = 0.04) and parity (0.04) and among married women (P = 0.03), but no effect modification was observed by race/ethnicity, body mass index, education, employment status, or alcohol or tobacco use. Conclusions: In ambulatory women with urgency-predominant urinary incontinence, older age, being married, and higher parity significantly moderated and potentiated the effects of pharmacologic therapy on incontinence frequency. This study identifies certain populations who may have increased responsiveness to treatment with antimuscarinic therapy andmay be used to inform and guide future therapy. C1 [Winkelman, William D.; Huang, Alison J.; Schembri, Michael; Brown, Janette S.; Subak, Leslee L.] Univ Calif San Francisco, Irene Betty Moore Womens Hosp, Dept Obstet Gynecol & Reprod Med, San Francisco, CA 94143 USA. [Rogers, Rebecca G.] Univ New Mexico, Albuquerque, NM 87131 USA. [Richter, Holly] Univ Alabama Birmingham, Birmingham, AL USA. [Myers, Deborah L.] Brown Univ, Providence, RI 02912 USA. [Kraus, Stephen R.] UT Hlth Sci Ctr, San Antonio, TX USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Hess, Rachel] Univ Utah, Salt Lake City, UT USA. [Gregory, Tomas] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bradley, Catherine S.] Univ Iowa, Iowa City, IA USA. [Arya, Lily] Univ Penn, Philadelphia, PA 19104 USA. [Subak, Leslee L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Subak, LL (reprint author), UCSF Womens Hlth Clin Res Ctr, 550 16th St,6th Floor, San Francisco, CA 94143 USA. EM Leslee.Subak@ucsf.edu FU Pfizer, Inc; NIDDK [K24 DK080775]; Astellas, Inc.; US National Institutes of Health [RR024130, 1K23AG038335-01A1, 2K24DK080775-06]; Astellas FX L.L.S., J.S.B., and A.J.H. have received a University of California San Francisco research grant from Pfizer, Inc, to conduct research related to urinary incontinence. Pfizer, Inc, provided funding for the study and the study medication but did not provide other input into the design of the study; collection, analysis, or interpretation of data; writing of the report; or the decision to submit the paper for publication. L.L.S. is additionally supported by NIDDK K24 DK080775. L.L.S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. No manuscript preparation assistance was provided by the study funders. L.L.S. and A.J.H. receive investigator-initiated trial funding from Astellas, Inc. A.J.H. was additionally supported by grants RR024130 and 1K23AG038335-01A1 and L.L.S. from 2K24DK080775-06 from the US National Institutes of Health; however, the views expressed in this article do not necessarily represent those of the National Institutes of Health. L. A. has received a research grant from Pfizer, Inc. H.R. has received a research grant and participated in a speaker's bureau for Pfizer, Inc; received a research grant and participated in an advisory board for Astellas; and served as a consultant for Uromedica and GlaxoSmithKline. S.R.K. has served as a consultant for Pfizer, Inc, and Allergan and has been a course director and teaching faculty member for Laborie. The other authors declare that they have nothing to disclose. NR 21 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 2151-8378 EI 2154-4212 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD MAR-APR PY 2017 VL 23 IS 2 BP 151 EP 156 DI 10.1097/SPV.0000000000000396 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EM8RX UT WOS:000395579800017 PM 28118174 ER PT J AU Papavasileiou, E Davoudi, S Roohipoor, R Cho, H Kudrimoti, S Hancock, H Wilson, JG Andreoli, C Husain, D James, M Penman, A Chen, CJ Sobrin, L AF Papavasileiou, Evangelia Davoudi, Samaneh Roohipoor, Ramak Cho, Heeyoon Kudrimoti, Shreyas Hancock, Heather Wilson, James G. Andreoli, Christopher Husain, Deeba James, Maurice Penman, Alan Chen, Ching J. Sobrin, Lucia TI Association of serum lipid levels with retinal hard exudate area in African Americans with type 2 diabetes SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Hard exudate area; Serum lipid levels; Type 2 diabetes; African Americans ID OPTICAL COHERENCE TOMOGRAPHY; MACULAR EDEMA; RISK-FACTORS; UNITED-STATES; RETINOPATHY; AGREEMENT; CHOLESTEROL; POPULATION; MANAGEMENT; PEOPLE AB Previous studies have yielded conflicting results regarding whether serum lipid levels are associated with retinal hard exudates in diabetic retinopathy. The majority of studies have assessed hard exudates only as a dichotomous trait (presence vs. absence) and included limited numbers of African Americans (AA). The purpose of this study was to determine if there are any associations between serum lipid levels and hard exudates in AA with type 2 diabetes (T2D). 890 AA participants with T2D were enrolled from 5 sites. Macular fundus photographs were graded by masked ophthalmologist investigators. Hard exudate areas were measured using a semi-automated algorithm and ImageJ software. Multivariate regression models were used to determine the association between serum lipid levels and (1) presence of hard exudate and (2) area of hard exudate. Presence of hard exudates was associated with higher total cholesterol [(odds ratio (OR) = 1.08, 95 % confidence interval (CI) 1.03-1.13, P = 0.001)] and higher low-density lipoprotein (LDL) cholesterol (OR = 1.08, 95 % CI 1.03-1.14, P = 0.005) in models controlling for other risk factors. Hard exudate area was also associated with both higher total and LDL cholesterol levels (P = 0.04 and 0.01, respectively) in multivariate models controlling for other risk factors. Higher total and LDL cholesterol were associated with the presence of hard exudates and a greater hard exudate area in AA with T2D. This information can be used to counsel diabetic patients regarding the importance of lipid control to decrease the risk of macular hard exudates. C1 [Papavasileiou, Evangelia; Davoudi, Samaneh; Roohipoor, Ramak; Cho, Heeyoon; Kudrimoti, Shreyas; Husain, Deeba; Sobrin, Lucia] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. [Roohipoor, Ramak] Univ Tehran Med Sci, Farabi Eye Hosp, Dept Ophthalmol, Eye Res Ctr, Tehran, Iran. [Cho, Heeyoon] Hanyang Univ, Dept Ophthalmol, Coll Med, Seoul, South Korea. [Hancock, Heather; Chen, Ching J.] Univ Mississippi, Med Ctr, Dept Ophthalmol, Jackson, MS 39216 USA. [Wilson, James G.; Penman, Alan] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Andreoli, Christopher] Harvard Vanguard Med Associates, Visual Serv Dept, Boston, MA USA. [James, Maurice] St Dominics Hosp, Ophthalmol, Jackson, MS USA. [Penman, Alan] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. RP Sobrin, L (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Lucia_sobrin@meei.harvard.edu FU American Diabetes Association Clinical Translational Research Award, Alexandria, VA [1-11-CT-51]; Research to Prevent Blindness Career Development Award, New York City, NY; Harvard Catalyst \ The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; Sara Elizabeth O'Brien Trust, Boston, MA; Research to Prevent Blindness William & Mary Greve Special Scholar Award; Alcon Research Institute Young Investigator Award FX This study was supported by the following grants: American Diabetes Association Clinical Translational Research Award 1-11-CT-51, Alexandria, VA. Research to Prevent Blindness Career Development Award, New York City, NY; Harvard Catalyst vertical bar The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; Sara Elizabeth O'Brien Trust, Boston, MA; Research to Prevent Blindness William & Mary Greve Special Scholar Award; Alcon Research Institute Young Investigator Award. The sponsors had no role in the design or conduct of this research. NR 37 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X EI 1435-702X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD MAR PY 2017 VL 255 IS 3 BP 509 EP 517 DI 10.1007/s00417-016-3493-9 PG 9 WC Ophthalmology SC Ophthalmology GA EM0CO UT WOS:000394986600009 PM 27632216 ER PT J AU Walsh, CE Workowski, K Terrault, NA Sax, PE Cohen, A Bowlus, CL Kim, AY Hyland, RH Han, B Wang, J Stamm, LM Brainard, DM McHutchison, JG von Drygalski, A Rhame, F Fried, MW Kouides, P Balba, G Reddy, KR AF Walsh, C. E. Workowski, K. Terrault, N. A. Sax, P. E. Cohen, A. Bowlus, C. L. Kim, A. Y. Hyland, R. H. Han, B. Wang, J. Stamm, L. M. Brainard, D. M. McHutchison, J. G. von Drygalski, A. Rhame, F. Fried, M. W. Kouides, P. Balba, G. Reddy, K. R. TI Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders SO HAEMOPHILIA LA English DT Article DE hepatitis C virus; ledipasvir-sofosbuvir fixed-dose combination; NS5A inhibitor; NS5B inhibitor; ribavirin; sofosbuvir ID HUMAN-IMMUNODEFICIENCY-VIRUS; STAGE LIVER-DISEASE; GENOTYPE 1 INFECTION; NATURAL-HISTORY; HEMOPHILIC PATIENTS; ITALIAN PATIENTS; HIV-INFECTION; UNITED-STATES; CHRONIC HCV; FOLLOW-UP AB Introduction: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. Aim: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. Methods: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. Results: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. Conclusion: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders. C1 [Walsh, C. E.] Mt Sinai Hosp, Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Workowski, K.] Emory Univ, Atlanta, GA 30322 USA. [Terrault, N. A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sax, P. E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sax, P. E.] Harvard Med Sch, Boston, MA USA. [Cohen, A.] Newark Beth Israel Med Ctr Barnabas Hlth, Newark, NJ USA. [Bowlus, C. L.] Univ Calif Davis, Davis, CA 95616 USA. [Kim, A. Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hyland, R. H.; Han, B.; Wang, J.; Stamm, L. M.; Brainard, D. M.; McHutchison, J. G.] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [von Drygalski, A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Rhame, F.] Abbott NW Hosp, Minneapolis, MN USA. [Fried, M. W.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Kouides, P.] Mary M Gooley Hemophilia Ctr, Rochester, NY USA. [Balba, G.] MedStar Georgetown Univ Hosp, Washington, DC USA. [Reddy, K. R.] Univ Penn, Philadelphia, PA 19104 USA. RP Walsh, CE (reprint author), Mt Sinai Sch Med, New York, NY 10029 USA. EM christopher.walsh@mountsinai.org FU Gilead Sciences, Inc. FX The authors extend their thanks to the patients who participated in this study, as well as their families, and to the staff at the Hemophilia Treatment Centers who supported this study. Christopher E. Walsh, Robert H. Hyland, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison and K. Rajender Reddy contributed to the design of the study. Christopher E. Walsh, Kimberly Workowski, Norah A. Terrault, Paul E. Sax, Alice Cohen, Christopher L. Bowlus, Arthur Y. Kim, Annette von Drygalski, Frank Rhame, Michael W. Fried, Peter Kouides, Gayle Balba and K. Rajender Reddy contributed to data collection. Jing Wang and Bin Han contributed to data analysis. All authors reviewed and approved the manuscript prior to submission. Writing and editorial support was provided by Sameera Kongara of AlphaBioCom, LLC, King of Prussia, PA, and funded by Gilead Sciences, Inc. This study was funded by Gilead Sciences, Inc. NR 40 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2017 VL 23 IS 2 BP 198 EP 206 DI 10.1111/hae.13178 PG 9 WC Hematology SC Hematology GA EP5GC UT WOS:000397406000005 PM 28124511 ER PT J AU Shi, CR Kandola, MS Tobey, M AF Shi, Connie R. Kandola, Manjinder S. Tobey, Matthew TI Managing Opioid Withdrawal for Hospital Patients in Custody SO HASTINGS CENTER REPORT LA English DT Article AB Dr. Brown, a hospitalist, admits Mark, a patient transferred from a local jail for management of cellulitis. The patient, who was taken into custody two days prior to hospital admission, has a history of intravenous heroin use. Mark explains that he had been prescribed buprenorphine-naloxone maintenance therapy for opioid use disorder for several years prior to being arrested and had not used other opioids during that time. As a policy, the jail where Mark is detained does not prescribe opioid agonists, and his maintenance therapy was stopped upon his arrival there.Dr. Brown discovers that Mark is diaphoretic and appears distressed. Mark's symptoms suggest to Dr. Brown that, in addition to having cellulitis, Mark is actively withdrawing from opioids. Mark tells Dr. Brown that he has felt horrible since his buprenorphine-naloxone therapy was stopped and that he now has intense cravings for opioids. He asks Dr. Brown to help alleviate the withdrawal symptoms. Dr. Brown, who is accustomed to treating opioid withdrawal with opioid replacement therapy, wonders if she should initiate ORT for Mark while he is in the hospital. C1 [Shi, Connie R.; Kandola, Manjinder S.; Tobey, Matthew] Harvard Med Sch, Boston, MA 02215 USA. [Tobey, Matthew] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Shi, CR (reprint author), Harvard Med Sch, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2017 VL 47 IS 2 BP 9 EP 10 DI 10.1002/hast.683 PG 2 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA EP5YO UT WOS:000397455200005 PM 28301697 ER PT J AU Matsue, Y van der Meer, P Damman, K Metra, M O'Connor, CM Ponikowski, P Teerlink, JR Cotter, G Davison, B Cleland, JG Givertz, MM Bloomfield, DM Dittrich, HC Gansevoort, RT Bakker, SJL van der Harst, P Hillege, HL van Veldhuisen, DJ Voors, AA AF Matsue, Yuya van der Meer, Peter Damman, Kevin Metra, Marco O'Connor, Christopher M. Ponikowski, Piotr Teerlink, John R. Cotter, Gad Davison, Beth Cleland, John G. Givertz, Michael M. Bloomfield, Daniel M. Dittrich, Howard C. Gansevoort, Ron T. Bakker, Stephan J. L. van der Harst, Pim Hillege, Hans L. van Veldhuisen, Dirk J. Voors, Adriaan A. TI Blood urea nitrogen-to-creatinine ratio in the general population and in patients with acute heart failure SO HEART LA English DT Article ID MUSCLE PROTEIN-SYNTHESIS; RECEPTOR ANTAGONIST ROLOFYLLINE; RENAL-FUNCTION; NITROGEN/CREATININE RATIO; POSTABSORPTIVE STATE; VOLUME OVERLOAD; MORTALITY; DYSFUNCTION; WOMEN; RISK AB Objective The blood urea nitrogen-to-creatinine (BUN/creatinine) ratio has been proposed as a useful parameter in acute heart failure (AHF), but data on the normal range and the added value of the ratio compared with its separate components in patients with AHF are lacking. The aim of this study is to define the normal range of BUN/creatinine ratio and to investigate its clinical significance in patients with AHF. Methods In 4484 subjects from the general population without cardiovascular comorbidities, we calculated agespecific and sex-specific normal values of the BUN/creatinine ratio, deriving a higher and lower than normal range of BUN/creatinine ratio (exceeding the 95% prediction intervals). Association of abnormal range to prognosis was tested in 2033 patients with AHF for the outcome of all-cause death through 180 days, death or cardiovascular or renal rehospitalisation through 60 days and heart failure (HF) rehospitalisation within 60 days. Results In a cohort of patients with AHF, 482 (24.6%) and 28 (1.4%) patients with HF were classified into higher and lower than normal range groups, respectively. In Cox regression analysis, higher than normal range of BUN/creatinine ratio group was an independent predictor for all-cause death (HR: 1.86, 95% CI 1.29 to 2.66) and death or cardiovascular or renal rehospitalisation (HR: 1.37, 95% CI 1.03 to 1.82), but not for HF rehospitalisation (HR: 1.23, 95% CI 0.81 to 1.86) after adjustment for other prognostic factors including both creatinine and BUN. Conclusions In patients with AHF, BUN/creatinine higher than age-specific and sex-specific normal range is associated with worse prognosis independently from both creatinine and BUN. C1 [Matsue, Yuya; van der Meer, Peter; Damman, Kevin; van der Harst, Pim; Hillege, Hans L.; van Veldhuisen, Dirk J.; Voors, Adriaan A.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Metra, Marco] Univ Brescia, Dept Expt & Clin Med, Brescia, Italy. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. [Teerlink, John R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Cotter, Gad; Davison, Beth] Momentum Res, Durham, NC USA. [Cleland, John G.] Imperial Coll, Royal Brompton Hosp, Natl Heart & Lung Inst, London, England. [Cleland, John G.] Imperial Coll, Harefield Hosp, London, England. [Givertz, Michael M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bloomfield, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Dittrich, Howard C.] Univ Iowa, Carver Coll Med, Cardiovasc Res Ctr, Iowa City, IA USA. [Gansevoort, Ron T.; Bakker, Stephan J. L.] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Bakker, Stephan J. L.] Top Inst Food & Nutr, Wageningen, Netherlands. [Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. RP Voors, AA (reprint author), Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM a.a.voors@umcg.nl FU NovaCardia; Merck FX The PROTECT trial was supported by NovaCardia, a subsidiary of Merck. Alere, Singulex and Sphingotec kindly provided assays and performed biomarker measurements. NR 30 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 MAR PY 2017 VL 103 IS 6 DI 10.1136/heartjnl-2016-310112 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN0AI UT WOS:000395672300004 ER PT J AU Idrees, MT Ulbright, TM Oliva, E Young, RH Montironi, R Egevad, L Berney, D Srigley, JR Epstein, JI Tickoo, SK AF Idrees, Muhammad T. Ulbright, Thomas M. Oliva, Esther Young, Robert H. Montironi, Rodolfo Egevad, Lars Berney, Daniel Srigley, John R. Epstein, Jonathan I. Tickoo, Satish K. CA Int Soc Urological Pathology TI The World Health Organization 2016 classification of testicular non-germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel SO HISTOPATHOLOGY LA English DT Review DE ISUP; non-germ cell tumours; testicular tumours; World Health Organization 2016 Classification ID CORD-STROMAL TUMORS; CONGENITAL ADRENAL-HYPERPLASIA; JUVENILE GRANULOSA-CELL; PEUTZ-JEGHERS-SYNDROME; CLINICOPATHOLOGICAL ANALYSIS; ADRENOGENITAL SYNDROME; NUCLEAR-LOCALIZATION; PROGNOSTIC-FACTORS; HODGKINS-LYMPHOMA; BETA-CATENIN AB The World Health Organization (WHO) released a new tumour classification for the genitourinary system in early 2016 after consensus by pathologists with expertise in these organs. It utilized the framework of the 2004 classification, and incorporated the most up-to-date information concerning these tumours. In testicular tumours, the majority of the changes occurred in the nomenclature and classification of germ cell tumours; however, several modifications were also made for non-germ cell tumours. Among sex cord-stromal tumours, sclerosing Sertoli cell tumour (SCT) is no longer recognized as a separate entity but as a morphological variant of SCT not otherwise specified (NOS), as CTNNB1 gene mutations have been noted in both neoplasms but not in the other forms of SCT. Similarly, the lipid cell variant is not separately classified, but is considered to be a morphological variant of SCT NOS. Large-cell calcifying SCT is recognized as a distinct entity that occurs either sporadically or in association with Carney complex, with the latter patients having a distinct germline PRKAR1A gene mutation. Intratubular large-cell hyalinizing Sertoli cell neoplasia is also accepted as a separate entity linked with Peutz-Jeghers syndrome. The subcategories of "mixed' and "incompletely differentiated' forms of sex cord/gonadal stromal tumours have been replaced by "mixed and unclassified sex cord-stromal tumours'. New entities introduced in the latest WHO revision include: myoid gonadal stromal tumour and "undifferentiated gonadal tissue', a putative precursor lesion of gonadoblastoma, whereas juvenile xanthogranuloma and haemangioma are included in the miscellaneous category of tumours. C1 [Idrees, Muhammad T.; Ulbright, Thomas M.] Indiana Univ, Dept Pathol & Lab Med, Indianapolis, IN 46204 USA. [Oliva, Esther; Young, Robert H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Montironi, Rodolfo] Univ Politecn Marche, Dept Pathol, Ancona, Italy. [Egevad, Lars] Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden. [Berney, Daniel] Queen Mary Univ London, Barts Canc Inst, Dept Mol Oncol, London, England. [Srigley, John R.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Epstein, Jonathan I.] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. [Tickoo, Satish K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. RP Idrees, MT (reprint author), Indiana Univ Sch Med, Dept Pathol, 350 West,11th St, Indianapolis, IN 46202 USA. EM midrees@iupui.edu FU Orchid FX The ISUP conference was generously supported by Orchid. NR 75 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD MAR PY 2017 VL 70 IS 4 BP 513 EP 521 DI 10.1111/his.13115 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA EM0DD UT WOS:000394988100001 PM 27801954 ER PT J AU Noto, MJ Becker, KW Boyd, KL Schmidt, AM Skaar, EP AF Noto, Michael J. Becker, Kyle W. Boyd, Kelli L. Schmidt, Ann Marie Skaar, Eric P. TI RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis SO INFECTION AND IMMUNITY LA English DT Article DE Acinetobacter baumannii; IL-10; innate immunity; pneumonia; RAGE; receptor for advanced glycation end products; sepsis ID GLYCATION END-PRODUCTS; FACTOR-KAPPA-B; PNEUMOCOCCAL PNEUMONIA; IMMUNE-RESPONSE; SEPTIC SHOCK; RECEPTOR; ACTIVATION; INFECTION; PATHOGENESIS; MICE AB The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and dangerassociated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. Acinetobacter baumannii is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of A. baumannii pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE(-/-) mice systemically infected with A. baumannii exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE(-/-) mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE(-/-) mice results in decreased survival during systemic A. baumannii infection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis. C1 [Noto, Michael J.] Vanderbilt Univ, Ctr Med, Div Allergy Pulm & Crit Care Med, Dept Med, Nashville, TN 37232 USA. [Becker, Kyle W.; Boyd, Kelli L.; Skaar, Eric P.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Schmidt, Ann Marie] NYU, Langone Med Ctr, New York, NY USA. [Skaar, Eric P.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN USA. RP Skaar, EP (reprint author), Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA.; Skaar, EP (reprint author), US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN USA. EM eric.skaar@vanderbilt.edu FU Department of Veterans Affairs Merit Award [INFB024-13F]; Cystic Fibrosis Foundation [NOTO15D0]; National Institutes of Health [2T32HL087738-06]; [5RO1AI101171] FX We thank members of the Skaar laboratory for review of the manuscript. This research was supported by Department of Veterans Affairs Merit Award INFB024-13F and grant 5RO1AI101171 to E.P.S. and Cystic Fibrosis Foundation award NOTO15D0 and National Institutes of Health grant 2T32HL087738-06 to M.J.N.E.P.S. is a Burroughs Wellcome Fellow in the Pathogenesis of Infectious Diseases. We declare that we have no conflicts of interest. NR 50 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2017 VL 85 IS 3 AR e00954-16 DI 10.1128/IAI.00954-16 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4SU UT WOS:000394612000016 ER PT J AU Reedy, JL Negoro, PE Feliu, M Lord, AK Khan, NS Lukason, DP Wiederhold, NP Tam, JM Mansour, MK Patterson, TF Vyas, JM AF Reedy, Jennifer L. Negoro, Paige E. Feliu, Marianela Lord, Allison K. Khan, Nida S. Lukason, Dan P. Wiederhold, Nathan P. Tam, Jenny M. Mansour, Michael K. Patterson, Thomas F. Vyas, Jatin M. TI The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum SO INFECTION AND IMMUNITY LA English DT Article DE Dectin-1; Exserohilum; fungi; macrophages; molds ID BETA-GLUCAN RECEPTOR; TOLL-LIKE RECEPTORS; ASPERGILLUS-FUMIGATUS CONIDIA; SURVEILLANCE NETWORK TRANSNET; INVASIVE FUNGAL-INFECTIONS; CANDIDA-ALBICANS; SACCHAROMYCES-CEREVISIAE; CRYPTOCOCCUS-NEOFORMANS; CELL-WALL; INFLAMMATORY RESPONSES AB Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen. C1 [Reedy, Jennifer L.; Negoro, Paige E.; Feliu, Marianela; Lord, Allison K.; Khan, Nida S.; Lukason, Dan P.; Tam, Jenny M.; Mansour, Michael K.; Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Reedy, Jennifer L.; Mansour, Michael K.; Vyas, Jatin M.] Harvard Med Sch, Dept Med, Boston, MA USA. [Wiederhold, Nathan P.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Wiederhold, Nathan P.; Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Vyas, JM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA.; Vyas, JM (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. EM jvyas@mgh.harvard.edu FU MGH Infectious Diseases Division; KL2/Catalyst Medical Research Investigator Training; Harvard Catalyst | The Harvard Clinical and Translational Science Center; National Center for Research Resources; National Center for Advancing Translational Sciences; National Institutes of Health[NIH] [KL2 TR001100, T32 AI007061, 5R01 AI092084, 5R21 AI109303]; NIH/NIAID [1K08 AI110655] FX We thank the MGH Infectious Diseases Division for support.; We are grateful to a patient of J.M.V. who provided unrestricted funds that were used in part to support this study. J.L.R. was supported by a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health[NIH], award KL2 TR001100), and NIH grant T32 AI007061. J.M.V. was supported by National Institutes of Health grants 5R01 AI092084 and 5R21 AI109303. M.K.M. was supported by NIH/NIAID grant 1K08 AI110655. NR 77 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2017 VL 85 IS 3 AR e00903-16 DI 10.1128/IAI.00903-16 PG 18 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4SU UT WOS:000394612000018 ER PT J AU Okland, T Karimkhani, C Pederson, H Boyers, LN Sawyer, MD Rove, KO Kenny, MC Steinberg, S Naghavi, M Dellavalle, RP AF Okland, Tyler Karimkhani, Chante Pederson, Hannah Boyers, Lindsay N. Sawyer, Mark D. Rove, Kyle O. Kenny, McCabe C. Steinberg, Steven Naghavi, Mohsen Dellavalle, Robert P. TI Research prioritization of men's health and urologic diseases SO INTERNATIONAL BRAZ J UROL LA English DT Article DE Men's Health; Urologic Diseases; Neoplasms; Infertility; Male ID SYSTEMATIC-REVIEWS; GLOBAL BURDEN; COCHRANE-DATABASE; RESEARCH GAPS; TRIALS AB Objectives: We sought to determine whether disease representation in the Cochrane Database of Systematic Reviews (CDSR) reflects disease burden, measured by the Global Burden of Disease (GBD) Study as disability-adjusted life-years (DALYs). Materials and Methods: Two investigators performed independent assessment of ten men's health and urologic diseases (MHUDs) in CDSR for systematic review and protocol representation, which were compared with percentage of total 2010 DALYs for the ten conditions. Data were analyzed for correlation using Spearman rank analysis. Results: Nine of ten MHUDs were represented by at least one CDSR review. There was a poor and statistically insignificant positive correlation between CDSR representation and disease burden (rho = 0.42, p = 0.23). CDSR representation was aligned with disease burden for three conditions, greater than disease burden for one condition, and less than disease burden for six conditions. Conclusions: These results yield high-quality estimates to inform future research prioritization for MHUDs. While prioritization processes are complex and multi-faceted, disease burden should be strongly considered. Awareness of research priority setting has the potential to minimize research disparities on a global scale. C1 [Okland, Tyler; Pederson, Hannah] Univ Colorado, Sch Med, Aurora, CO USA. [Karimkhani, Chante] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Boyers, Lindsay N.] Georgetown Univ, Sch Med, Washington, DC USA. [Sawyer, Mark D.; Steinberg, Steven] Eastern Colorado Hlth Care Syst, Urol Serv, US Dept Vet Affairs, Denver, CO USA. [Rove, Kyle O.; Kenny, McCabe C.; Steinberg, Steven] Univ Colorado, Dept Urol, Anschutz Med Campus, Aurora, CO USA. [Naghavi, Mohsen] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Dellavalle, Robert P.] Univ Colorado, Dept Dermatol, Anschutz Med Campus, Aurora, CO USA. [Dellavalle, Robert P.] Eastern Colorado Hlth Care Syst, Dermatol Serv, US Dept Vet, Denver, CO USA. [Dellavalle, Robert P.] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Anschutz Med Campus, Aurora, CO USA. RP Dellavalle, RP (reprint author), US Dept Vet Affairs, Med Ctr, Dermatol Serv, 1055 Clermont St,Box 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu FU Bill and Melinda Gates Foundation; CDC; National Institutes of Health FX There was no direct funding to the current study. The Global Burden of Disease study received funding from the Bill and Melinda Gates Foundation (PI: Christopher J.L. Murray). Lindsay Boyers, Mark Sawyer, and Robert Dellavalle are employees of the U.S. Department of Veterans Affairs. The U.S. Department of Veterans Affairs had no role in the design and execution of the study. Robert Dellavalle is supported by grants from the CDC and National Institutes of Health. Tyler Okland, Chante Karimkhani, Hannah Pederson, Lindsay Boyers, Mohsen Naghavi, and Mark Sawyer report no relevant disclosures. Any opinions expressed herein do not necessarily reflect the opinions of the CDC or the Department of Veterans Affairs. NR 15 TC 0 Z9 0 U1 0 U2 0 PU BRAZILIAN SOC UROL PI RIO DE JANEIRO PA RUA BAMBINA, 153, RIO DE JANEIRO, 2251-050, BRAZIL SN 1677-5538 EI 1677-6119 J9 INT BRAZ J UROL JI Int. Braz J Urol PD MAR-APR PY 2017 VL 43 IS 2 BP 289 EP 303 DI 10.1590/S1677-5538.IBJU.2016.0047 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA EN4UR UT WOS:000396002900017 PM 28128909 ER PT J AU Adler, LA Faraone, SV Spencer, TJ Berglund, P Alperin, S Kessler, RC AF Adler, Lenard A. Faraone, Stephen V. Spencer, Thomas J. Berglund, Patricia Alperin, Samuel Kessler, Ronald C. TI The structure of adult ADHD SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE adults; ADHD; attention-deficit hyperactivity disorder; epidemiology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; WORLD-HEALTH-ORGANIZATION; COMORBIDITY SURVEY REPLICATION; EMOTIONAL SELF-REGULATION; REPORT SCALE ASRS; PSYCHOMETRIC PROPERTIES; NCS-R; DIAGNOSIS; METHYLPHENIDATE AB Although DSM-5 stipulates that symptoms of attention-deficit hyperactivity disorder (ADHD) are the same for adults as children, clinical observations suggest that adults have more diverse deficits than children in higher-level executive functioning and emotional control. Previous psychometric analyses to evaluate these observations have been limited in ways addressed in the current study, which analyzes the structure of an expanded set of adult ADHD symptoms in three pooled US samples: a national household sample, a sample of health plan members, and a sample of adults referred for evaluation at an adult ADHD clinic. Exploratory factor analysis found four factors representing executive dysfunction/inattention (including, but not limited to, all the DSM-5 inattentive symptoms, with non-DSM symptoms having factor loadings comparable to those of DSM symptoms), hyperactivity, impulsivity, and emotional dyscontrol. Empirically-derived multivariate symptom profiles were broadly consistent with the DSM-5 inattentive-only, hyperactive/impulsive-only, and combined presentations, but with inattention including executive dysfunction/inattention and hyperactivity-only limited to hyperactivity without high symptoms of impulsivity. These results show that executive dysfunction is as central as DSM-5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD. C1 [Adler, Lenard A.; Alperin, Samuel] NYU, Langone Sch Med, Dept Psychiat & Child & Adolescent Psychiat, New York, NY 10003 USA. [Adler, Lenard A.; Alperin, Samuel] NYU, Psychiat Serv, New York, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Spencer, Thomas J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Spencer, Thomas J.] Harvard Med Sch, Boston, MA USA. [Berglund, Patricia] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Alperin, Samuel] Hofstra Univ, Hofstra Northwell Sch Med, Hempstead, NY 11550 USA. [Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. RP Adler, LA (reprint author), NYU, Langone Sch Med, Dept Psychiat & Child & Adolescent Psychiat, New York, NY 10003 USA.; Adler, LA (reprint author), NYU, Psychiat Serv, New York, NY USA. EM lenard.adler@nyumc.org FU Eli Lilly and Company; HealthCore Inc.; National Institute of Mental Health [R01 MH070884]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; US Public Health Service [R13-MH066849, R01-MH069864, R01 DA016558]; Fogarty International Center [FIRCA R01-TW006481]; Pan American Health Organization; Ortho-McNeil Pharmaceutical, Inc.; GlaxoSmithKline; Bristol-Myers Squibb; K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; European Union's Seventh Framework Program for research, technological development and demonstration [602805]; NIMH [R01MH094469] FX The ASRS Screener was developed in collaboration with the WHO World Mental Health (WMH) Survey Initiative in conjunction with the revision of the WHO Composite International Diagnostic Interview (CIDI) (Kessler & Ustun, 2004). Development of the ASRS screener was supported by Eli Lilly and Company. The ASRS Screener cross-validation study was supported by Eli Lilly and Company and HealthCore Inc. The larger series of WMH methodological studies in which the ASRS development work was embedded were supported by the National Institute of Mental Health (R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R01-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, Inc., GlaxoSmithKline, and Bristol-Myers Squibb. The WMH CIDI Advisory Group that developed the ASRS included Lenard Adler (New York University School of Medicine), Russell Barkley (Medical University of South Carolina), Joseph Biederman (Massachusetts General Hospital and Harvard Medical School), Keith Conners (Duke University School of Medicine), Stephen Faraone (Massachusetts General Hospital and Harvard Medical School), Laurence Greenhill (New York State Psychiatric Institute), Molly Howes (Harvard Medical School), Ronald Kessler (Harvard Medical School), Thomas Spencer (Massachusetts General Hospital and Harvard Medical School) and T. Bedirhan Ustun (World Health Organization). All WMH instruments and publications are posted at http://www.hcp.med.harvard.edu/wmh. Professor Faraone is supported by the K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement no 602805 and NIMH grant R01MH094469. NR 48 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD MAR PY 2017 VL 26 IS 1 DI 10.1002/mpr.1555 PG 12 WC Psychiatry SC Psychiatry GA EP6QL UT WOS:000397503900009 ER PT J AU Franck, LS Gay, CL Cooper, B Ezrre, S Murphy, B Chan, JSL Buick, M Meer, CR AF Franck, Linda S. Gay, Caryl L. Cooper, Bruce Ezrre, Suzanne Murphy, Barbette Chan, June Shu-Ling Buick, Maureen Meer, Carrie R. TI The Little Schmidy Pediatric Hospital Fall Risk Assessment Index: A diagnostic accuracy study SO INTERNATIONAL JOURNAL OF NURSING STUDIES LA English DT Article DE Children; Young adult; Pediatric hospital; Fall prevention; Fall risk; Risk assessment ID PREVENTION PROGRAMS; PATIENT FALLS; INJURIES; EVENTS; MODEL AB Background: Falls are among the most common potentially preventable adverse events. Current pediatric falls risk assessment methods have poor precision and accuracy. Objective: To evaluate an inpatient pediatric fall risk assessment index, known as the Little Schmidy, and describe characteristics of pediatric falls. Design: Retrospective case control and descriptive study. The dataset included 114 reported falls and 151,678 Little Schmidy scores documented in medical records during the 5-year study period (20072011). Setting: Pediatric medical and surgical inpatient units of an academic medical center in the western United States. Participants: Pediatric hospital inpatients <25 years of age. Methods: Nurses used the 5-item, 7-point Little Schmidy to assess fall risk each day and night shift throughout the patient's hospitalization. Conditional fixed-effects logistic regressions were used to examine predictive relationships between Little Schmidy scores (at admission, highest prior to fall, and just prior to fall) and the patient's fall status (fell or not). The sensitivity and specificity of different cut-off scores were explored. Associations between Little Schmidy scores and patient and hospitalization factors were examined using multilevel mixed-effects logistic regression and multilevel mixed-effects ordinal logistic regression. Results: Little Schmidy scores were significantly associated with pediatric falls (p < 0.005). Maximal performance was achieved with a 4-item, 4-point, Little Schmidy index (LS4) using a cut-off score of i to indicate fall risk with sensitivity of 79% and specificity of 49%. Patients with an LS4 score >1 were 4 times more likely to fall before the next assessment than patients with a score of 0. LS4 scores indicative of fall risk were associated with age >5 years, neurological diagnosis, multiple hospitalizations, and night shift, but not with sex, length of hospital stay, or hospital unit. Of the 114 reported falls, 64% involved a male patient, nearly one third (32%) involved adolescents (13-17 years), most resulted in no (59%) or mild (36%) injury, and most (54%) were related to diagnosis or clinical characteristics. For 60% of the falls, fall precautions had been implemented prior to the fall. Conclusions: The revised 4-item Little Schmidy, the LS4, predicts pediatric falls when administered every day and night shift, but identifies most patients (65%) as being at risk for fall. Strategies for improving the accuracy and efficiency of the assessments are proposed. Further research is needed to develop more effective pediatric fall prevention strategies tailored to patient's age, diagnosis, and time of day. (C) 2017 Elsevier Ltd. All rights reserved. C1 [Franck, Linda S.; Gay, Caryl L.] Univ Calif San Francisco, Dept Family Hlth Care Nursing, 2 Koret Way,N411Y,Box 0606, San Francisco, CA 94143 USA. [Cooper, Bruce] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Ezrre, Suzanne] Univ Calif San Francisco, Benioff Childrens Hosp, Pediat Hematol Oncol Unit, San Francisco, CA 94143 USA. [Murphy, Barbette] Univ Calif San Francisco, Benioff Childrens Hosp, Pediat Med Surg Unit, San Francisco, CA 94143 USA. [Murphy, Barbette] Univ Calif San Francisco, Benioff Childrens Hosp, Pediat Transit Care Unit, San Francisco, CA 94143 USA. [Chan, June Shu-Ling] Univ Calif San Francisco, Benioff Childrens Hosp, Nursing Practice Patient Experience & Special Pro, San Francisco, CA 94143 USA. [Buick, Maureen; Meer, Carrie R.] Univ Calif San Francisco, Med Ctr, Dept Nursing, Nursing Performance Improvement, San Francisco, CA 94143 USA. [Buick, Maureen; Meer, Carrie R.] UCSF Benioff Childrens Hosp, San Francisco, CA USA. [Ezrre, Suzanne] Dana Farber Canc Inst, Dept Pediat Hematol & Oncol, Boston, MA 02115 USA. RP Franck, LS (reprint author), Univ Calif San Francisco, Dept Family Hlth Care Nursing, 2 Koret Way,N411Y,Box 0606, San Francisco, CA 94143 USA. EM linda.franck@ucsf.edu FU University of California, San Francisco FX The study was supported by the University of California, San Francisco. The funder had no role in the study design, or in the collection, analysis, interpretation or presentation of the information. NR 32 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 0020-7489 EI 1873-491X J9 INT J NURS STUD JI Int. J. Nurs. Stud. PD MAR PY 2017 VL 68 BP 51 EP 59 DI 10.1016/j.ijnurstu.2016.12.011 PG 9 WC Nursing SC Nursing GA EP4TQ UT WOS:000397373200007 PM 28086112 ER PT J AU Blackmon, JE Liptak, C Recklitis, CJ AF Blackmon, Jaime E. Liptak, Cori Recklitis, Christopher J. TI Validation of Three Previously Developed Short Forms of the Beck Depression Inventory for Youth: A Replication SO JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY LA English DT Article DE BDI-Y; validation; depression; screening; survivorship ID CHILDHOOD-CANCER SURVIVOR AB Three previously developed short forms of the Beck Depression Inventory-Youth (BDI-Y) were validated against the standard 20-item BDI-Y; 168 adolescent survivors completed the standard and short-form versions of the BDI-Y. The short forms were evaluated for internal consistency and compared with the standard BDI-Y using correlation coefficients and receiver operating characteristic curve analyses. The three short forms had good internal consistency ( alpha> 0.85), high correlations with the total BDI-Y scale (r>0.85), and good discrimination compared with the standard BDI-Y cutoff score (area under the ROC curve >0.95). Consistent with prior findings, strong psychometric properties of an eight-item short form support its use as a screening measure for adolescent cancer survivors. C1 [Blackmon, Jaime E.; Liptak, Cori; Recklitis, Christopher J.] Dana Farber Canc Inst, 450 Brookline Ave SW 320, Boston, MA 02215 USA. [Liptak, Cori; Recklitis, Christopher J.] Harvard Med Sch, Boston, MA USA. RP Recklitis, CJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave SW 320, Boston, MA 02215 USA. EM christopher_recklitis@dfci.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2156-5333 EI 2156-535X J9 J ADOLESC YOUNG ADUL JI J. Adolesc. Young Adult Oncol. PD MAR PY 2017 VL 6 IS 1 BP 190 EP 192 DI 10.1089/jayao.2016.0052 PG 3 WC Oncology SC Oncology GA EN1JH UT WOS:000395765800024 PM 27828715 ER PT J AU Choi, KW Sikkema, KJ Vythilingum, B Geerts, L Faure, SC Watt, MH Roos, A Stein, DJ AF Choi, Karmel W. Sikkema, Kathleen J. Vythilingum, Bavi Geerts, Lut Faure, Sheila C. Watt, Melissa H. Roos, Annerine Stein, Dan J. TI Maternal childhood trauma, postpartum depression, and infant outcomes: Avoidant affective processing as a potential mechanism SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE South Africa; Early adversity; Perinatal depression; Intergenerational transmission; Emotional Stroop; Emotion processing; Child outcomes ID POSTTRAUMATIC-STRESS-DISORDER; MIDDLE-INCOME COUNTRIES; SOUTH-AFRICAN BIRTH; PERINATAL MENTAL-DISORDERS; INTIMATE PARTNER VIOLENCE; PREGNANT-WOMEN; ANTENATAL DEPRESSION; POSTNATAL DEPRESSION; SELECTIVE ATTENTION; PROSPECTIVE COHORT AB Background: Women who have experienced childhood trauma may be at risk for postpartum depression, increasing the likelihood of negative outcomes among their children. Predictive pathways from maternal childhood trauma to child outcomes, as mediated by postpartum depression, require investigation. Methods: A longitudinal sample of South African women (N=150) was followed through pregnancy and postpartum. Measures included maternal trauma history reported during pregnancy; postpartum depression through six months; and maternal-infant bonding, infant development, and infant physical growth at one year. Structural equation models tested postpartum depression as a mediator between maternal experiences of childhood trauma and children's outcomes. A subset of women (N=33) also participated in a lab-based emotional Stroop paradigm, and their responses to fearful stimuli at six weeks were explored as a potential mechanism linking maternal childhood trauma, postpartum depression, and child outcomes. Results: Women with childhood trauma experienced greater depressive symptoms through six months postpartum, which then predicted negative child outcomes at one year. Mediating effects of postpartum depression were significant, and persisted for maternal-infant bonding and infant growth after controlling for covariates and antenatal distress. Maternal avoidance of fearful stimuli emerged as a potential affective mechanism. Limitations: Limitations included modest sample size, self-report measures, and unmeasured potential confounders. Conclusions: Findings suggest a mediating role of postpartum depression in the intergenerational transmission of negative outcomes. Perinatal interventions that address maternal trauma histories and depression, as well as underlying affective mechanisms, may help interrupt cycles of disadvantage, particularly in high-trauma settings such as South Africa. C1 [Choi, Karmel W.; Sikkema, Kathleen J.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Choi, Karmel W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Choi, Karmel W.; Sikkema, Kathleen J.; Watt, Melissa H.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Sikkema, Kathleen J.; Vythilingum, Bavi; Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa. [Geerts, Lut] Univ Stellenbosch, Dept Obstet & Gynecol, ZA-7600 Stellenbosch, South Africa. [Faure, Sheila C.; Roos, Annerine; Stein, Dan J.] Univ Stellenbosch, MRC Res Unit Anxiety & Stress Disorders, Cape Town, South Africa. RP Choi, KW (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, Boston, MA 02114 USA. EM kwchoi@mgh.harvard.edu NR 99 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR PY 2017 VL 211 BP 107 EP 115 DI 10.1016/j.jad.2017.01.004 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EN2LP UT WOS:000395842100013 PM 28110156 ER PT J AU Carrellas, NW Biederman, J Uchida, M AF Carrellas, Nicholas W. Biederman, Joseph Uchida, Mai TI How prevalent and morbid are subthreshold manifestations of major depression in adolescents? A literature review SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Review DE Subthreshold; Subsyndromal; Minor; Depression; Impairment; Adolescent ID MINOR DEPRESSION; HEALTH OUTCOMES; DISORDER; CHILDREN; RISK; ESCALATION; PREDICTORS; ADULTHOOD; SYMPTOMS; ONSET AB Introduction: Major Depressive Disorder (MDD) among youth is a public health concern. Our aim was to examine the current body of knowledge to better characterize the prevalence and morbidity associated with subthreshold forms of MDD among youth. Given that MDD tends to develop gradually over time, we hypothesized a high prevalence and considerable impairment associated with youth suffering from depressive symptoms that fall short of full, syndromic status. Methods: A literature search was conducted using PubMed exclusively to identify studies assessing the prevalence and clinical characteristics of subthreshold MDD in adolescents. Results: Six scientific papers that met our priori inclusion and exclusion criteria were identified. All papers sampled adolescents. The prevalence of subthreshold MDD ranged from 5% over the past year, to 29% over the two weeks prior to screening. These papers reported clinically significant morbidity associated with subthreshold MDD among adolescents, with evidence for elevated rates of psychiatric comorbidities, impaired functioning in social and familial domains, increased suicidality, and frequent mental health service utilization. Limitations: Though we examined a sizeable and diverse sample, we only identified six cross-sectional informative studies for this review. Variability of subthreshold MDD and major outcome definitions across studies, likely limits the specificity of findings. Conclusions: Subthreshold MDD is prevalent among youth, and is associated with emotional and social impairments that reach the level of obtaining clinical care. These findings could lead to early intervention efforts aimed at mitigating the adverse outcomes associated with subthreshold MDD as well as the progression to full syndrome MDD. Our review documents that regardless of whether progression to full diagnostic status occurs, this condition is morbid. C1 [Carrellas, Nicholas W.; Biederman, Joseph; Uchida, Mai] Massachusetts Gen Hosp, Div Child Psychiat, Pediat Psychopharmacol Program, Boston, MA 02114 USA. [Biederman, Joseph; Uchida, Mai] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Biederman, Joseph; Uchida, Mai] Harvard Med Sch, Boston, MA 02114 USA. RP Uchida, M (reprint author), Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, 55 Fruit St,Warren Bldg,6th Floor, Boston, MA 02114 USA. EM muchida@partners.org NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 1 PY 2017 VL 210 BP 166 EP 173 DI 10.1016/j.jad.2016.12.037 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EL5AL UT WOS:000394633700023 PM 28049101 ER PT J AU Halaney, DL Sanyal, A Nafissi, NA Escobedo, D Goros, M Michalek, J Acevedo, PJ Perez, W Escobar, GP Feldman, MD Han, HC AF Halaney, David L. Sanyal, Arnav Nafissi, Navid A. Escobedo, Daniel Goros, Martin Michalek, Joel Acevedo, Pedro J. Perez, William Escobar, G. Patricia Feldman, Marc D. Han, Hai-Chao TI The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE trabeculae carneae; LV compliance; wall stress; stiffness; hypertrophy; surgery ID NON-COMPACTION CARDIOMYOPATHY; DIFFERENT CARDIAC-DISEASES; HEART-FAILURE; MAGNETIC-RESONANCE; EJECTION FRACTION; PAPILLARY-MUSCLES; EUROPEAN-SOCIETY; OF-CARDIOLOGY; TASK-FORCE; QUANTIFICATION AB The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure-volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance. C1 [Halaney, David L.; Nafissi, Navid A.; Escobedo, Daniel; Escobar, G. Patricia; Feldman, Marc D.] Univ Texas Hlth Sci, Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Halaney, David L.; Escobedo, Daniel; Feldman, Marc D.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. [Sanyal, Arnav; Han, Hai-Chao] Univ Texas San Antonio, Dept Mech Engn, San Antonio, TX 78249 USA. [Goros, Martin; Michalek, Joel] Univ Texas Hlth Sci, Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Acevedo, Pedro J.] Univ Environm & Appl Sci UDCA, Dept Anat, Bogota, Colombia. [Perez, William] Univ Republica, Fac Vet Med, Dept Anat, Montevideo 11200, Uruguay. RP Feldman, MD (reprint author), Univ Texas Hlth Sci, Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.; Feldman, MD (reprint author), South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. OI Perez, William/0000-0002-9647-4731 FU South Texas Veterans Health Care System (VA Merit Grant, San Antonio, TX); Janey and Dolph Briscoe Center for Cardiovascular Research (San Antonio, TX); National Heart, Lung, and Blood Institute [HL095852]; Clayton Foundation; AHA National Innovation Award [15IRG23320009]; Office of the Vice President for Research of the University of Texas at San Antonio FX This work was supported by the South Texas Veterans Health Care System (VA Merit Grant, San Antonio, TX), the Janey and Dolph Briscoe Center for Cardiovascular Research (San Antonio, TX), Grant No. HL095852 from the National Heart, Lung, and Blood Institute, the Clayton Foundation, and an AHA National Innovation Award (15IRG23320009). This project was also funded in part by the GREAT program from the Office of the Vice President for Research of the University of Texas at San Antonio. NR 41 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD MAR PY 2017 VL 139 IS 3 AR 031012 DI 10.1115/1.4035585 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA EM2XR UT WOS:000395179600012 ER PT J AU Telfer, S Kindig, MW Sangeorzan, BJ Ledoux, WR AF Telfer, Scott Kindig, Matthew W. Sangeorzan, Bruce J. Ledoux, William R. TI Metatarsal Shape and Foot Type: A Geometric Morphometric Analysis SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE foot type; bone morphology; pes planus; pes cavus; metatarsal ID LOWER-LIMB KINEMATICS; PLANTAR PRESSURE; STATISTICAL SHAPE; FRAMINGHAM FOOT; BONE MORPHOLOGY; CAVUS FOOT; PES PLANUS; WALKING; POSTURE; DEFORMITY AB Planus and cavus foot types have been associated with an increased risk of pain and disability. Improving our understanding of the geometric differences between bones in different foot types may provide insights into injury risk profiles and have implications for the design of musculoskeletal and finite-element models. In this study, we performed a geometric morphometric analysis on the geometry of metatarsal bones from 65 feet, segmented from computed tomography (CT) scans. These were categorized into four foot types: pes cavus, neutrally aligned, asymptomatic pes planus, and symptomatic pes planus. Generalized procrustes analysis (GPA) followed by permutation tests was used to determine significant shape differences associated with foot type and sex, and principal component analysis was used to find the modes of variation for each metatarsal. Significant shape differences were found between foot types for all the metatarsals (p < 0.01), most notably in the case of the second metatarsal which showed significant pairwise differences across all the foot types. Analysis of the principal components of variation showed pes cavus bones to have reduced cross-sectional areas in the sagittal and frontal planes. The first (p = 0.02) and fourth metatarsals (p = 0.003) were found to have significant sex-based differences, with first metatarsals from females shown to have reduced width, and fourth metatarsals from females shown to have reduced frontal and sagittal plane cross-sectional areas. Overall, these findings suggest that metatarsal bones have distinct morphological characteristics that are associated with foot type and sex, with implications for our understanding of anatomy and numerical modeling of the foot. C1 [Telfer, Scott; Sangeorzan, Bruce J.; Ledoux, William R.] Univ Washington, Dept Orthopaed & Sports Med, Box 356500,1959 Northeasr Pacific St, Seattle, WA 98195 USA. [Kindig, Matthew W.; Ledoux, William R.] VA Puget Sound, RR&D Ctr Excellence, Seattle, WA 98108 USA. [Ledoux, William R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. RP Telfer, S (reprint author), Univ Washington, Dept Orthopaed & Sports Med, Box 356500,1959 Northeasr Pacific St, Seattle, WA 98195 USA. EM telfers@uw.edu NR 45 TC 0 Z9 0 U1 0 U2 0 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD MAR PY 2017 VL 139 IS 3 AR 031008 DI 10.1115/1.4035077 PG 8 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA EM2XR UT WOS:000395179600008 ER PT J AU Silva, AFG Bonatti, R Batatinha, JAP Nearing, BD Zeng, D Belardinelli, L Verrier, RL AF Silva, Ana F. G. Bonatti, Rodolfo Batatinha, Julio A. P. Nearing, Bruce D. Zeng, Dewan Belardinelli, Luiz Verrier, Richard L. TI The Selective Late Sodium Current Inhibitor Eleclazine, Unlike Amiodarone, Does Not Alter Defibrillation Threshold or Dominant Frequency of Ventricular Fibrillation SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE eleclazine; sodium; amiodarone; defibrillation; dominant frequency ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; ENERGY-REQUIREMENTS; ANTIARRHYTHMIC DRUGS; RANOLAZINE; THERAPY; VULNERABILITY; DECREASES AB Introduction: We examined the effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter defibrillators (ICDs). Methods and Results: In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex through jugular vein. ICDs were implanted subcutaneously. Dominant frequency of ventricular fibrillation was analyzed by fast Fourier transform. The measurements were made before drug administration (control), and at 40 minutes after vehicle, eleclazine (2 mg/kg, i.v., bolus over 15 minutes), or subsequent/single amiodarone administration (10 mg/kg, i.v., bolus over 10 minutes). Eleclazine did not alter DFT50, dominant frequency, heart rate, or mean arterial pressure (MAP). Subsequent amiodarone increased DFT50 (P = 0.006), decreased dominant frequency (P = 0.022), and reduced heart rate (P = 0.031) with no change in MAP. Amiodarone alone increased DFT50 (P = 0.005; NS compared to following eleclazine) and decreased dominant frequency (P = 0.003; NS compared to following eleclazine). Conclusion: Selective late INa inhibition with eleclazine does not alter DFT50 or dominant frequency of ventricular fibrillation when administered alone or in combination with amiodarone. Accordingly, eleclazine would not be anticipated to affect the margin of defibrillation safety in patients with ICDs. C1 [Silva, Ana F. G.; Bonatti, Rodolfo; Batatinha, Julio A. P.; Nearing, Bruce D.; Verrier, Richard L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Silva, Ana F. G.; Bonatti, Rodolfo; Batatinha, Julio A. P.] Univ Sao Paulo, Fac Med, BR-05508 Sao Paulo, Brazil. [Nearing, Bruce D.; Verrier, Richard L.] Harvard Med Sch, Boston, MA USA. [Zeng, Dewan; Belardinelli, Luiz] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Verrier, Richard L.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Div Cardiovasc Med, RN-301,99 Brookline Ave, Boston, MA 02215 USA. RP Verrier, RL (reprint author), Beth Israel Deaconess Med Ctr, Harvard Med Sch, Div Cardiovasc Med, RN-301,99 Brookline Ave, Boston, MA 02215 USA. EM rverrier@bidmc.harvard.edu FU Gilead Sciences, Inc, to Beth Israel Deaconess Medical Center; Santander Bank and Science without Borders FX Supported by a research grant from Gilead Sciences, Inc, to Beth Israel Deaconess Medical Center. R.L. Verrier, Principal Investigator. Implantable devices and leads were provided as a gift from Medtronic, Inc, to Beth Israel Deaconess Medical Center. A.F.G. Silva, R. Bonatti, and J.A.P. Batatinha received support from Santander Bank and Science without Borders. NR 25 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 0160-2446 EI 1533-4023 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD MAR PY 2017 VL 69 IS 3 BP 178 EP 182 PG 5 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA EN1VN UT WOS:000395798500008 PM 28045761 ER PT J AU Shams, S Granberg, T Martola, J Charidimou, A Li, XZ Shams, M Fereshtehnejad, SM Cavallin, L Aspelin, P Wiberg-Kristoffersen, M Wahlund, LO AF Shams, Sara Granberg, Tobias Martola, Juha Charidimou, Andreas Li, Xiaozhen Shams, Mana Fereshtehnejad, Seyed-Mohammad Cavallin, Lena Aspelin, Peter Wiberg-Kristoffersen, Maria Wahlund, Lars-Olof TI Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE Amyloid angiopathy; cerebrospinal fluid biomarkers; cognitive impairment; intracerebral hemorrhage; magnetic resonance imaging ID SMALL-VESSEL DISEASE; KAROLINSKA IMAGING DEMENTIA; AMYLOID ANGIOPATHY; ALZHEIMER-DISEASE; RISK-FACTORS; BRAIN MICROBLEEDS; ROTTERDAM SCAN; PREVALENCE; PATHOLOGY; PATHOGENESIS AB Cerebral microbleeds, a marker of small vessel disease, are thought to be of importance in cognitive impairment. We aimed to study topographical distribution of cerebral microbleeds, and their involvement in disease pathophysiology, reflected by cerebrospinal fluid biomarkers; 1039 patients undergoing memory investigation underwent lumbar puncture and a brain magnetic resonance imaging scan. Cerebrospinal fluid samples were analyzed for amyloid beta(A beta)42, total tau(T-tau), tau phosphorylated at threonine 18(P-tau) and cerebrospinal fluid/serum albumin ratios. Magnetic resonance imaging sequences were evaluated for small vessel disease markers, including cerebral microbleeds, white matter hyperintensities and lacunes. Low A beta 42 levels were associated with lobar cerebral microbleeds in the whole cohort and Alzheimer's disease (P<0.001). High cerebrospinal fluid/serum albumin ratios were seen with increased number of cerebral microbleeds in the brainstem (P<0.001). There were tendencies for increased A beta 42 levels and decreased Tau levels with deep and infratentorial cerebral microbleeds (P<0.05). Lobar cerebral microbleeds were associated with white matter hyperintensities and lacunes (P<0.001). Probable cerebral amyloid angiopathy-related cerebral microbleeds were associated with low A beta 42 levels and lacunes, whereas probable cerebral amyloid angiopathy-unrelated cerebral microbleeds were associated with white matter hyperintensities (P<0.001). Our findings show that cerebral microbleed distribution is associated with different patterns of cerebrospinal fluid biomarkers, supporting different pathogenesis of deep/infratentorial and lobar cerebral microbleeds. C1 [Shams, Sara; Granberg, Tobias; Martola, Juha; Shams, Mana; Cavallin, Lena; Aspelin, Peter; Wiberg-Kristoffersen, Maria] Karolinska Inst, Div Med Imaging & Technol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Shams, Sara; Granberg, Tobias; Martola, Juha; Shams, Mana; Cavallin, Lena; Aspelin, Peter; Wiberg-Kristoffersen, Maria] Karolinska Univ Hosp, Dept Radiol, SE-14186 Stockholm, Sweden. [Charidimou, Andreas] Harvard Med Sch, Ctr Stroke Res, Massachusetts Gen Hosp, Dept Neurol,Hemorrhag Stroke Res Program, Boston, MA USA. [Li, Xiaozhen; Fereshtehnejad, Seyed-Mohammad; Wahlund, Lars-Olof] Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, HI, Stockholm, Sweden. [Li, Xiaozhen; Fereshtehnejad, Seyed-Mohammad; Wahlund, Lars-Olof] Karolinska Univ Hosp, Div Clin Geriatr, Stockholm, Sweden. RP Shams, S (reprint author), Karolinska Univ Hosp, Dept Radiol, SE-14186 Stockholm, Sweden. EM sara.shams@ki.se FU Stockholm County Council; Karolinska Institutet; Swedish Dementia Association FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Stockholm County Council, Karolinska Institutet and the Swedish Dementia Association. NR 33 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 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2017 VL 37 IS 3 BP 1006 EP 1013 DI 10.1177/0271678X16649401 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA EL5KQ UT WOS:000394660400022 PM 27178426 ER PT J AU Hamada, T Keum, N Nishihara, R Ogino, S AF Hamada, Tsuyoshi Keum, NaNa Nishihara, Reiko Ogino, Shuji TI Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis SO JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Colorectal neoplasms; Drug therapy; Immunology; Microbiology; Personalized therapy ID COLORECTAL-CANCER RISK; BODY-MASS INDEX; ISLAND METHYLATOR PHENOTYPE; BETA-CATENIN ALTERATIONS; UNIQUE TUMOR PRINCIPLE; LIFE-STYLE FACTORS; MICROSATELLITE-INSTABILITY; PHYSICAL-ACTIVITY; ASPIRIN USE; PRECISION MEDICINE AB Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine. C1 [Hamada, Tsuyoshi; Nishihara, Reiko; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room SM1036, Boston, MA 02215 USA. [Hamada, Tsuyoshi; Nishihara, Reiko; Ogino, Shuji] Harvard Med Sch, 450 Brookline Ave,Room SM1036, Boston, MA 02215 USA. [Keum, NaNa; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol, Dept Pathol, Boston, MA 02215 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA. RP Nishihara, R; Ogino, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room SM1036, Boston, MA 02215 USA.; Nishihara, R; Ogino, S (reprint author), Harvard Med Sch, 450 Brookline Ave,Room SM1036, Boston, MA 02215 USA.; Nishihara, R (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.; Nishihara, R; Ogino, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.; Nishihara, R (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.; Ogino, S (reprint author), Brigham & Womens Hosp, Div MPE Mol Pathol Epidemiol, Dept Pathol, Boston, MA 02215 USA.; Ogino, S (reprint author), Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA. EM rnishiha@hsph.harvard.edu; shuji_ogino@dfci.harvard.edu FU U.S. National Institutes of Health (NIH) [R01 CA151993, R35 CA197735, K07 CA190673]; Nodal Award from the Dana-Farber Harvard Cancer Center; Friends of the Dana-Farber Cancer Institute; Uehara Memorial Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research FX This work was supported by U.S. National Institutes of Health (NIH) grants (R01 CA151993 to S.O., R35 CA197735 to S.O., and K07 CA190673 to R.N.); by Nodal Award from the Dana-Farber Harvard Cancer Center (to S.O.); and by The Friends of the Dana-Farber Cancer Institute. T.H. was supported by a fellowship grant from the Uehara Memorial Foundation, and by a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in decision to submit the manuscript to publication, or preparation of the manuscript. NR 151 TC 4 Z9 4 U1 1 U2 1 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0944-1174 EI 1435-5922 J9 J GASTROENTEROL JI J. Gastroenterol. PD MAR PY 2017 VL 52 IS 3 BP 265 EP 275 DI 10.1007/s00535-016-1272-3 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM0JY UT WOS:000395005800001 PM 27738762 ER PT J AU Ripley, B Levin, D Kelil, T Hermsen, JL Kim, S Maki, JH Wilson, GJ AF Ripley, Beth Levin, Dmitry Kelil, Tatiana Hermsen, Joshua L. Kim, Sooah Maki, Jeffrey H. Wilson, Gregory J. TI 3D Printing From MRI Data: Harnessing Strengths and Minimizing Weaknesses SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE 3D printing; 3D printing; dditive manufacturing; MRI ID 3-DIMENSIONAL PRINTERS; TEMPORAL BONE; LONG BONES; RECONSTRUCTION; MODELS; ACCURACY; BRAIN; SEGMENTATION; REPLACEMENT; ANGIOGRAPHY AB 3D printing facilitates the creation of accurate physical models of patient-specific anatomy from medical imaging datasets. While the majority of models to date are created from computed tomography (CT) data, there is increasing interest in creating models from other datasets, such as ultrasound and magnetic resonance imaging (MRI). MRI, in particular, holds great potential for 3D printing, given its excellent tissue characterization and lack of ionizing radiation. There are, however, challenges to 3D printing from MRI data as well. Here we review the basics of 3D printing, explore the current strengths and weaknesses of printing from MRI data as they pertain to model accuracy, and discuss considerations in the design of MRI sequences for 3D printing. Finally, we explore the future of 3D printing and MRI, including creative applications and new materials. C1 [Ripley, Beth; Kim, Sooah; Maki, Jeffrey H.; Wilson, Gregory J.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Levin, Dmitry] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. [Kelil, Tatiana] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Hermsen, Joshua L.] Univ Washington, Dept Surg, Div Cardiothorac Surg, Seattle, WA 98195 USA. [Ripley, Beth] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA 98108 USA. RP Ripley, B (reprint author), 1959 Pacific Ave NE, Seattle, WA 98195 USA. NR 69 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2017 VL 45 IS 3 BP 635 EP 645 DI 10.1002/jmri.25526 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4QF UT WOS:000394605200001 PM 27875009 ER PT J AU Nguyen, KL Yoshida, T Han, F Ayad, I Reemtsen, BL Salusky, IB Satou, GM Hu, P Finn, JP AF Nguyen, Kim-Lien Yoshida, Takegawa Han, Fei Ayad, Ihab Reemtsen, Brian L. Salusky, Isidro B. Satou, Gary M. Hu, Peng Finn, J. Paul TI MRI With Ferumoxytol: A Single Center Experience of Safety Across the Age Spectrum SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article ID AMBULATORY BLOOD-PRESSURE; IRON-DEFICIENCY ANEMIA; CHRONIC KIDNEY-DISEASE; YOUNG-ADULTS; PHYSICOCHEMICAL PROPERTIES; HEMODIALYSIS-PATIENTS; CONTRAST AGENTS; HIGH-RESOLUTION; UNITED-STATES; POOL AGENT AB Purpose: To summarize our single-center safety experience with the off-label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium. Materials and Methods: Consecutive patients who underwent ferumoxytol-enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end-tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset-enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed. Results: In all, 217 unique patients, ages 3 days to 94 years, underwent FE-MRI. No ferumoxytol-related severe, life-threatening, or fatal AEs occurred acutely or at follow-up. Two patients developed ferumoxytol-related nausea. Between-group (FE- vs. GE-MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96-113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44-52 mmHg), oxygen saturation (P = 0.76, 95% CI 94-98%), and end-tidal CO2 (P = 0.73, 95% CI 31-37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50-58 mmHg) or heart rate (P=0.25, 95% CI 91-105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104). Conclusion: In our single-center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. C1 [Nguyen, Kim-Lien; Yoshida, Takegawa; Han, Fei; Hu, Peng; Finn, J. Paul] Univ Calif Los Angeles, David Geffen Sch Med, Diagnost Cardiovasc Imaging Lab, Los Angeles, CA 90095 USA. [Nguyen, Kim-Lien] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA 90095 USA. [Nguyen, Kim-Lien] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Yoshida, Takegawa; Han, Fei; Hu, Peng; Finn, J. Paul] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [Ayad, Ihab] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Salusky, Isidro B.; Satou, Gary M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Reemtsen, Brian L.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiothorac Surg, Los Angeles, CA 90095 USA. RP Finn, JP (reprint author), Univ Calif Los Angeles, Dept Radiol Sci, Peter V Ueberroth Bldg Suite 3371, Los Angeles, CA 90095 USA. EM pfinn@mednet.ucla.edu OI Nguyen, Kim-Lien/0000-0002-8854-2976 FU National Heart, Lung, and Blood Institute [R01HL127153]; NIH/ National Center for Advancing Translational Science (NCATS) CTSI [UL1TR000124] FX Contract grant sponsor: National Heart, Lung, and Blood Institute; contract grant number: R01HL127153; Contract grant sponsor: REDCap hosting by the NIH/ National Center for Advancing Translational Science (NCATS) CTSI; contract grant number: UL1TR000124. NR 51 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2017 VL 45 IS 3 BP 804 EP 812 DI 10.1002/jmri.25412 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4QF UT WOS:000394605200019 PM 27480885 ER PT J AU Lin, YC Wu, JS Baltzis, D Veves, A Greenman, RL AF Lin, Yu-Ching Wu, Jim S. Baltzis, Dimitrios Veves, Aristidis Greenman, Robert L. TI MRI Assessment of Regional Differences in Phosphorus-31 Metabolism and Morphological Abnormalities of the Foot Muscles in Diabetes Imaging (vol 44, pg 1132, 2016) SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Correction C1 [Lin, Yu-Ching; Wu, Jim S.; Greenman, Robert L.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02115 USA. [Lin, Yu-Ching] Chang Gung Mem Hosp, Dept Med Imaging & Intervent, Keelung, Taiwan. [Lin, Yu-Ching] Chang Gung Univ, Taoyuan, Taiwan. [Baltzis, Dimitrios; Veves, Aristidis] Beth Israel Deaconess Med Ctr, Microcirculat Lab, Boston, MA 02215 USA. [Baltzis, Dimitrios; Veves, Aristidis] Beth Israel Deaconess Med Ctr, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02215 USA. [Greenman, Robert L.] RLG Sci, Millis, MA USA. RP Lin, YC (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02115 USA.; Lin, YC (reprint author), Chang Gung Mem Hosp, Dept Med Imaging & Intervent, Keelung, Taiwan.; Lin, YC (reprint author), Chang Gung Univ, Taoyuan, Taiwan. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAR PY 2017 VL 45 IS 3 BP 938 EP 938 DI 10.1002/jmri.25608 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL4QF UT WOS:000394605200035 ER EF