FN Thomson Reuters Web of Science™ VR 1.0 PT J AU McNeill, SA Galovski, TE AF McNeill, Shannon A. Galovski, Tara E. TI Coping Styles Among Individuals with Severe Mental Illness and Comorbid PTSD SO COMMUNITY MENTAL HEALTH JOURNAL LA English DT Article DE Coping; Trauma; Posttraumatic stress disorder; Avoidance; Severe mental illness ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; BRIEF COPE; PSYCHOMETRIC PROPERTIES; SYMPTOM SEVERITY; TRAUMA; SCHIZOPHRENIA; ADULTS; ABUSE; VICTIMIZATION AB There is little known about coping styles used by individuals with severe mental illness (SMI) and even less known about the influence of a comorbid posttraumatic stress disorder (SMI-PTSD) diagnosis on coping. The current study examines differences in utilization of coping strategies, overall psychological distress, and exposure to traumatic events between SMI only and SMI-PTSD individuals seeking community mental health clinic services (N = 90). Results demonstrate that overall psychological distress and use of avoidance coping were significantly higher among the SMI-PTSD sample. Avoidance coping partially mediated the relationship between PTSD symptom severity and psychological distress. Findings suggest that the experience of PTSD for those with SMI is associated with increases in avoidance coping, a coping style that significantly contributes to psychological distress. Implications for further study and treatment within community mental health clinics are considered. C1 [McNeill, Shannon A.] Univ Missouri, Dept Psychol, St Louis, MO 63121 USA. [McNeill, Shannon A.; Galovski, Tara E.] VA Boston Healthcare Syst, Dept Vet Affairs, Brockton, MA 02301 USA. RP McNeill, SA (reprint author), Univ Missouri, Dept Psychol, One Univ Blvd, St Louis, MO 63121 USA. EM shannon.mcneill2@va.gov NR 59 TC 1 Z9 1 U1 4 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0010-3853 EI 1573-2789 J9 COMMUNITY MENT HLT J JI Community Ment. Health J. PD AUG PY 2015 VL 51 IS 6 BP 663 EP 673 DI 10.1007/s10597-015-9887-z PG 11 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA CN1DK UT WOS:000358156900005 PM 26044653 ER PT J AU Kojic, N Milosevic, M Petrovic, D Isailovic, V Sarioglu, AF Haber, DA Kojic, M Toner, M AF Kojic, Nikola Milosevic, Miljan Petrovic, Dejan Isailovic, Velibor Sarioglu, A. Fatih Haber, Daniel A. Kojic, Milos Toner, Mehmet TI A computational study of circulating large tumor cells traversing microvessels SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Circulating tumor cell; Finite element; Computational model; Capillary; Microvessel ID PARTICULATE FLOWS; ELEMENT-METHOD; BLOOD-FLOW; LEUKEMIA; DEFORMABILITY; METASTASIS; SIMULATION; MECHANICS; PRESSURE; SYSTEMS AB Circulating tumor cells (CTCs) are known to be a harbinger of cancer metastasis. The CTCs are known to circulate as individual cells or as a group of interconnected cells called CTC clusters. Since both single CTCs and CTC clusters have been detected in venous blood samples of cancer patients, they needed to traverse at least one capillary bed when crossing from arterial to venous circulation. The diameter of a typical capillary is about 7 gm, whereas the size of an individual CTC or CTC clusters can be greater than 20 gm and thus size exclusion is believed to be an important factor in the capillary arrest of CTCs - a key early event in metastasis. To examine the biophysical conditions needed for capillary arrest, we have developed a custom-built viscoelastic solid-fluid 3D computational model that enables us to calculate, under physiological conditions, the maximal CTC diameter that will pass through the capillary. We show that large CTCs and CTC clusters can successfully cross capillaries if their stiffness is relatively small. Specifically, under physiological conditions, a 13 gm diameter CTC passes through a 7 gm capillary only if its stiffness is less than 500 Pa and conversely, for a stiffness of 10 Pa the maximal passing diameter can be as high as 140 gm, such as for a cluster of CTCs. By exploring the parameter space, a relationship between the capillary blood pressure gradient and the CTC mechanical properties (size and stiffness) was determined. The presented computational platform and the resulting pressure-size-stiffness relationship can be employed as a tool to help study the biomechanical conditions needed for capillary arrest of CTCs and CTC clusters, provide predictive capabilities in disease progression based on biophysical CTC parameters, and aid in the rational design of size-based CTC isolation technologies where CTCs can experience large deformations due to high pressure gradients. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Kojic, Nikola; Sarioglu, A. Fatih; Toner, Mehmet] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kojic, Nikola; Sarioglu, A. Fatih; Toner, Mehmet] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02115 USA. [Kojic, Nikola; Sarioglu, A. Fatih; Toner, Mehmet] Shriners Hosp Children, Boston, MA USA. [Milosevic, Miljan; Petrovic, Dejan; Isailovic, Velibor; Kojic, Milos] Belgrade Metropolitan Univ, Bioengn Res & Dev Ctr BioIRC Kragujevac, Belgrade, Serbia. [Kojic, Milos] Houston Methodist Res Inst, Dept Nanomed, Houston, TX USA. [Haber, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. RP Kojic, N (reprint author), Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM kojic@mit.edu FU NIBIB NIH HHS [P41 EB002503, U01 EB012493] NR 43 TC 2 Z9 2 U1 2 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD AUG 1 PY 2015 VL 63 BP 187 EP 195 DI 10.1016/j.compbiomed.2015.05.024 PG 9 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA CN2RJ UT WOS:000358269300021 PM 26093786 ER PT J AU Rudders, SA Camargo, CA AF Rudders, Susan A. Camargo, Carlos A., Jr. TI Sunlight, vitamin D and food allergy SO CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review ID SERUM 25-HYDROXYVITAMIN D; 1,25-DIHYDROXYVITAMIN D-3; UNITED-STATES; EARLY-CHILDHOOD; D DEFICIENCY; INDUCED ANAPHYLAXIS; REGIONAL-VARIATION; BIRTH COHORT; US CHILDREN; SENSITIZATION AB Purpose of review The role of vitamin D in the development of food allergy is unclear. We summarize recent data on the epidemiologic link between sunlight (UVB) and food allergy, and evidence for and against a specific role for vitamin D status. Recent findings Since 2007, most epidemiologic studies have supported low sunlight (as measured by season of birth and latitude) as a risk factor for food allergy. Investigators have also looked directly at vitamin D status (as measured by serum 25OHD level) and its potential role. Although conflicting, the vitamin D studies suggest a more complicated association than a linear dose response in all individuals, with some studies indicating different associations based on host characteristics (e.g. concominant eczema, genetic polymorphisms, country of birth). Most studies have not fully examined the myriad effects of sunlight but have instead focused on a single maternal, neonatal or childhood 25OHD level. Many studies have linked sunlight with the development of food allergy but whether this is directly related to vitamin D status or a myriad of other sunlight-derived, seasonal and/or geographic factors remains uncertain. More studies are needed to investigate the role of sunlight and vitamin D status in food allergy because of their potential for primary prevention and disease modification. C1 [Rudders, Susan A.] Brown Univ, Rhode Isl Hosp, Alpert Sch Med, Dept Pediat,Div Asthma & Allergy, Providence, RI 02903 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Rheumatol Allergy & Immunol, Boston, MA USA. RP Rudders, SA (reprint author), Hasbro Childrens Hosp, Rhode Isl Hosp, 593 Eddy St, Providence, RI 02906 USA. EM srudders@lifespan.org NR 62 TC 2 Z9 2 U1 0 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-4050 EI 1473-6322 J9 CURR OPIN ALLERGY CL JI Curr. Opin. Allergy Clin. Immunol. PD AUG PY 2015 VL 15 IS 4 BP 350 EP 357 DI 10.1097/ACI.0000000000000177 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA CN1GJ UT WOS:000358166200012 PM 26110686 ER PT J AU Quijije, N AF Quijije, Nadia TI Updates in the neuroendocrinology of stress and its clinical management SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review ID DEPRESSION; BEHAVIOR; BRAIN; NEUROGENESIS; HIPPOCAMPUS; RESPONSES; DISORDER; CORTISOL; ANXIETY; LEPTIN AB Purpose of review This review will provide updates on the neurobiology of stress, with specific focus on the transmitting mechanism of stress, the intricacies of integrating stress-related information, variability in response to stressors and clinical interventions. Recent findings Neuropeptides have been implicated as a potential modulator for pathological stress via effects on neurogenesis, alterations in functional states of the cortico-limbic circuits and possible neuroprotection. Glucocorticoid receptors and mineralocorticoid receptors have been implicated in limbic modulation of stress and changes in the hypothalamic pituitary adrenal axis activity via corticosteroid signalling and feedback regulation. Chronic stress and genetic susceptibility have been found to promote intracellular mitochondrial and cellular DNA damage resulting in structural and functional alterations of neuroanatomy and neural circuitries. The interplay of stress and the neuroendocrine system appears to be influenced by alterations in genetic expression, resulting in neurochemical messenger and inflammatory cytokine alterations that impact neuroanatomy and neural circuitries to affect both central nervous system structure and function. These neurobiological contributions have been alluded to as possible contributors to stress-related psychopathologies. Clinical interventions with psychotropics, mind body therapies and behavioural therapies have been found to attenuate and reverse stress-related responses. C1 [Quijije, Nadia] Gregory Fricchione MD Massachusetts Gen Hosp, Massachusetts Gen Hosp, Boston, MA USA. RP Quijije, N (reprint author), 55 Fruit St,Warren 605, Boston, MA 02114 USA. EM nquijije@mgh.harvard.edu NR 31 TC 0 Z9 0 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD AUG PY 2015 VL 22 IS 4 BP 319 EP 324 DI 10.1097/MED.0000000000000176 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN1GN UT WOS:000358166700011 PM 26087342 ER PT J AU Al-Share, QY DeAngelis, AM Lester, SG Bowman, TA Ramakrishnan, SK Abdallah, SL Russo, L Patel, PR Kaw, MK Raphael, CK Kim, AJ Heinrich, G Lee, AD Kim, JK Kulkarni, RN Philbrick, WM Najjar, SM AF Al-Share, Qusai Y. DeAngelis, Anthony M. Lester, Sumona Ghosh Bowman, Thomas A. Ramakrishnan, Sadeesh K. Abdallah, Simon L. Russo, Lucia Patel, Payal R. Kaw, Meenakshi K. Raphael, Christian K. Kim, Andrea Jung Heinrich, Garrett Lee, Abraham D. Kim, Jason K. Kulkarni, Rohit N. Philbrick, William M. Najjar, Sonia M. TI Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance SO DIABETES LA English DT Article ID CELL-ADHESION MOLECULE-1; LOW AEROBIC CAPACITY; GROWTH-FACTOR 21; ENERGY-EXPENDITURE; LIPID-METABOLISM; ADIPOSE-TISSUE; C57BL/6 MICE; WEIGHT-LOSS; PPAR-ALPHA; PKC-DELTA AB Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic beta-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance. C1 [Al-Share, Qusai Y.; DeAngelis, Anthony M.; Lester, Sumona Ghosh; Bowman, Thomas A.; Ramakrishnan, Sadeesh K.; Abdallah, Simon L.; Russo, Lucia; Patel, Payal R.; Kaw, Meenakshi K.; Raphael, Christian K.; Kim, Andrea Jung; Heinrich, Garrett; Lee, Abraham D.; Najjar, Sonia M.] Univ Toledo, Ctr Diabet & Endocrine Res, Coll Med & Life Sci, Toledo, OH 43606 USA. [Al-Share, Qusai Y.; DeAngelis, Anthony M.; Lester, Sumona Ghosh; Bowman, Thomas A.; Ramakrishnan, Sadeesh K.; Abdallah, Simon L.; Russo, Lucia; Patel, Payal R.; Kaw, Meenakshi K.; Raphael, Christian K.; Najjar, Sonia M.] Univ Toledo, Coll Med & Life Sci, Dept Physiol & Pharmacol, Toledo, OH 43606 USA. [Kim, Andrea Jung; Heinrich, Garrett; Lee, Abraham D.] Univ Toledo, Coll Hlth Sci, Dept Rehabil Sci, Toledo, OH 43606 USA. [Kim, Jason K.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Res Div, Boston, MA 02115 USA. [Philbrick, William M.] Yale Univ, Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06510 USA. RP Najjar, SM (reprint author), Univ Toledo, Ctr Diabet & Endocrine Res, Coll Med & Life Sci, 2801 W Bancroft St, Toledo, OH 43606 USA. EM sonia.najjar@utoledo.edu FU National Institutes of Health [R01-DK-67536, R01-DK-103215, R01-DK-054254, R01-DK-083850, R01-HL-112248, U24-DK-093000]; U.S. Department of Agriculture [USDA 38903-19826] FX This work was supported by grants from the National Institutes of Health: R01-DK-67536 and R01-DK-103215 to R.N.K.; R01-DK-054254, R01-DK-083850, and R01-HL-112248 to S.M.N.; and U24-DK-093000 to the National Mouse Metabolic Phenotyping Center at University of Massachusetts. It was also partially supported by grants from the U.S. Department of Agriculture (USDA 38903-19826) to S.M.N. NR 50 TC 11 Z9 11 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2015 VL 64 IS 8 BP 2780 EP 2790 DI 10.2337/db14-1772 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN8EL UT WOS:000358671300017 PM 25972571 ER PT J AU Magnusson, M Wang, TJ Clish, C Engstrom, G Nilsson, P Gerszten, RE Melander, O AF Magnusson, Martin Wang, Thomas J. Clish, Clary Engstrom, Gunnar Nilsson, Peter Gerszten, Robert E. Melander, Olle TI Dimethylglycine Deficiency and the Development of Diabetes SO DIABETES LA English DT Article ID AMINO-ACID-METABOLISM; INSULIN SENSITIVITY; GLYCINE METABOLISM; INBORN ERROR; MALMO DIET; RISK; HUMANS; DEHYDROGENASE; VALIDATION; PREDICTION AB Experimental studies have suggested possible protective effects of dimethylglycine (DMG) on glucose metabolism. DMG is degraded to glycine through a DMG-dehydrogenase (DMGDH)-catalyzed reaction, and this is the only known pathway for the breakdown of DMG in mammals. In this study, we aimed to identify the strongest genetic determinant of circulating DMG concentration and to investigate its associations with metabolic traits and incident diabetes. In the cohort with full metabolomics data (n = 709), low plasma levels of DMG were significantly associated with higher blood glucose levels (P = 3.9E(-4)). In the genome-wide association study (GWAS) of the discovery cohort (n = 5,205), the strongest genetic signal of plasma DMG was conferred by rs2431332 at the DMGDH locus, where the major allele was associated with lower DMG levels (P = 2.5E(-15)). The same genetic variant (major allele of rs2431332) was also significantly associated with higher plasma insulin (P = 0.019), increased HOMA insulin resistance (P = 0.019), and an increased risk of incident diabetes (P = 0.001) in the pooled analysis of the discovery cohort together with the two replication cohorts (n = 20,698 and n = 7,995). These data are consistent with a possible causal role of DMG deficiency in diabetes development and encourage future studies examining if inhibition of DMGDH, or alternatively, supplementation of DMG, might prove useful for the treatment/prevention of diabetes. C1 [Magnusson, Martin] Skane Univ Hosp, Dept Heart Failure & Valvular Dis, Malmo, Sweden. [Magnusson, Martin; Engstrom, Gunnar; Nilsson, Peter; Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Wang, Thomas J.] Vanderbilt Heart & Vasc Inst, Div Cardiovasc Med, Nashville, TN USA. [Clish, Clary; Gerszten, Robert E.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. [Nilsson, Peter; Melander, Olle] Skane Univ Hosp, Dept Internal Med, Malmo, Sweden. [Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div, Boston, MA USA. [Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Magnusson, M (reprint author), Skane Univ Hosp, Dept Heart Failure & Valvular Dis, Malmo, Sweden. EM martin.magnusson@med.lu.se OI Magnusson, Martin/0000-0003-1710-5936 FU Swedish Medical Research Council; Swedish Heart and Lung Foundation; Medical Faculty of Lund University; Skane University Hospital; Albert Pahlsson Research Foundation; Crafoord Foundation; Ernhold Lundstroms Research Foundation; Region Skane; Hulda and Conrad Mossfelt Foundation; Southwest Skanes Diabetes Foundation; King Gustaf V and Queen Victoria's Foundation; Lennart Hanssons Memorial Fund; Knut and Alice Wallenberg Foundation; Marianne and Marcus Wallenberg Foundation; National Institutes of Health [NO1-HC-25195, R01-DK-HL081572]; Leducq Foundation; American Heart Association FX M.M. and O.M. were supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Skane University Hospital, the Albert Pahlsson Research Foundation, the Crafoord Foundation, the Ernhold Lundstroms Research Foundation, the Region Skane, the Hulda and Conrad Mossfelt Foundation, the Southwest Skanes Diabetes Foundation, the King Gustaf V and Queen Victoria's Foundation, the Lennart Hanssons Memorial Fund, Knut and Alice Wallenberg Foundation, and the Marianne and Marcus Wallenberg Foundation. P.N. was supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Skane University Hospital, and the Ernhold Lundstroms Research Foundation. T.J.W. and R.E.G. were supported by National Institutes of Health NO1-HC-25195 and R01-DK-HL081572, the Leducq Foundation, and the American Heart Association. NR 36 TC 8 Z9 8 U1 5 U2 18 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 AUG PY 2015 VL 64 IS 8 BP 3010 EP 3016 DI 10.2337/db14-1863 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN8EL UT WOS:000358671300038 PM 25795213 ER PT J AU Khosraviani, K Goldberg, Y Salari, B Nezami, N Peng, CF Taub, CC AF Khosraviani, Khashayar Goldberg, Ythan Salari, Behzad Nezami, Nariman Peng, Chang-Fu Taub, Cynthia C. TI The Biplane Modified Simpson's Method Accurately Estimates Pericardial Effusion Volume: A Comparison with Pericardiocentesis SO ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES LA English DT Article DE pericardial effusion; Simpson's rule; two-dimensional transthoracic echocardiogram; pericardiocentesis ID ECHOCARDIOGRAPHIC-ASSESSMENT; COMPUTED-TOMOGRAPHY; DISEASE; QUANTIFICATION; DIAGNOSIS; PITFALLS AB BackgroundPericardial effusion (PE) volume is often assessed semiqualitatively by echocardiography and categorized into minimal, small, moderate, or large. Several methods of echocardiographic quantification have been proposed, but their application is limited either by complexity or inaccuracy. We evaluated the accuracy of PE volume quantification by two-dimensional transthoracic echocardiogram (2DTTE) and commercially available volume quantification software in patients undergoing pericardiocentesis. MethodsIn a retrospective case series, immediate preprocedure echocardiograms of 33 patients for pericardiocentesis were analyzed. 2DTTE using the Simpson's method was adopted for volume measurement in the apical two- and four-chamber views. Pericardial fluid volume was calculated by taking the difference between volumes obtained by tracing the epicardial border of the heart and the pericardium. Postprocedure echocardiograms were performed to verify adequate pericardiocentesis. ResultsThe mean pericardiocentesis fluid volume was 725.1299.5mL (range, 250-1420mL). The average volume estimated echocardiographically by the Simpson's method was 657.5 +/- 276.9mL (range, 205.7-1193.2mL). There was strong direct linear correlation between echocardiographic and pericardiocentesis-derived volumes (P<0.001, r=+0.823). Echocardiography underestimated PE volume by a mean of 9.3%. ConclusionTwo-dimensional transthoracic echocardiography using biplane Simpson's method of disks can simply and accurately estimate PE volume. C1 [Khosraviani, Khashayar; Nezami, Nariman; Peng, Chang-Fu] Albert Einstein Coll Med, Jacobi Med Ctr, Dept Med, Bronx, NY 10467 USA. [Goldberg, Ythan; Taub, Cynthia C.] Montefiore Med Ctr, Albert Einstein Coll Med, Div Cardiol, Bronx, NY 10461 USA. [Salari, Behzad] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Nezami, Nariman] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol, Baltimore, MD 21287 USA. RP Taub, CC (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Noninvas Cardiol Div, Bronx, NY 10461 USA. EM ctaub@montefiore.org NR 19 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-2822 EI 1540-8175 J9 ECHOCARDIOGR-J CARD JI Echocardiography-J. Cardiovasc. Ultrasound Allied Tech. PD AUG PY 2015 VL 32 IS 8 BP 1215 EP 1220 DI 10.1111/echo.12833 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CN3IZ UT WOS:000358320500001 PM 25363313 ER PT J AU Raine, T Thoma, B Chan, TM Lin, M AF Raine, Todd Thoma, Brent Chan, Teresa M. Lin, Michelle TI FOAMSearch.net: A custom search engine for emergency medicine and critical care SO EMERGENCY MEDICINE AUSTRALASIA LA English DT Editorial Material DE custom search engine; emergency medicine; medical education; search engine ID EDUCATION; FOAM AB The number of online resources read by and pertinent to clinicians has increased dramatically. However, most healthcare professionals still use mainstream search engines as their primary port of entry to the resources on the Internet. These search engines use algorithms that do not make it easy to find clinician-oriented resources. FOAMSearch, a custom search engine (CSE), was developed to find relevant, high-quality online resources for emergency medicine and critical care (EMCC) clinicians. Using Google(TM) algorithms, it searches a vetted list of >300 blogs, podcasts, wikis, knowledge translation tools, clinical decision support tools and medical journals. Utilisation has increased progressively to >3000 users/month since its launch in 2011. Further study of the role of CSEs to find medical resources is needed, and it might be possible to develop similar CSEs for other areas of medicine. C1 [Raine, Todd] Univ British Columbia, Dept Emergency Med, Vancouver, BC V5Z 1M9, Canada. [Thoma, Brent] Massachusetts Gen Hosp, Dept Emergency Med, Learning Lab, Boston, MA 02114 USA. [Thoma, Brent] Massachusetts Gen Hosp, Dept Emergency Med, Div Med Simulat, Boston, MA 02114 USA. [Thoma, Brent] Univ Saskatchewan, Emergency Med, Saskatoon, SK, Canada. [Thoma, Brent; Chan, Teresa M.; Lin, Michelle] MedEdLIFE Res Collaborat, San Francisco, CA USA. [Chan, Teresa M.] McMaster Univ, Dept Med, Div Emergency Med, Hamilton, ON, Canada. [Lin, Michelle] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. RP Raine, T (reprint author), St Pauls Hosp, Dept Emergency Med, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. EM todd.raine@ubc.ca OI Chan, Teresa/0000-0001-6104-462X; Thoma, Brent/0000-0003-1124-5786 NR 9 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-6731 EI 1742-6723 J9 EMERG MED AUSTRALAS JI Emerg. Med. Australas. PD AUG PY 2015 VL 27 IS 4 BP 363 EP 365 DI 10.1111/1742-6723.12404 PG 3 WC Emergency Medicine SC Emergency Medicine GA CN3MO UT WOS:000358331000017 PM 25939364 ER PT J AU Forsmark, CE Diniz, AL Zhu, AX AF Forsmark, Christopher E. Diniz, Alessandro L. Zhu, Andrew X. TI Consensus Conference on Hilar Cholangiocarcinoma SO HPB LA English DT Editorial Material ID INTRAHEPATIC CHOLANGIOCARCINOMAS; MUTATIONS; RESECTION C1 [Forsmark, Christopher E.] Univ Florida, Coll Med, Gainesville, FL 32611 USA. [Diniz, Alessandro L.] AC Camargo Hosp, Sao Paulo, Brazil. [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Forsmark, CE (reprint author), Univ Florida, Coll Med, Gainesville, FL 32611 USA. EM forsmce@medicine.ufl.edu NR 10 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1365-182X EI 1477-2574 J9 HPB JI HPB PD AUG PY 2015 VL 17 IS 8 BP 666 EP 668 DI 10.1111/hpb.12451 PG 3 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CN0ZL UT WOS:000358144500003 PM 26172133 ER PT J AU van den Heuvel, MP de Reus, MA Barrett, LF Scholtens, LH Coopmans, FMT Schmidt, R Preuss, TM Rilling, JK Li, LC AF van den Heuvel, Martijn P. de Reus, Marcel A. Barrett, Lisa Feldman Scholtens, Lianne H. Coopmans, Fraukje M. T. Schmidt, Ruben Preuss, Todd M. Rilling, James K. Li, Longchuan TI Comparison of diffusion tractography and tract-tracing measures of connectivity strength in rhesus macaque connectome SO HUMAN BRAIN MAPPING LA English DT Article DE connectome; macaque; diffusion imaging; tract tracing; connectivity; white matter; connectomics ID RICH-CLUB ORGANIZATION; BRAIN NETWORKS; FUNCTIONAL CONNECTIVITY; MRI TRACTOGRAPHY; CEREBRAL-CORTEX; FIBER TRACTS; ARCHITECTURE; MATTER; SCHIZOPHRENIA; RECONSTRUCTION AB With the mapping of macroscale connectomes by means of in vivo diffusion-weighted MR Imaging (DWI) rapidly gaining in popularity, one of the necessary steps is the examination of metrics of connectivity strength derived from these reconstructions. In the field of human macroconnectomics the number of reconstructed fiber streamlines (NOS) is more and more used as a metric of cortico-cortical interareal connectivity strength, but the link between DWI NOS and in vivo animal tract-tracing measurements of anatomical connectivity strength remains poorly understood. In this technical report, we communicate on a comparison between DWI derived metrics and tract-tracing metrics of projection strength. Tract-tracing information on projection strength of interareal pathways was extracted from two commonly used macaque connectome datasets, including (1) the CoCoMac database of collated tract-tracing experiments of the macaque brain and (2) the high-resolution tract-tracing dataset of Markov and Kennedy and coworkers. NOS and density of reconstructed fiber pathways derived from DWI data acquired across 10 rhesus macaques was found to positively correlate to tract-tracing based measurements of connectivity strength across both the CoCoMac and Markov dataset (both P<0.001), suggesting DWI NOS to form a valid method of assessment of the projection strength of white matter pathways. Our findings provide confidence of in vivo DWI connectome reconstructions to represent fairly realistic estimates of the wiring strength of white matter projections. Our cross-modal comparison supports the notion of in vivo DWI to be a valid methodology for robust description and interpretation of brain wiring. Hum Brain Mapp 36:3064-3075, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [van den Heuvel, Martijn P.; de Reus, Marcel A.; Scholtens, Lianne H.; Coopmans, Fraukje M. T.] Univ Med Ctr Utrecht, Dept Psychiat, NL-3508 GA Utrecht, Netherlands. [van den Heuvel, Martijn P.; de Reus, Marcel A.; Scholtens, Lianne H.; Coopmans, Fraukje M. T.; Schmidt, Ruben] Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Psychiat Neuroimaging Program, Dept Psychiat, Charlestown, MA USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Schmidt, Ruben] Univ Med Ctr Utrecht, Dept Neurol, NL-3508 GA Utrecht, Netherlands. [Preuss, Todd M.] Yerkes Natl Primate Res Ctr, Dept Neuropharmacol & Neurol Dis, Atlanta, GA 30329 USA. [Preuss, Todd M.; Rilling, James K.] Yerkes Natl Primate Res Ctr, Ctr Translat Social Neurosci, Atlanta, GA 30329 USA. [Rilling, James K.] Emory Univ, Dept Anthropol, Atlanta, GA 30322 USA. [Rilling, James K.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Rilling, James K.] Emory Univ, Yerkes Natl Primate Res Ctr, Div Dev & Cognit Neurosci, Atlanta, GA 30322 USA. [Li, Longchuan] Emory Univ, Marcus Autism Ctr, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Li, Longchuan] Emory Univ, Biomed Imaging Technol Ctr, Georgia Inst Technol, Atlanta, GA 30322 USA. RP van den Heuvel, MP (reprint author), Univ Med Ctr Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Heidelberglaan 100,POB 85500,Room A01-126, NL-3508 GA Utrecht, Netherlands. EM M.P.vandenheuvel@umcutrecht.nl OI van den Heuvel, Martijn/0000-0003-1570-1195 FU VENI (Netherlands Organization for Scientific Research [NWO] [451-12-001]; Fellowship of the Brain Center Rudolf Magnus; John Templeton Foundation [40463]; NIH/National Institute on Aging [P01 AG026423-01A2]; National Center for Research Resources [P51RR165] FX Contract grant sponsor: Martijn van den Heuvel was supported by a VENI (Netherlands Organization for Scientific Research [NWO]; # 451-12-001) and a Fellowship of the Brain Center Rudolf Magnus. Todd Preuss and Jim Rilling were supported by the the John Templeton Foundation (Award 40463), NIH/National Institute on Aging (P01 AG026423-01A2) and National Center for Research Resources P51RR165 (superceded by the Office of Research Infrastructure Programs/OD P51OD11132). NR 61 TC 13 Z9 13 U1 1 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 AUG PY 2015 VL 36 IS 8 BP 3064 EP 3075 DI 10.1002/hbm.22828 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CM8KP UT WOS:000357949900016 PM 26058702 ER PT J AU Sadeh, N Spielberg, JM Miller, MW Milberg, WP Salat, DH Amick, MM Fortier, CB McGlinchey, RE AF Sadeh, Naomi Spielberg, Jeffrey M. Miller, Mark W. Milberg, William P. Salat, David H. Amick, Melissa M. Fortier, Catherine B. McGlinchey, Regina E. TI Neurobiological indicators of disinhibition in posttraumatic stress disorder SO HUMAN BRAIN MAPPING LA English DT Article DE cortical thickness; resting-state connectivity; impulsivity; veterans; go; no-go; trauma ID ANTERIOR CINGULATE CORTEX; GO/NO-GO TASKS; RESPONSE-INHIBITION; OEF/OIF VETERANS; METAANALYSIS; FMRI; PTSD; PSYCHOPATHOLOGY; PERFORMANCE; IMPULSIVITY AB Deficits in impulse control are increasingly recognized in association with posttraumatic stress disorder (PTSD). To our further understanding of the neurobiology of PTSD-related disinhibition, we examined alterations in brain morphology and network connectivity associated with response inhibition failures and PTSD severity. The sample consisted of 189 trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans (89% male, ages 19-62) presenting with a range of current PTSD severity. Disinhibition was measured using commission errors on a Go/No-Go (GNG) task with emotional stimuli, and PTSD was assessed using a measure of current symptom severity. Whole-brain vertex-wise analyses of cortical thickness revealed two clusters associated with PTSD-related disinhibition (Monte Carlo cluster corrected P<0.05). The first cluster included portions of right inferior and middle frontal gyri and frontal pole. The second cluster spanned portions of left medial orbital frontal, rostral anterior cingulate, and superior frontal gyrus. In both clusters, commission errors were associated with reduced cortical thickness at higher (but not lower) levels of PTSD symptoms. Resting-state functional magnetic resonance imaging analyses revealed alterations in the functional connectivity of the right frontal cluster. Together, study findings suggest that reductions in cortical thickness in regions involved in flexible decision-making, emotion regulation, and response inhibition contribute to impulse control deficits in PTSD. Furthermore, aberrant coupling between frontal regions and networks involved in selective attention, memory/learning, and response preparation suggest disruptions in functional connectivity may also play a role. Hum Brain Mapp 36:3076-3086, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Sadeh, Naomi; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Spielberg, Jeffrey M.; Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Sadeh, Naomi; Spielberg, Jeffrey M.; Miller, Mark W.; Amick, Melissa M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Milberg, William P.; Amick, Melissa M.; Fortier, Catherine B.; McGlinchey, Regina E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders & Geriatr, Educ & Clin Ctr, Boston, MA USA. [Milberg, William P.; Fortier, Catherine B.; McGlinchey, Regina E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Salat, David H.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Salat, David H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Sadeh, N (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, 150 S Huntington Ave, Boston, MA 02114 USA. EM Naomi.SamimiSadeh@va.gov RI McGlinchey, Regina/R-1971-2016; OI Sadeh, Naomi/0000-0002-8101-3190 FU NIMH [R21MH102834]; Translational Research Center for TBI and Stress Disorders (TRACTS); VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B9254-C] FX Contract grant sponsors: NIMH grant R21MH102834 "Neuroimaging Genetics of PTSD", Translational Research Center for TBI and Stress Disorders (TRACTS), and VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B9254-C). NR 55 TC 5 Z9 5 U1 1 U2 10 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 AUG PY 2015 VL 36 IS 8 BP 3076 EP 3086 DI 10.1002/hbm.22829 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CM8KP UT WOS:000357949900017 PM 25959594 ER PT J AU Wen, J Barber, GE Ananthakrishnan, AWN AF Wen, Jing Barber, Grant E. Ananthakrishnan, Ash-Win N. TI Identification of Recurrent Clostridium difficile Infection Using Administrative Codes: Accuracy and Implications for Surveillance SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID DIAGNOSIS; DISEASE; EPIDEMIOLOGY; VANCOMYCIN; STRATEGIES; GUIDELINES; MANAGEMENT; UPDATE; IMPACT; ADULTS AB OBJECTIVE. To develop an algorithm using administrative codes, laboratory data, and medication data to identify recurrent Clostridium difficile infection (CDI) and to examine the sensitivity, specificity, positive and negative predictive values, and performance of this algorithm. METHODS. We identified all patients with 2 or more International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes for CDI (008.45) from January 1 through December 31, 2013. Information on number of diagnosis codes, stool toxin assays (enzyme immunoassay or polymerase chain reaction), and unique prescriptions for metronidazole and vancomycin was identified. Logistic regression was used to identify independent predictors of recurrent CDI and a predictive model was developed. RESULTS. A total of 591 patients with at least 2 ICD-9 codes for CDI were included (median age, 66 years). The derivation cohort consisted of 157 patients among whom 43 (27%) had recurrent CDI. Presence of 3 or more ICD-9 codes for CDI (odds ratio, 2.49), 2 or more stool tests (odds ratio, 2.88), and 2 or more prescriptions for vancomycin (odds ratio, 5.87) were independently associated with confirmed recurrent CDI. A classifier incorporating 2 or more prescriptions for vancomycin and either 2 or more stool tests or 3 or more ICD-9-CM codes had a positive predictive value of 41% and negative predictive value of 90%. The area under the receiver operating characteristic curve for this combined classifier was modest (0.69). CONCLUSION. Identification of recurrent episodes of CDI in administrative data poses challenges. Accurate assessment of burden requires individual case review to confirm diagnosis. C1 [Wen, Jing] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Barber, Grant E.; Ananthakrishnan, Ash-Win N.] Harvard Univ, Sch Med, Boston, MA USA. [Ananthakrishnan, Ash-Win N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ananthakrishnan, AWN (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,9th Fl, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU Cubist; National Institutes of Health [DK097142] FX Financial support. Cubist; National Institutes of Health (grant DK097142 to A.N.A.). NR 44 TC 3 Z9 3 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2015 VL 36 IS 8 BP 893 EP 898 DI 10.1017/ice.2015.102 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CN4HS UT WOS:000358391800004 PM 25924718 ER PT J AU Menendez, ME Thornton, E Kent, S Kalajian, T Ring, D AF Menendez, Mariano E. Thornton, Emily Kent, Suzanne Kalajian, Tyler Ring, David TI A prospective randomized clinical trial of prescription of full-time versus as-desired splint wear for de Quervain tendinopathy SO INTERNATIONAL ORTHOPAEDICS LA English DT Article DE de Quervain; Splint; Disability; DASH; Outcomes ID NONSURGICAL TREATMENT; DEQUERVAINS DISEASE; TENOSYNOVITIS; INJECTION; HISTOPATHOLOGY; VALIDATION; DEPRESSION; MANAGEMENT; SYMPTOMS; WRIST AB Purpose There is no consensus on the best protocol for splint wear in the non-operative management of de Quervain tendinopathy. This study aimed to determine if there is a difference between prescription of strict splint wear compared to selective splint wear in patients with de Quervain tendinopathy. We tested the primary null hypothesis that there is no difference in upper-extremity disability eight weeks after initiating splinting between patients prescribed full-time or as-desired splint wear. Secondary study questions addressed differences in grip strength, pain intensity, and treatment satisfaction. Additionally, we evaluated the influence of psychological factors on disability. Methods Eighty-three patients diagnosed with de Quervain tendinopathy were randomly allocated into two different splint-wearing instructions: full-time wear (N = 43) or as-desired wear (N = 40). At enrollment, patients had grip strength measured and completed measures of upper-extremity disability, pain intensity, and psychological distress. An average of 7.5 weeks later, patients returned for a second visit. Analysis was by intention-to-treat and with use of mean imputation for missing data. Results Fifty-eight patients (70 %; 26 in the full-time cohort and 32 in the as-desired cohort) completed the study. There were no statistically significant differences in disability (p = 0.77), grip strength (p = 0.82), pain intensity (p = 0.36), and treatment satisfaction (p = 0.91) between patients instructed to wear the splint full-time and those instructed to use it as desired. Disability at final evaluation correlated significantly with baseline levels of pain anxiety (p = 0.008), catastrophic thinking (p = 0.001), and symptoms of depression (p < 0.001). The best multivariable linear regression model included symptoms of depression alone and accounted for 32 % of the variability in disability (p < 0.001). Conclusion There is no difference in patient-reported outcomes and grip strength with prescription of full-time or as-desired splinting, and patients can wear the splint as they prefer. These results suggest that splinting for de Quervain tendinopathy is palliative at best and strict rest is not disease modifying. C1 [Menendez, Mariano E.; Thornton, Emily; Kent, Suzanne; Kalajian, Tyler; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, Boston, MA 02114 USA. RP Menendez, ME (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr, 55 Fruit St,Suite 2100, Boston, MA 02114 USA. EM memenendez@partners.org NR 39 TC 0 Z9 0 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 EI 1432-5195 J9 INT ORTHOP JI Int. Orthop. PD AUG PY 2015 VL 39 IS 8 BP 1563 EP 1569 DI 10.1007/s00264-015-2779-6 PG 7 WC Orthopedics SC Orthopedics GA CN4FE UT WOS:000358385000015 PM 25916954 ER PT J AU Mascitelli, JR Oermann, EK Mocco, J Fifi, JT Paramasivam, S Stapleton, CJ Patel, AB AF Mascitelli, Justin R. Oermann, Eric K. Mocco, J. Fifi, Johanna T. Paramasivam, Srinivasan Stapleton, Christopher J. Patel, Aman B. TI Predictors of success following endovascular retreatment of intracranial aneurysms SO INTERVENTIONAL NEURORADIOLOGY LA English DT Article DE Intracranial aneurysm; endovascular retreatment ID STENT-ASSISTED COILING; CEREBRAL ANEURYSMS; UNRUPTURED ANEURYSMS; RECURRENT ANEURYSMS; COILED ANEURYSMS; SINGLE-CENTER; EMBOLIZATION; RECANALIZATION; MANAGEMENT; TRIAL AB Introduction: Although approximately one in every 10 patients undergoing coil embolization of intracranial aneurysms requires retreatment, the factors that are associated with outcome following retreatment remain to be fully elucidated. Methods: This is a single-center, retrospective review of 43 patients with 58 intracranial aneurysms that were retreated from 2004 to 2014. Aneurysms undergoing first time or microsurgical retreatment were excluded. Retreatment types were grouped into those without permanent parent vessel support (stand-alone and balloon-assisted coiling) versus those with permanent parent vessel support (stent-assisted coiling, stand-alone stenting, and flow diversion). The Modified Raymond Roy Classification was used to group aneurysms at all angiographic follow-up points either in the successful outcome group (Class I or II) or the unsuccessful outcome group (Class IIIa or IIIb). Results: Of aneurysms with follow-up, 50% were in the successful group and 50% in the unsuccessful group. In univariate analysis, small aneurysm size (p < 0.001), previous treatment type (p = 0.022), retreatment type (p = 0.001), and initial occlusion class (p = 0.005) were all associated with angiographic outcome. In multivariate analysis, small aneurysm size (p = 0.005, odds ratio (OR) 24.56, confidence interval (CI) 2.68-225.4) and retreatment type with permanent parent vessel support, namely stent-assisted coiling (p = 0.017, OR 31.1, CI 1.89-517.7), were associated with retreatment success. Conclusions: Small aneurysm size and retreatment with permanent parent vessel support, namely stent-assisted coiling, are predictors of success following endovascular retreatment of intracranial aneurysms. These findings could be useful in the effort to both prevent and predict treatment failure following endovascular retreatment. C1 [Mascitelli, Justin R.; Oermann, Eric K.; Mocco, J.; Fifi, Johanna T.; Paramasivam, Srinivasan] Icahn Sch Med Mt Sinai, Dept Neurosurg, New York, NY 10029 USA. [Oermann, Eric K.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Stapleton, Christopher J.; Patel, Aman B.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Stapleton, Christopher J.; Patel, Aman B.] Harvard Univ, Sch Med, Boston, MA USA. RP Patel, AB (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,WAC 745, Boston, MA 02114 USA. EM ABPATEL@mgh.harvard.edu NR 36 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 1591-0199 EI 2385-2011 J9 INTERV NEURORADIOL JI Interv. Neuroradiol. PD AUG PY 2015 VL 21 IS 4 BP 426 EP 432 DI 10.1177/1591019915590070 PG 7 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CN3LR UT WOS:000358328400001 PM 26092439 ER PT J AU Wong, CA Asch, DA Vinoya, CM Ford, CA Baker, T Town, R Merchant, RM AF Wong, Charlene A. Asch, David A. Vinoya, Cjloe M. Ford, Carol A. Baker, Tom Town, Robert Merchant, Raina M. TI Seeing Health Insurance and HealthCare.gov Through the Eyes of Young Adults SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Young adults; Health insurance; Health reform; Affordable Care Act; Health insurance exchange ID UNITED-STATES; CARE ACCESS; UNINSURANCE AB Purpose: We describe young adults' perspectives on health insurance and HealthCare.gov, including their attitudes toward health insurance, health insurance literacy, and benefit and plan preferences. Methods: We observed young adults aged 19-30 years in Philadelphia from January to March 2014 as they shopped for health insurance on HealthCare.gov. Participants were then interviewed to elicit their perceived advantages and disadvantages of insurance and factors considered important for plan selection. A 1-month follow-up interview assessed participants' plan enrollment decisions and intended use of health insurance. Data were analyzed using qualitative methodology, and salience scores were calculated for free-listing responses. Results: We enrolled 33 highly educated young adults; 27 completed the follow-up interview. The most salient advantages of health insurance for young adults were access to preventive or primary care (salience score.28) and peace of mind (. 27). The most salient disadvantage was the financial strain of paying for health insurance (. 72). Participants revealed poor health insurance literacy with 48% incorrectly defining deductible and 78% incorrectly defining coinsurance. The most salient factors reported to influence plan selection were deductible (. 48) and premium (. 45) amounts as well as preventive care (. 21) coverage. The most common intended health insurance use was primary care. Eight participants enrolled in HealthCare.gov plans: six selected silver plans, and three qualified for tax credits. Conclusions: Young adults' perspective on health insurance and enrollment via HealthCare.gov can inform strategies to design health insurance plans and communication about these plans in a way that engages and meets the needs of young adult populations. (C) 2015 Society for Adolescent Health and Medicine. All rights reserved. C1 [Wong, Charlene A.; Asch, David A.; Vinoya, Cjloe M.; Merchant, Raina M.] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, Philadelphia, PA 19104 USA. [Wong, Charlene A.; Asch, David A.; Vinoya, Cjloe M.; Baker, Tom; Town, Robert; Merchant, Raina M.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Wong, Charlene A.; Ford, Carol A.] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Div Adolescent Med, Philadelphia, PA 19104 USA. [Asch, David A.; Town, Robert] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Baker, Tom] Univ Penn, Sch Law, Philadelphia, PA 19104 USA. RP Wong, CA (reprint author), Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, 1303 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM charwong@upenn.edu FU Leonard Davis Institute Health Insurance Exchange Research Group at the University of Pennsylvania; Robert Wood Johnson Foundation Clinical Scholars Program at the University of Pennsylvania FX The study was funded by the Leonard Davis Institute Health Insurance Exchange Research Group and the Robert Wood Johnson Foundation Clinical Scholars Program, both at the University of Pennsylvania. NR 28 TC 3 Z9 3 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD AUG PY 2015 VL 57 IS 2 BP 137 EP 143 DI 10.1016/j.jadohealth.2015.04.017 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA CN2OZ UT WOS:000358262900004 PM 26092178 ER PT J AU Raines, BT Ponce, BA Reed, RD Richman, JS Hawn, MT AF Raines, Benjamin Todd Ponce, Brent A. Reed, Rhiannon D. Richman, Joshua S. Hawn, Mary T. TI Hospital Acquired Conditions Are the Strongest Predictor for Early Readmission: An Analysis of 26,710 Arthroplasties SO JOURNAL OF ARTHROPLASTY LA English DT Article DE arthroplasty; hospital acquired conditions; readmission; strongest predictor; predictors; HAC ID TOTAL JOINT ARTHROPLASTY; TOTAL HIP-ARTHROPLASTY; KNEE ARTHROPLASTY; SURGICAL CARE; UNITED-STATES; RISK-FACTORS; QUALITY; PROGRAM; REPLACEMENT; MORTALITY AB Hospital readmission is a metric of hospital quality of care, yet little is known what factors predict hospital readmission following arthroplasty. Our aim was to identify variables associated with early readmission following knee and hip arthroplasty, with focus upon hospital acquired conditions (HACs). Retrospective cohort analysis using Surgical Care Improvement Project (SCIP) and Veteran's Affairs Surgical Quality Improvement Program (VASQIP) data was performed over a five-year period. Following 26,710 total and partial primary arthroplasties (16,808 knees and 9902 hips), the overall 30-day readmission was 7.3% (1940) with readmission rates of 6.6% for knee arthroplasty and 8.4% for hip arthroplasty. HACs accounted for 42% of all complications and were the strongest predictor of readmission. Efforts to reduce these events may improve cost and safety of arthroplasty. Published by Elsevier Inc. C1 [Raines, Benjamin Todd] Univ Missouri, Dept Orthopaed Surg, Columbia, MO 65211 USA. [Raines, Benjamin Todd] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Ponce, Brent A.] Univ Alabama Birmingham, Div Orthopaed Surg, Birmingham, AL USA. [Reed, Rhiannon D.; Richman, Joshua S.; Hawn, Mary T.] Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL USA. [Reed, Rhiannon D.; Richman, Joshua S.; Hawn, Mary T.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL USA. RP Ponce, BA (reprint author), Orthopaed Specialties Bldg,1313 13th St South, Birmingham, AL USA. NR 36 TC 6 Z9 6 U1 2 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD AUG PY 2015 VL 30 IS 8 BP 1299 EP 1307 DI 10.1016/j.arth.2015.02.024 PG 9 WC Orthopedics SC Orthopedics GA CN0DN UT WOS:000358083400002 PM 25770864 ER PT J AU Schafer, AL Weaver, CM Black, DM Wheeler, AL Chang, HL Szefc, GV Stewart, L Rogers, SJ Carter, JT Posselt, AM Shoback, DM Sellmeyer, DE AF Schafer, Anne L. Weaver, Connie M. Black, Dennis M. Wheeler, Amber L. Chang, Hanling Szefc, Gina V. Stewart, Lygia Rogers, Stanley J. Carter, Jonathan T. Posselt, Andrew M. Shoback, Dolores M. Sellmeyer, Deborah E. TI Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE CALCIUM ABSORPTION; VITAMIN D; NUTRITION; BARIATRIC SURGERY; GASTRIC BYPASS SURGERY; BIOCHEMICAL MARKERS OF BONE TURNOVER ID BONE-MINERAL DENSITY; MORBIDLY OBESE-PATIENTS; BARIATRIC SURGERY; WEIGHT-LOSS; DIETARY CALCIUM; WOMEN; ASSOCIATION; VALIDATION; DEFICIENCY; INCREASES AB Roux-en-Y gastric bypass (RYGB) surgery has negative effects on bone, mediated in part by effects on nutrient absorption. Not only can RYGB result in vitamin D malabsorption, but the bypassed duodenum and proximal jejunum are also the predominant sites of active, transcellular, 1,25(OH)(2)D-mediated calcium (Ca) uptake. However, Ca absorption occurs throughout the intestine, and those who undergo RYGB might maintain sufficient Ca absorption, particularly if vitamin D status and Ca intake are robust. We determined the effects of RYGB on intestinal fractional Ca absorption (FCA) while maintaining ample 25OHD levels (goal 30ng/mL) and Ca intake (1200mg daily) in a prospective cohort of 33 obese adults (BMI 44.7 +/- 7.4kg/m(2)). FCA was measured preoperatively and 6 months postoperatively with a dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and BMD by DXA and QCT. Mean 6-month weight loss was 32.5 +/- 8.4kg (25.8%+/- 5.2% of preoperative weight). FCA decreased from 32.7%+/- 14.0% preoperatively to 6.9%+/- 3.8% postoperatively (p<0.0001), despite median (interquartile range) 25OHD levels of 41.0 (33.1 to 48.5) and 36.5 (28.8 to 40.4) ng/mL, respectively. Consistent with the FCA decline, 24-hour urinary Ca decreased, PTH increased, and 1,25(OH)(2)D increased (p0.02). Bone turnover markers increased markedly, areal BMD decreased at the proximal femur, and volumetric BMD decreased at the spine (p<0.001). Those with lower postoperative FCA had greater increases in serum CTx (=-0.43, p=0.01). Declines in FCA and BMD were not correlated over the 6 months. In conclusion, FCA decreased dramatically after RYGB, even with most 25OHD levels 30ng/mL and with recommended Ca intake. RYGB patients may need high Ca intake to prevent perturbations in Ca homeostasis, although the approach to Ca supplementation needs further study. Decline in FCA could contribute to the decline in BMD after RYGB, and strategies to avoid long-term skeletal consequences should be investigated. (c) 2015 American Society for Bone and Mineral Research. C1 [Schafer, Anne L.; Wheeler, Amber L.; Chang, Hanling; Szefc, Gina V.; Shoback, Dolores M.] San Francisco VA Med Ctr, Med Serv, San Francisco, CA 94158 USA. [Schafer, Anne L.; Wheeler, Amber L.; Chang, Hanling; Shoback, Dolores M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Weaver, Connie M.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. [Black, Dennis M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Stewart, Lygia; Rogers, Stanley J.; Carter, Jonathan T.; Posselt, Andrew M.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Stewart, Lygia] San Francisco VA Med Ctr, Surg Serv, San Francisco, CA USA. [Sellmeyer, Deborah E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Schafer, AL (reprint author), San Francisco VA Med Ctr, Endocrine Res Unit, 1700 Owens St,Room 367, San Francisco, CA 94158 USA. EM anne.schafer@ucsf.edu OI Wheeler, Amber/0000-0002-9926-1301 FU US Department of Veterans Affairs, VHA, CSRD Service [2 5 IK2 CX000549-04]; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI [UL1 TR000004]; NIH [5 K12 HD052163-15]; Endocrine Society FX This study was supported by the US Department of Veterans Affairs, VHA, CSR&D Service (Career Development Award-2 5 IK2 CX000549-04, to ALS, SFVAMC). Additional support was provided by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI grant UL1 TR000004, by NIH grant 5 K12 HD052163-15, and by an Endocrine Society Summer Research Fellowship. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Laboratory assay kits were provided by Immunodiagnostic Systems (IDS), and calcium citrate supplements were supplied by Bariatric Advantage. We thank Berdine Martin, PhD for her work in isotope ratio assessment; Barbara Arnold for study coordination and data collection; Viva Tai, RD, MPH for test meal preparation and DXA scan acquisition; Lisa Palermo, MA and Lucy Wu, MPH, for their work in data management; Nooshin Yashar, MD for study support; Saunak Sen, PhD for biostatistical advice; and Aldric Chau, Dimitry Petrenko, and Thomas Lang, PhD for CT image analysis. NR 45 TC 13 Z9 13 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2015 VL 30 IS 8 BP 1377 EP 1385 DI 10.1002/jbmr.2467 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN1JL UT WOS:000358175500005 PM 25640580 ER PT J AU Swanson, CM Srikanth, P Lee, CG Cummings, SR Jans, I Cauley, JA Bouillon, R Vanderschueren, D Orwoll, ES Nielson, CM AF Swanson, Christine M. Srikanth, Priya Lee, Christine G. Cummings, Steven R. Jans, Ivo Cauley, Jane A. Bouillon, Roger Vanderschueren, Dirk Orwoll, Eric S. Nielson, Carrie M. CA Osteoporotic Fractures Men MrOS TI Associations of 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D With Bone Mineral Density, Bone Mineral Density Change, and Incident Nonvertebral Fracture SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE 1,25-DIHYDROXYVITAMIN D; CALCITRIOL; FRACTURE; BONE MINERAL DENSITY (BMD); 25-HYDROXYVITAMIN D ID VITAMIN-D DEFICIENCY; GROWTH-FACTOR 23; OSTEOPOROTIC FRACTURES; OLDER MEN; PARATHYROID-HORMONE; ELDERLY-MEN; HIP FRACTURE; SERUM; RISK; MROS AB Relationships between 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)(2)D with bone mineral density (BMD), BMD change, and incident non-vertebral fractures in a cohort of older men and compared them with those of 25-hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 +/- 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual-energy X-ray absorptiometry (DXA) data (4.5 years of follow-up). A case-cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)(2)D were tested for each outcome. Over an average follow-up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)(2)D had lower baseline BMD. 1,25(OH)(2)D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)(2)D levels (8.70 to 51.60pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR]=1.99, 95% confidence interval [CI] 1.19-3.33). Adjustment of 1,25(OH)(2)D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)(2)D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)(2)D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)(2)D. These results do not support the hypothesis that measures of 1,25(OH)(2)D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. (c) 2015 American Society for Bone and Mineral Research. C1 [Swanson, Christine M.; Lee, Christine G.; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Div Endocrinol, Portland, OR 97239 USA. [Swanson, Christine M.; Lee, Christine G.; Orwoll, Eric S.; Nielson, Carrie M.] Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97239 USA. [Srikanth, Priya; Nielson, Carrie M.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Lee, Christine G.] Portland VA Med Ctr, Res Serv, Portland, OR USA. [Cummings, Steven R.] Calif Pacific Med Res Inst, San Francisco, CA USA. [Jans, Ivo; Vanderschueren, Dirk] Univ Hosp Leuven, KU Leuven, Lab Diagnost Med, Leuven, Belgium. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Bouillon, Roger; Vanderschueren, Dirk] Univ Hosp Leuven, KU Leuven, Lab Clin & Expt Endocrinol, Leuven, Belgium. RP Nielson, CM (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM Nielsoca@ohsu.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU National Institutes of Health; 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]; Merck Co., Inc. [SRA-12-009]; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007674-20]; VA Clinical Science Research and Development (CSR&D) Career Development Award [5IK2CW000729-02] FX The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: 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 study was supported in part by an independent investigator grant (SRA-12-009) from Merck & Co., Inc. CMS is supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant T32DK007674-20. CGL receives support from a VA Clinical Science Research and Development (CSR&D) Career Development Award, project number 5IK2CW000729-02. NR 45 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD AUG PY 2015 VL 30 IS 8 BP 1403 EP 1413 DI 10.1002/jbmr.2487 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CN1JL UT WOS:000358175500008 PM 25707402 ER PT J AU Lalama, CM Jennings, C Johnson, VA Coombs, RW McKinnon, JE Bremer, JW Cobb, BR Cloherty, GA Mellors, JW Ribaudo, HJ AF Lalama, Christina M. Jennings, Cheryl Johnson, Victoria A. Coombs, Robert W. McKinnon, John E. Bremer, James W. Cobb, Bryan R. Cloherty, Gavin A. Mellors, John W. Ribaudo, Heather J. CA AIDS Clin Trials Grp TI Comparison of Three Different FDA-Approved Plasma HIV-1 RNA Assay Platforms Confirms the Virologic Failure Endpoint of 200 Copies per Milliliter Despite Improved Assay Sensitivity SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VIRUS TYPE-1 RNA; INITIAL TREATMENT; VERSION 2.0; INFECTION; REGIMENS AB Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of <= 50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice. C1 [Lalama, Christina M.; Ribaudo, Heather J.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Jennings, Cheryl; Bremer, James W.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Johnson, Victoria A.] Univ Alabama Birmingham, Birmingham, AL USA. [Coombs, Robert W.] Univ Washington, Seattle, WA 98195 USA. [McKinnon, John E.] Case Western Reserve Univ, Henry Ford Hosp, Dept Psychiat, Detroit, MI 48202 USA. [Cobb, Bryan R.] Roche Mol Syst, Pleasanton, CA USA. [Cloherty, Gavin A.] Abbott Mol, Des Plaines, IL USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. RP Lalama, CM (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM lalama@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [UM1 AI068636, AI38858]; Statistical and Data Management Center of the AIDS Clinical Trials Group [UM1 AI068634, AI38855]; NIAID [HHSN272201200023C, HHSN266200500044C]; Abbott Molecular FX This project was supported by award numbers UM1 AI068636 and AI38858 from the National Institute of Allergy and Infectious Diseases (NIAID). This work was also supported by the Statistical and Data Management Center of the AIDS Clinical Trials Group (UM1 AI068634 and AI38855) and the Virology Quality Assurance Program (HHSN272201200023C and HHSN266200500044C) from NIAID.; V.A.J. has had Roche laboratory equipment with training support. R.W.C. has served on Roche and Abbott Molecular expert panels. J.E.M. has received grant funding from Abbott Molecular. B.R.C. is an employee of Roche Molecular Systems. G.A.C. is an employee of Abbott Molecular. J.W.M. is a consultant to Gilead Sciences and holds share options in RFS Pharmaceuticals. H.J.R. has served on a Roche expert panel. There are no other conflicts of interest to report. NR 16 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2015 VL 53 IS 8 BP 2659 EP 2666 DI 10.1128/JCM.00801-15 PG 8 WC Microbiology SC Microbiology GA CN2YV UT WOS:000358290200035 PM 26063861 ER PT J AU El-Jawahri, A Mitchell, SL Paasche-Orlow, MK Temel, JS Jackson, VA Rutledge, RR Parikh, M Davis, AD Gillick, MR Barry, MJ Lopez, L Walker-Corkery, ES Chang, YC Finn, K Coley, C Volandes, AE AF El-Jawahri, Areej Mitchell, Susan L. Paasche-Orlow, Michael K. Temel, Jennifer S. Jackson, Vicki A. Rutledge, Renee R. Parikh, Mihir Davis, Aretha D. Gillick, Muriel R. Barry, Michael J. Lopez, Lenny Walker-Corkery, Elizabeth S. Chang, Yuchiao Finn, Kathleen Coley, Christopher Volandes, Angelo E. TI A Randomized Controlled Trial of a CPR and Intubation Video Decision Support Tool for Hospitalized Patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID NOT-RESUSCITATE ORDERS; OF-LIFE CARE; ADVANCE DIRECTIVES; MEDICARE BENEFICIARIES; CRITICALLY ILL; END; CANCER; OUTCOMES; IMPACT; DEATH AB Decisions about cardiopulmonary resuscitation (CPR) and intubation are a core part of advance care planning, particularly for seriously ill hospitalized patients. However, these discussions are often avoided. We aimed to examine the impact of a video decision tool for CPR and intubation on patients' choices, knowledge, medical orders, and discussions with providers. This was a prospective randomized trial conducted between 9 March 2011 and 1 June 2013 on the internal medicine services at two hospitals in Boston. One hundred and fifty seriously ill hospitalized patients over the age of 60 with an advanced illness and a prognosis of 1 year or less were included. Mean age was 76 and 51 % were women. Three-minute video describing CPR and intubation plus verbal communication of participants' preferences to their physicians (intervention) (N = 75) or control arm (usual care) (N = 75). The primary outcome was participants' preferences for CPR and intubation (immediately after viewing the video in the intervention arm). Secondary outcomes included: orders to withhold CPR/intubation, documented discussions with providers during hospitalization, and participants' knowledge of CPR/ intubation (five-item test, range 0-5, higher scores indicate greater knowledge). Intervention participants (vs. controls) were more likely not to want CPR (64 % vs. 32 %, p < 0.0001) and intubation (72 % vs. 43 %, p < 0.0001). Intervention participants (vs. controls) were also more likely to have orders to withhold CPR (57 % vs. 19 %, p < 0.0001) and intubation (64 % vs.19 %, p < 0.0001) by hospital discharge, documented discussions about their preferences (81 % vs. 43 %, p < 0.0001), and higher mean knowledge scores (4.11 vs. 2.45; p < 0.0001). Seriously ill patients who viewed a video about CPR and intubation were more likely not to want these treatments, be better informed about their options, have orders to forgo CPR/ intubation, and discuss preferences with providers. Trial registration: Clinicaltrials.gov NCT01325519 Registry Name: A prospective randomized trial using video images in advance care planning in seriously ill hospitalized patients. C1 [El-Jawahri, Areej; Temel, Jennifer S.; Jackson, Vicki A.; Barry, Michael J.; Lopez, Lenny; Walker-Corkery, Elizabeth S.; Chang, Yuchiao; Finn, Kathleen; Coley, Christopher; Volandes, Angelo E.] Massachusetts Gen Hosp, Hematol Oncol Dept, Boston, MA 02114 USA. [El-Jawahri, Areej; Mitchell, Susan L.; Temel, Jennifer S.; Jackson, Vicki A.; Davis, Aretha D.; Gillick, Muriel R.; Barry, Michael J.; Lopez, Lenny; Chang, Yuchiao; Finn, Kathleen; Coley, Christopher; Volandes, Angelo E.] Harvard Univ, Sch Med, Boston, MA USA. [Mitchell, Susan L.] Hebrew Senior Life Inst Aging Res, Boston, MA USA. [Paasche-Orlow, Michael K.] Boston Univ, Boston, MA 02215 USA. [Rutledge, Renee R.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Parikh, Mihir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Davis, Aretha D.] Mt Auburn Hosp, Cambridge, MA USA. [Gillick, Muriel R.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP El-Jawahri, A (reprint author), Massachusetts Gen Hosp, Hematol Oncol Dept, 55 Fruit St,Cox 120, Boston, MA 02114 USA. EM ael-jawahri@partners.org OI Paasche-Orlow, Michael/0000-0002-9276-7190 FU Informed Medical Decisions Foundation [0177-1]; National Institute on Aging [K24 AG033640] FX This work was supported by a grant to Dr. Volandes from the Informed Medical Decisions Foundation (Research Grant 0177-1). Dr. Mitchell is supported by Grant No. K24 AG033640 from the National Institute on Aging. None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or approval of the manuscript. NR 27 TC 4 Z9 4 U1 5 U2 8 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 AUG PY 2015 VL 30 IS 8 BP 1071 EP 1080 DI 10.1007/s11606-015-3200-2 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400013 PM 25691237 ER PT J AU Simonetti, JA Lapham, GT Williams, EC AF Simonetti, Joseph A. Lapham, Gwen T. Williams, Emily C. TI Association Between Receipt of Brief Alcohol Intervention and Quality of Care among Veteran Outpatients with Unhealthy Alcohol Use SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE Alcoholism and addictive behavior; Quality assessment; Veterans; Patient satisfaction ID PRIMARY-HEALTH-CARE; BEHAVIORAL-COUNSELING INTERVENTIONS; SERVICES-TASK-FORCE; SCREENING SCORES; RECOMMENDATION STATEMENT; GENERAL-PRACTITIONERS; PHYSICIANS ATTITUDES; AFFAIRS OUTPATIENTS; PATIENT; CONSUMPTION AB Brief alcohol intervention, including advice to reduce or abstain from drinking, is widely recommended for general medical outpatients with unhealthy alcohol use, but it is challenging to implement. Among other implementation challenges, providers report reluctance to deliver such interventions, citing concerns about negatively affecting their patient relationships. The purpose of this study was to determine whether patient-reported receipt of brief intervention was associated with patient-reported indicators of high-quality care among veteran outpatients with unhealthy alcohol use. Cross-sectional secondary data analysis was performed using the Veterans Health Administration (VA) Survey of Healthcare Experiences of Patients (SHEP). The study included veteran outpatients who (1) responded to the outpatient long-form SHEP (2009-2011), (2) screened positive for unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire score a parts per thousand yen 3 for women, a parts per thousand yen 4 for men), and (3) responded to questions assessing receipt of brief intervention and quality of care. We used logistic regression models to estimate the adjusted predicted prevalence of reporting two indicators of high-quality care-patient ratings of their VA provider and of overall VA healthcare (range 0-10, dichotomized as a parts per thousand yen 9 indicating high quality)-for both patients who did and did not report receipt of brief intervention (receiving alcohol-related advice from a provider) within the previous year. Among 10,612 eligible veterans, 43.8 % reported having received brief intervention, and 84.2 % and 79.1 % rated their quality of care as high from their provider and the VA healthcare system, respectively. In adjusted analyses, compared to veterans who reported receiving no brief intervention, a higher proportion of veterans reporting receipt of brief intervention rated the quality of healthcare from their provider (86.9 % vs. 82.0 %, p < 0.01) and the VA overall (82.7 % vs. 75.9 %, p < 0.01) as high. In this cross-sectional analysis of veterans with unhealthy alcohol use, a higher proportion of those who reported receipt of brief intervention reported receiving high-quality care compared to those who reported having received no such intervention. These findings do not support provider concerns that delivering brief intervention adversely affects patients' perceptions of care. C1 [Simonetti, Joseph A.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Simonetti, Joseph A.; Lapham, Gwen T.; Williams, Emily C.] VA Hlth Serv Res & Dev, VA Puget Sound Healthcare Syst, Seattle Denver Ctr Innovat, Seattle, WA USA. [Simonetti, Joseph A.; Williams, Emily C.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Lapham, Gwen T.] Grp Hlth Res Inst, Seattle, WA USA. [Simonetti, Joseph A.] VA Puget Sound Healthcare Syst, Ctr Innovat Vet Ctr Value Driven Care, Seattle, WA USA. RP Simonetti, JA (reprint author), VA Hlth Serv Res Dev, VA Puget Sound Healthcare Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM simonja@uw.edu FU Ruth L. Kirschstein National Research Service Award [T32HP10002]; VA Health Services Research Development [CDA 12-276]; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI) FX During the preparation of this manuscript, Dr. Simonetti received fellowship support from the Ruth L. Kirschstein National Research Service Award (T32HP10002), administered by the Health Resources and Services Administration. Dr. Williams is supported by a Career Development Award from VA Health Services Research & Development (CDA 12-276) and is an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work at Washington University in St. Louis, MO. IRI is supported through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of any organization. Preliminary findings of this study were presented at the 2014 annual meeting of the Society of General Internal Medicine (San Diego, CA). NR 54 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2015 VL 30 IS 8 BP 1097 EP 1104 DI 10.1007/s11606-015-3218-5 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400015 PM 25691238 ER PT J AU Williams, EC Achtmeyer, CE Thomas, RM Grossbard, JR Lapham, GT Chavez, LJ Ludman, EJ Berger, D Bradley, KA AF Williams, Emily C. Achtmeyer, Carol E. Thomas, Rachel M. Grossbard, Joel R. Lapham, Gwen T. Chavez, Laura J. Ludman, Evette J. Berger, Douglas Bradley, Katharine A. TI Factors Underlying Quality Problems with Alcohol Screening Prompted by a Clinical Reminder in Primary Care: A Multi-site Qualitative Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE alcohol screening; qualitative; clinical reminders; quality ID IDENTIFICATION TEST AUDIT; HEALTH-SERVICES RESEARCH; DECISION-SUPPORT-SYSTEM; BRIEF INTERVENTION; IMPLEMENTATION STRATEGIES; PREVENTIVE SERVICES; USE DISORDERS; PERFORMANCE; SETTINGS; MISUSE AB Population-based alcohol screening is recommended in primary care, and increasingly incentivized by policies, yet is challenging to implement. The U.S. Veterans Health Administration (VA) achieved high rates of screening using a national performance measure and associated electronic clinical reminder to prompt and facilitate screening and document results. However, the sensitivity of alcohol screening for identifying unhealthy alcohol use is low in VA clinics. We aimed to understand factors that might contribute to low sensitivity of alcohol screening. This was an observational, qualitative study. Participants included clinical staff responsible for conducting alcohol screening and nine independently managed primary care clinics of a single VA medical center in the Northwestern U.S. Four researchers observed clinical staff as they conducted alcohol screening. Observers took handwritten notes, which were transcribed and coded iteratively. Template analysis identified a priori and emergent themes. We observed 72 instances of alcohol screening conducted by 31 participating staff. Observations confirmed known challenges to implementation of care using clinical reminders, including workflow and flexibility limitations. Three themes specific to alcohol screening emerged. First, most observed screening was conducted verbally, guided by the clinical reminder, although some variability in approaches to screening (e.g., paper-based or laminate-based screening) was observed. Second, specific verbal screening practices that might contribute to low sensitivity of clinical screening were identified, including conducting non-verbatim screening and making inferences, assumptions, and/or suggestions to input responses. Third, staff introduced and adapted screening questions to enhance patient comfort. This qualitative study in nine clinics found that implementation of alcohol screening facilitated by a clinical reminder resulted primarily in verbal screening in which questions were not asked vertbatim and were otherwise adapted. Non-verbal approaches to screening, or patient self-administration, may enhance validity and standardization of screening while simultaneously addressing limitations of the clinical reminder and issues related to perceived discomfort. C1 [Williams, Emily C.; Achtmeyer, Carol E.; Thomas, Rachel M.; Lapham, Gwen T.; Chavez, Laura J.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Ctr Innovat Vet Ctr & Value Driven Care, Hlth Serv Res & Dev HSR&D, Seattle, WA USA. [Achtmeyer, Carol E.; Berger, Douglas] VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA 98101 USA. [Grossbard, Joel R.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Ctr Excellence Substance Abuse Treatment & Educ C, Seattle, WA 98101 USA. [Berger, Douglas; Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Chavez, Laura J.; Bradley, Katharine A.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Ludman, Evette J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lapham, Gwen T.; Ludman, Evette J.; Bradley, Katharine A.] Grp Hlth Res Inst, Seattle, WA USA. RP Williams, EC (reprint author), VA Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM emily.williams3@va.gov FU VA Health Services Research Development; VA Quality Enhancement Research Initiative [RRP 09-178]; Career Development Award from VA Health Services Research Development [CDA 12-276]; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI); Agency for Healthcare Research and Quality (AHRQ) [NIH 1R36HS022800-01] FX This study was funded by VA Health Services Research & Development and VA Quality Enhancement Research Initiative (RRP 09-178). Dr. Williams is supported by a Career Development Award from VA Health Services Research & Development (CDA 12-276), and is an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work at Washington University in St. Louis. IRI is supported through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI). Dr. Bradley's time on this study was supported by the Center of Excellence for Substance Abuse Treatment and Education (CESATE) at VA Puget Sound. Ms. Chavez is supported by an Agency for Healthcare Research and Quality (AHRQ) Dissertation Grant (NIH 1R36HS022800-01). NR 62 TC 14 Z9 14 U1 6 U2 12 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 AUG PY 2015 VL 30 IS 8 BP 1125 EP 1132 DI 10.1007/s11606-015-3248-z PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400019 PM 25731916 ER PT J AU Shelton, JB Ochotorena, L Bennett, C Shekelle, P Kwan, L Skolarus, T Goldzweig, C AF Shelton, Jeremy B. Ochotorena, Lee Bennett, Carol Shekelle, Paul Kwan, Lorna Skolarus, Ted Goldzweig, Caroline TI Reducing PSA-Based Prostate Cancer Screening in Men Aged 75 Years and Older with the Use of Highly Specific Computerized Clinical Decision Support SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE electronic health records; physician decision support; cancer screening; applied informatics; implementation research; quality improvement ID HEALTH INFORMATION-TECHNOLOGY; ORDER ENTRY; CARE; INTERVENTIONS; MORTALITY; ALERTS; PHYSICIANS; IMPLEMENT; BENEFITS; DELIVERY AB In 2012, the Veterans Health Administration (VHA) implemented guidelines seeking to reduce PSA-based screening for prostate cancer in men aged 75 years and older. To reduce the use of inappropriate PSA-based prostate cancer screening among men aged 75 and over. The Veterans Affairs Greater Los Angeles Healthcare System (VA GLA) We developed a highly specific computerized clinical decision support (CCDS) alert to remind providers, at the moment of PSA screening order entry, of the current guidelines and institutional policy. We implemented the tool in a prospective interrupted time series study design over 15 months, and compared the trends in monthly PSA screening rate at baseline to the CCDS on and off periods of the intervention. A total of 30,150 men were at risk, or eligible, for screening, and 2,001 men were screened. The mean monthly screening rate during the 15-month baseline period was 8.3 %, and during the 15-month intervention period, was 4.6 %. The screening rate declined by 38 % during the baseline period and by 40 % and 30 %, respectively, during the two periods when the CCDS tool was turned on. The screening rate ratios for the baseline and two periods when the CCDS tool was on were 0.97, 0.78, and 0.90, respectively, with a significant difference between baseline and the first CCDS-on period (p < 0.0001), and a trend toward a difference between baseline and the second CCDS-on period (p = 0.056). Implementation of a highly specific CCDS tool alone significantly reduced inappropriate PSA screening in men aged 75 years and older in a reproducible fashion. With this simple intervention, evidence-based guidelines were brought to bear at the point of care, precisely for the patients and providers for whom they were most helpful, resulting in more appropriate use of medical resources. C1 [Shelton, Jeremy B.; Ochotorena, Lee; Bennett, Carol; Shekelle, Paul; Goldzweig, Caroline] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Shelton, Jeremy B.; Bennett, Carol; Kwan, Lorna] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Skolarus, Ted] Vet Adm Ann Arbor Healthcare Syst, Hlth Serv Res & Dev, Ann Arbor, MI USA. RP Shelton, JB (reprint author), Greater Los Angeles VA, Los Angeles, CA 90073 USA. EM jeremybshelton@gmail.com NR 34 TC 2 Z9 2 U1 2 U2 5 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 AUG PY 2015 VL 30 IS 8 BP 1133 EP 1139 DI 10.1007/s11606-015-3249-y PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400020 PM 25740462 ER PT J AU Clair, C Cohen, MJ Eichler, F Selby, KJ Rigotti, NA AF Clair, Carole Cohen, Marya J. Eichler, Florian Selby, Kevin J. Rigotti, Nancy A. TI The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE Diabetes; Smoking cessation; Comorbidity ID POTENTIAL RISK-FACTORS; GLYCEMIC CONTROL; MICROVASCULAR COMPLICATIONS; SENSORY NEUROPATHY; PUBLICATION BIAS; FOLLOW-UP; MELLITUS; POLYNEUROPATHY; PREVALENCE; POPULATION AB Studies suggest that smoking may be a risk factor for the development of microvascular complications such as diabetic peripheral neuropathy (DPN). The objective of this study was to assess the relationship between smoking and DPN in persons with type 1 or type 2 diabetes. A systematic review of the PubMed, Embase, and Cochrane clinical trials databases was conducted for the period from January 1966 to November 2014 for cohort, cross-sectional and case-control studies that assessed the relationship between smoking and DPN. Separate meta-analyses for prospective cohort studies and case-control or cross-sectional studies were performed using random effects models. Thirty-eight studies (10 prospective cohort and 28 cross-sectional) were included. The prospective cohort studies included 5558 participants without DPN at baseline. During follow-up ranging from 2 to 10 years, 1550 cases of DPN occurred. The pooled unadjusted odds ratio (OR) of developing DPN associated with smoking was 1.26 (95 % CI 0.86-1.85; I (2) = 74 %; evidence grade: low strength). Stratified analyses of the prospective studies revealed that studies of higher quality and with better levels of adjustment and longer follow-up showed a significant positive association between smoking and DPN, with less heterogeneity. The cross-sectional studies included 27,594 participants. The pooled OR of DPN associated with smoking was 1.42 (95 % CI 1.21-1.65; I (2) = 65 %; evidence grade: low strength). There was no evidence of publication bias. Smoking may be associated with an increased risk of DPN in persons with diabetes. Further studies are needed to test whether this association is causal and whether smoking cessation reduces the risk of DPN in adults with diabetes. C1 [Clair, Carole; Selby, Kevin J.] Univ Lausanne Hosp, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Cohen, Marya J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Internal Med, Boston, MA USA. [Eichler, Florian] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rigotti, Nancy A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tobacco Res & Treatment Ctr,Div Gen Internal Med, Boston, MA USA. RP Clair, C (reprint author), Policlin Med Univ, Rue Bugnon 44, CH-1011 Lausanne, Switzerland. EM carole.clair@hospvd.ch RI Clair, Carole/D-9786-2014 OI Clair, Carole/0000-0001-5281-0943 FU Swiss National Science Foundation [PBLAP3-127728/1]; SICPA foundation FX CC was supported by a grant from the Swiss National Science Foundation PBLAP3-127728/1 and by a grant from the SICPA foundation. NR 71 TC 2 Z9 3 U1 1 U2 8 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 AUG PY 2015 VL 30 IS 8 BP 1193 EP 1203 DI 10.1007/s11606-015-3354-y PG 11 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CN3WR UT WOS:000358359400035 PM 25947882 ER PT J AU Gelber, SE Brent, E Redecha, P Perino, G Tomlinson, S Davisson, RL Salmon, JE AF Gelber, Shari E. Brent, Elyssa Redecha, Patricia Perino, Giorgio Tomlinson, Stephen Davisson, Robin L. Salmon, Jane E. TI Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; COLLAGEN-INDUCED ARTHRITIS; TNF-ALPHA; NEUTROPHIL ACTIVATION; GROWTH RESTRICTION; MOUSE MODEL; ANGIOGENIC FACTORS; TROPHOBLAST CELLS; FETAL INJURY; COMPLEMENT AB Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome, but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human adverse pregnancy outcome, with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal/fetal interface leads to elevation in local TNF-alpha levels, reduction of the essential angiogenic factor vascular endothelial growth factor, and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-alpha improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation. C1 [Gelber, Shari E.; Brent, Elyssa] Weill Cornell Med Ctr, Dept Obstet & Gynecol, New York, NY 10065 USA. [Redecha, Patricia; Salmon, Jane E.] Hosp Special Surg, Cornell Med Ctr, Dept Med, New York, NY 10021 USA. [Perino, Giorgio] Hosp Special Surg, Dept Pathol & Lab Med, New York, NY 10021 USA. [Tomlinson, Stephen] Med Univ S Carolina, Darby Childrens Res Inst, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Davisson, Robin L.] Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA. [Davisson, Robin L.] Weill Cornell Med Ctr, Dept Cell & Dev Biol, New York, NY 10065 USA. RP Salmon, JE (reprint author), Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. EM SalmonJ@hss.edu FU March of Dimes; National Institute of Child Health and Human Development [NIHK12HD000849]; Clinical and Translation Science Center at Weill Cornell Medical Center [UL1RR024996]; National Institutes of Health [R01 HL086576]; Veterans Affairs Grants [1I01RX001141, 5I01BX001218]; Qatar National Research Fund Grant [NPRP09-1099-279]; National Cancer Institute [P30 CA008748] FX This work was supported by the March of Dimes, National Institute of Child Health and Human Development Grant NIHK12HD000849, and Clinical and Translation Science Center at Weill Cornell Medical Center Grant UL1RR024996 (all to S.E.G.); by National Institutes of Health Grant R01 HL086576 and Veterans Affairs Grants 1I01RX001141 and 5I01BX001218 (all to S.T.); and by Qatar National Research Fund Grant NPRP09-1099-279 (to R.L.D.). Immunohistochemistry was performed at the Molecular Cytology Core Facility of Memorial Sloan Kettering Cancer Center, which is supported by National Cancer Institute Grant P30 CA008748. NR 62 TC 8 Z9 8 U1 0 U2 5 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 AUG 1 PY 2015 VL 195 IS 3 BP 1129 EP 1138 DI 10.4049/jimmunol.1402220 PG 10 WC Immunology SC Immunology GA CM9ZO UT WOS:000358070400042 PM 26071558 ER PT J AU Li, HW Andreola, G Carlson, AL Shao, S Lin, CP Zhao, GL Sykes, M AF Li, Hao Wei Andreola, Giovanna Carlson, Alicia L. Shao, Steven Lin, Charles P. Zhao, Guiling Sykes, Megan TI Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; IN-VIVO; CD8-T-CELL MEMORY; CLONAL EXPANSION; CD4-T-CELL HELP; ACUTE INFECTION; EFFECTOR-CELLS; MIXED CHIMERAS; CD8(+); RESPONSES AB Inflammation in the priming host environment has critical effects on the graft-versus-host (GVH) responses mediated by naive donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show in this article that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared with naive T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation, and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared with freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-gamma dependent. TLR stimulation after transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for graft-versus-host disease and T cell-mediated immunotherapies. C1 [Li, Hao Wei; Shao, Steven; Zhao, Guiling; Sykes, Megan] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA. [Li, Hao Wei; Andreola, Giovanna; Zhao, Guiling; Sykes, Megan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Carlson, Alicia L.; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Adv Microscopy Program, Boston, MA 02114 USA. [Carlson, Alicia L.; Lin, Charles P.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Sykes, M (reprint author), Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, 650 West 168th St,BB 15-12, New York, NY 10032 USA. EM Megan.Sykes@columbia.edu FU National Cancer Institute PO1 Grant [CA111519]; Fondazione Umberto Veronesi, Italy FX This work was supported by National Cancer Institute PO1 Grant CA111519 and a research award from the Fondazione Umberto Veronesi, Italy (to G.A.). NR 41 TC 0 Z9 0 U1 0 U2 2 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 AUG 1 PY 2015 VL 195 IS 3 BP 1282 EP 1292 DI 10.4049/jimmunol.1401511 PG 11 WC Immunology SC Immunology GA CM9ZO UT WOS:000358070400056 PM 26085679 ER PT J AU Ho, AW Tsao, H AF Ho, Allen W. Tsao, Hensin TI Targeted Therapies in Melanoma: Translational Research at Its Finest SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID BRAF-MUTATED MELANOMA; MEK INHIBITION; METASTATIC MELANOMA; MALIGNANT-MELANOMA; IMPROVED SURVIVAL; OPEN-LABEL; MUTATIONS; VEMURAFENIB; DABRAFENIB; TRIAL C1 [Ho, Allen W.; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Edwards 211,55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org FU NCI NIH HHS [K24 CA149202] NR 33 TC 3 Z9 3 U1 0 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 AUG PY 2015 VL 135 IS 8 BP 1929 EP 1933 DI 10.1038/jid.2015.14 PG 5 WC Dermatology SC Dermatology GA CN2SL UT WOS:000358272100001 PM 26174532 ER PT J AU Lohn, JS Vedak, P Strazzula, L Kroshinsky, D AF Lohn, J. St. Vedak, P. Strazzula, L. Kroshinsky, D. TI Estimating health care costs associated with recurrent outpatient cellulitis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology CY MAY 06-09, 2015 CL Atlanta, GA SP Soc Investigat Dermatol C1 [Lohn, J. St.; Vedak, P.; Strazzula, L.; Kroshinsky, D.] Massachusetts Gen Hosp, Dermatol, Boston, MA 02114 USA. NR 0 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2015 VL 135 IS 8 MA LB744 BP S2 EP S2 PG 1 WC Dermatology SC Dermatology GA CN2SL UT WOS:000358272100040 ER PT J AU Govindarajan, ST Cohen-Adad, J Sormani, MP Fan, AP Louapre, C Mainero, C AF Govindarajan, Sindhuja T. Cohen-Adad, Julien Sormani, Maria Pia Fan, Audrey P. Louapre, Celine Mainero, Caterina TI Reproducibility of T-2* mapping in the human cerebral cortex in vivo at 7 tesla MRI SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE 7T MRI; T-2*; reproducibility; cortex; myelin; iron ID SURFACE-BASED ANALYSIS; INTRACORTICAL LAMINAR PATHOLOGY; MULTIPLE-SCLEROSIS; FIELD-STRENGTH; IRON CONTENT; BRAIN; CONTRAST; PHASE AB BackgroundTo assess the test-retest reproducibility of cortical mapping of T-2* relaxation rates at 7 Tesla (T) MRI. T-2* maps have been used for studying cortical myelo-architecture patterns in vivo and for characterizing conditions associated with changes in iron and/or myelin concentration. MethodsT(2)* maps were calculated from 7T multi-echo T-2*-weighted images acquired during separate scanning sessions on 8 healthy subjects. The reproducibility of surface-based cortical T-2* mapping was assessed at different depths of the cortex; from pial surface (0% depth) towards gray/white matter boundary (100% depth), across cortical regions and hemispheres, using coefficients of variation (COVs=SD/mean) between each couple (scan-rescan) of average T-2* measurements. ResultsAverage cortical T-2* was significantly different among 25%, 50%, and 75% depths (analysis of variance, P<0.001). Coefficient of variations were very low within cortical regions, and whole cortex (average COV=0.83-1.79%), indicating a high degree of reproducibility in T-2* measures. ConclusionSurface-based mapping of T-2* relaxation rates as a function of cortical depth is reproducible and could prove useful for studying the laminar architecture of the cerebral cortex in vivo, and for investigating physiological and pathological states associated with changes in iron and/or myelin concentration. J. Magn. Reson. Imaging 2015;42:290-296. C1 [Govindarajan, Sindhuja T.; Cohen-Adad, Julien; Fan, Audrey P.; Louapre, Celine; Mainero, Caterina] Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Cohen-Adad, Julien] Polytechn Montreal, Inst Biomed Engn, Montreal, PQ, Canada. [Sormani, Maria Pia] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Fan, Audrey P.] MIT, Cambridge, MA 02139 USA. [Louapre, Celine; Mainero, Caterina] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Mainero, C (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM caterina@nmr.mgh.harvard.edu FU National Multiple Sclerosis Society [4281-RG-A-1]; Claflin Award; National Center for Research Resources [P41-RR14075]; NCRR BIRN Morphometric [BIRN002, U24 RR021382]; NMSS [FG 1892A1] FX Contract grant sponsor: National Multiple Sclerosis Society; Contract grant number: 4281-RG-A-1; Contract grant sponsor: the Claflin Award; Contract grant sponsor: the National Center for Research Resources; Contract grant sponsor: P41-RR14075; Contract grant sponsor: the NCRR BIRN Morphometric; Contract grant numbers: Project BIRN002; U24 RR021382; Contract grant sponsor: NMSS; Contract grant number: FG 1892A1 NR 31 TC 5 Z9 5 U1 2 U2 2 PU WILEY-BLACKWELL 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 AUG PY 2015 VL 42 IS 2 BP 290 EP 296 DI 10.1002/jmri.24789 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN2NM UT WOS:000358258600007 PM 25407671 ER PT J AU Reyhan, M Wang, Z Li, M Kim, HJ Gupta, HS Lloyd, SG Dell'Italia, LJ Denney, T Ennis, DB AF Reyhan, Meral Wang, Zhe Li, Ming Kim, Hyun J. Gupta, Himanshu Lloyd, Steven G. Dell'Italia, Louis J. Denney, Thomas Ennis, Daniel B. TI Left ventricular twist and shear in patients with primary mitral regurgitation SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE mitral regurgitation; left ventricle; twist; shear; torsion ID CARDIOVASCULAR MAGNETIC-RESONANCE; CARDIAC-FUNCTION; TORSION; MECHANICS; IMAGES; MODEL AB PurposeTo evaluate the relationship between left ventricular (LV) twist, shear, and twist-per-volume and the severity of mitral regurgitation (MR). Primary MR is a valvular disorder that induces LV dysfunction. There exist several measures of LV rotational mechanics, but it remains unclear which measure of LV dysfunction best accords with the severity of MR. We hypothesized that LV systolic twist-per-volume slope would decrease with increasing severity of MR because of both decreases in rotational mechanics and increases in stroke volumes. Materials and MethodsNormal subjects (n=54), moderate MR patients (n=29), and severe MR patients (n=54) were studied. Magnetic resonance imaging (MRI) was performed on a 1.5T scanner and grid-tagged LV images were collected at the LV base and LV apex. Measures of LV rotational mechanics were derived from tagged images using Fourier Analysis of STimulated echoes (FAST). ResultsPeak systolic twist-per-volume slope was significantly different for all pairwise comparisons (P<0.0001) and compared to normal subjects (-0.140.05 degrees/mL) was decreased in moderate MR (-0.12 +/- 0.04 degrees/mL) and further decreased in severe MR (-0.07 +/- 0.03 degrees/mL). ConclusionPeak systolic twist-per-volume slope significantly decreased with increasing severity of MR and is therefore a suitable quantitative imaging biomarker for LV dysfunction in patients with MR. J. Magn. Reson. Imaging 2015;42:400-406. C1 [Reyhan, Meral; Ennis, Daniel B.] Univ Calif Los Angeles, Biomed Phys Interdept Program, Los Angeles, CA USA. [Reyhan, Meral; Wang, Zhe; Ennis, Daniel B.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Wang, Zhe; Kim, Hyun J.; Ennis, Daniel B.] Univ Calif Los Angeles, Dept Radiol Sci, Los Angeles, CA USA. [Li, Ming; Denney, Thomas] Auburn Univ, Dept Elect & Comp Engn, Auburn, AL 36849 USA. [Gupta, Himanshu; Lloyd, Steven G.; Dell'Italia, Louis J.] Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Birmingham, AL USA. [Gupta, Himanshu; Lloyd, Steven G.; Dell'Italia, Louis J.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Ennis, DB (reprint author), 10945 LeConte Ave,Ste 1417, Los Angeles, CA 90095 USA. EM Daniel.Ennis@ucla.edu FU American Heart Association [AHA 11PRE6080005]; National Institutes of Health National Heart, Lung, and Blood Institute [NIH/NHLIB R00-HL087614, NIH/NHLIB grant P50-HL077100] FX Contract grant sponsor: American Heart Association and the National Institutes of Health National Heart, Lung, and Blood Institute; Contract grant numbers: AHA 11PRE6080005 (to M.R.), NIH/NHLIB R00-HL087614 (to D.E.), NIH/NHLIB grant P50-HL077100 (to T.D.). NR 23 TC 2 Z9 2 U1 2 U2 6 PU WILEY-BLACKWELL 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 AUG PY 2015 VL 42 IS 2 BP 400 EP 406 DI 10.1002/jmri.24811 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN2NM UT WOS:000358258600018 PM 25408263 ER PT J AU Krieg, TD Salinas, FS Narayana, S Fox, PT Mogul, DJ AF Krieg, Todd D. Salinas, Felipe S. Narayana, Shalini Fox, Peter T. Mogul, David J. TI Computational and experimental analysis of TMS-induced electric field vectors critical to neuronal activation SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE transcranial magnetic stimulation; PET; finite element modeling; neocortex ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; DORSOLATERAL PREFRONTAL CORTEX; SURFACE-BASED ANALYSIS; DESCENDING VOLLEYS; CONSCIOUS HUMANS; CEREBRAL-CORTEX; BRAIN; EXCITATION; NERVE AB Objective. Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation. Approach. Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject's cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E-field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET. Main results. This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E-field vectors in the outward normal direction suggesting inhibitory responses. Significance. These results provide critical new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality. C1 [Krieg, Todd D.; Mogul, David J.] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Salinas, Felipe S.; Narayana, Shalini; Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Narayana, Shalini] Univ Tennessee Hlth Sci Ctr, Dept Pediat, Memphis, TN USA. [Fox, Peter T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Krieg, TD (reprint author), IIT, Dept Biomed Engn, Chicago, IL 60616 USA. EM mogul@iit.edu NR 53 TC 5 Z9 5 U1 7 U2 13 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2015 VL 12 IS 4 AR 046014 DI 10.1088/1741-2560/12/4/046014 PG 11 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA CN1KM UT WOS:000358178900016 PM 26052136 ER PT J AU Westover, MB Kim, SE Ching, S Purdon, PL Brown, EN AF Westover, M. Brandon Kim, Seong-Eun Ching, ShiNung Purdon, Patrick L. Brown, Emery N. TI Robust control of burst suppression for medical coma SO JOURNAL OF NEURAL ENGINEERING LA English DT Article DE control; burst suppression; medical coma; anesthesia; electroencephalogram ID CLOSED-LOOP CONTROL; REFRACTORY STATUS EPILEPTICUS; CRITICALLY-ILL PATIENTS; BISPECTRAL INDEX BIS; INTENSIVE-CARE-UNIT; CIRCULATORY ARREST; PHARMACOKINETIC MODELS; PERFORMANCE ASSESSMENT; PROPOFOL ANESTHESIA; GENERAL-ANESTHESIA AB Objective. Medical coma is an anesthetic-induced state of brain inactivation, manifest in the electroencephalogram by burst suppression. Feedback control can be used to regulate burst suppression, however, previous designs have not been robust. Robust control design is critical under real-world operating conditions, subject to substantial pharmacokinetic and pharmacodynamic parameter uncertainty and unpredictable external disturbances. We sought to develop a robust closed-loop anesthesia delivery (CLAD) system to control medical coma. Approach. We developed a robust CLAD system to control the burst suppression probability (BSP). We developed a novel BSP tracking algorithm based on realistic models of propofol pharmacokinetics and pharmacodynamics. We also developed a practical method for estimating patient-specific pharmacodynamics parameters. Finally, we synthesized a robust proportional integral controller. Using a factorial design spanning patient age, mass, height, and gender, we tested whether the system performed within clinically acceptable limits. Throughout all experiments we subjected the system to disturbances, simulating treatment of refractory status epilepticus in a real-world intensive care unit environment. Main results. In 5400 simulations, CLAD behavior remained within specifications. Transient behavior after a step in target BSP from 0.2 to 0.8 exhibited a rise time (the median (min, max)) of 1.4 [1.1, 1.9] min; settling time, 7.8 [4.2, 9.0] min; and percent overshoot of 9.6 [2.3, 10.8]%. Under steady state conditions the CLAD system exhibited a median error of 0.1 [-0.5, 0.9]%; inaccuracy of 1.8 [0.9, 3.4]%; oscillation index of 1.8 [0.9, 3.4]%; and maximum instantaneous propofol dose of 4.3 [2.1, 10.5] mg kg(-1). The maximum hourly propofol dose was 4.3 [2.1, 10.3] mg kg(-1) h(-1). Performance fell within clinically acceptable limits for all measures. Significance. A CLAD system designed using robust control theory achieves clinically acceptable performance in the presence of realistic unmodeled disturbances and in spite of realistic model uncertainty, while maintaining infusion rates within acceptable safety limits. C1 [Westover, M. Brandon; Brown, Emery N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kim, Seong-Eun; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Ching, ShiNung] Washington Univ, Dept Elect & Syst Engn, St Louis, MO USA. [Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Westover, MB (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM mwestover@mgh.harvard.edu; enb@neurostat.mit.edu FU NIGMS NIH HHS [R01 GM104948]; NIH HHS [DP1 OD003646]; NINDS NIH HHS [K23 NS090900] NR 81 TC 2 Z9 2 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 EI 1741-2552 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2015 VL 12 IS 4 AR 046004 DI 10.1088/1741-2560/12/4/046004 PG 22 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA CN1KM UT WOS:000358178900006 PM 26020243 ER PT J AU Rahman, R Catalano, PJ Reardon, DA Norden, AD Wen, PY Lee, EQ Nayak, L Beroukhim, R Dunn, IF Golby, AJ Johnson, MD Chiocca, EA Claus, EB Alexander, BM Arvold, ND AF Rahman, Rifaquat Catalano, Paul J. Reardon, David A. Norden, Andrew D. Wen, Patrick Y. Lee, Eudocia Q. Nayak, Lakshmi Beroukhim, Rameen Dunn, Ian F. Golby, Alexandra J. Johnson, Mark D. Chiocca, E. Antonio Claus, Elizabeth B. Alexander, Brian M. Arvold, Nils D. TI Incidence, risk factors, and reasons for hospitalization among glioblastoma patients receiving chemoradiation SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article; Proceedings Paper CT 56th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) CY SEP 14-17, 2014 CL San Francisco, CA SP Amer Soc Radiat Oncol DE Glioblastoma; Chemoradiation; Toxicity; Hospitalization; Survival ID HIGH-GRADE GLIOMAS; RADIOTHERAPY PLUS CONCOMITANT; BRAIN-TUMOR PATIENTS; QUALITY-OF-LIFE; RADIATION-THERAPY; MALIGNANT GLIOMA; ADJUVANT TEMOZOLOMIDE; ELDERLY-PATIENTS; DECISION-MAKING; OLDER PATIENTS AB Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score a parts per thousand yen 70. Twenty-six percent of patients underwent gross total resection, 77 % received a parts per thousand yen 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival. C1 [Rahman, Rifaquat] Harvard Univ, Harvard Radiat Oncol Program, Sch Med, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Reardon, David A.; Norden, Andrew D.; Wen, Patrick Y.; Lee, Eudocia Q.; Nayak, Lakshmi; Beroukhim, Rameen] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Dunn, Ian F.; Golby, Alexandra J.; Johnson, Mark D.; Chiocca, E. Antonio; Claus, Elizabeth B.] Dana Farber Brigham & Womens Canc Ctr, Dept Neurosurg, Boston, MA USA. [Claus, Elizabeth B.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Alexander, Brian M.; Arvold, Nils D.] Harvard Univ, Dept Radiat Oncol, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. RP Arvold, ND (reprint author), Harvard Univ, Dept Radiat Oncol, Sch Med, Dana Farber Brigham & Womens Canc Ctr, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM narvold@partners.org NR 52 TC 3 Z9 3 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2015 VL 124 IS 1 BP 137 EP 146 DI 10.1007/s11060-015-1820-3 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CN1EO UT WOS:000358160300017 PM 26033544 ER PT J AU Dinkel, J Khalilzadeh, O Phan, CM Goenka, AH Yoo, AJ Hirsch, JA Gupta, R AF Dinkel, Julien Khalilzadeh, Omid Phan, Catherine M. Goenka, Ajit H. Yoo, Albert J. Hirsch, Joshua A. Gupta, Rajiv TI Technical limitations of dual-energy CT in neuroradiology: 30-month institutional experience and review of literature SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID IODINATED CONTRAST; URINARY STONES; PHANTOM; PRINCIPLES; HEMORRHAGE; SCATTER; IMAGES AB Background Dual-energy CT (DECT) has been shown to be a useful modality in neuroradiology. Objective To assess failure modes and limitations of DECT in different neuroimaging applications. Patients and methods Dual-source DECT scans were performed in 72 patients over 30 months to differentiate contrast agent staining or extravasation from intracranial hemorrhage (ICH) (n=40); to differentiate calcium from ICH (n=2); for metal-artifact reduction (n=5); and for angiographic assessment (n=25). A three-material decomposition algorithm was used to obtain virtual non-contrast (VNC) and iodine (or calcium) overlay images. Images were analyzed in consensus by two board-certified radiologists to determine the success of the algorithm and to assess confounding factors. Furthermore, a dilution experiment using cylinders containing defined heparinized swine blood, normal saline, and selected iodine concentrations was conducted to assess other possible confounding factors. Results Dual-energy analysis was successful in 65 (90.2%) patients. However, the algorithm failed when images were affected by beam hardening (n=3, 4.2%), the presence of a fourth material (parenchymal calcification) (n=3, 4.2%), or motion (n=1, 1.4%). In the dilution experiment, a saturation effect was seen at high iodine concentrations (>= 37 mg/ml). VNC and iodine overlay images were not reliable above this concentration, and beam-hardening artifacts were noted. Conclusions DECT material decomposition is usually successful in neuroradiology. However, it can only distinguish up to three preselected materials. A fourth material such as parenchymal calcium may confound the analysis. Artifacts such as beam hardening, metallic streak, or saturation effect can also impair material decomposition. C1 [Dinkel, Julien; Khalilzadeh, Omid; Phan, Catherine M.; Goenka, Ajit H.; Yoo, Albert J.; Hirsch, Joshua A.; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dinkel, Julien; Khalilzadeh, Omid; Phan, Catherine M.; Goenka, Ajit H.; Yoo, Albert J.; Hirsch, Joshua A.; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA USA. [Dinkel, Julien] Univ Heidelberg Hosp, Dept Radiol, D-69120 Heidelberg, Germany. RP Dinkel, J (reprint author), Univ Heidelberg Hosp, Dept Radiol, D-69120 Heidelberg, Germany. EM julien.dinkel@med.uni-heidelberg.de NR 25 TC 5 Z9 5 U1 0 U2 5 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 AUG PY 2015 VL 7 IS 8 BP 596 EP 602 DI 10.1136/neurintsurg-2014-011241 PG 7 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA CN2OI UT WOS:000358261100013 PM 24951287 ER PT J AU Hirsch, JA Leslie-Mazwi, TM Nicola, GN Oklu, R Schoppe, KA Silva, E Manchikanti, L AF Hirsch, Joshua A. Leslie-Mazwi, Thabele M. Nicola, Gregory N. Oklu, Rahmi Schoppe, Kurt A. Silva, Ezequiel, III Manchikanti, Laxmaiah TI The ICD-10 system: a gift that keeps on taking SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review ID ELECTRONIC HEALTH RECORDS; PRIMARY-CARE PRACTICES; READY AB The Protecting Access to Medicare Act of 2014 was signed into law on April Fool's Day. Indeed, 2014 saw unprecedented enthusiasm for the possibility of a permanent solution to the sustainable growth rate formula. Congress failed to come together on methods to pay for that fix. Instead, Congress provided another temporary patch on April 1. As part of that law, International Classification of Diseases-10 (ICD-10) adoption was pushed back by at least 1 year until, at the earliest, October 1, 2015. While many physicians support the delay in ICD-10 implementation, there are those that disagree. C1 [Hirsch, Joshua A.; Leslie-Mazwi, Thabele M.] Harvard Univ, Sch Med, Neuroendovasc Program, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nicola, Gregory N.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Oklu, Rahmi] Harvard Univ, Sch Med, Div Intervent Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schoppe, Kurt A.] Radiol Associates North Texas, Ft Worth, TX USA. [Silva, Ezequiel, III] Univ Texas Hlth Sci Ctr San Antonio, South Texas Radiol Grp, San Antonio, TX 78229 USA. [Silva, Ezequiel, III] Univ Texas Hlth Sci Ctr, Dept Radiol, San Antonio, TX USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. RP Hirsch, JA (reprint author), Harvard Univ, Sch Med, Neuroendovasc Program, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM Hirsch@snisonline.org NR 27 TC 5 Z9 5 U1 0 U2 2 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 AUG PY 2015 VL 7 IS 8 BP 619 EP 622 DI 10.1136/neurintsurg-2014-011321 PG 4 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA CN2OI UT WOS:000358261100017 PM 24951285 ER PT J AU Wang, XY Pierre, JF Heneghan, AF Busch, RA Kudsk, KA AF Wang, Xinying Pierre, Joseph F. Heneghan, Aaron F. Busch, Rebecca A. Kudsk, Kenneth A. TI Glutamine Improves Innate Immunity and Prevents Bacterial Enteroinvasion During Parenteral Nutrition SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE parenteral nutrition; glutamine; innate immunity; intestinal mucosa; lysozyme; cryptdin 4 ID RESPIRATORY-TRACT IMMUNITY; SMALL-INTESTINE; LYMPHOID-TISSUE; ESCHERICHIA-COLI; MUCOSAL IMMUNITY; GENE-EXPRESSION; MICE; DEFENSINS; SUPPLEMENTATION; PRESERVES AB Background: Patients receiving parenteral nutrition (PN) are at increased risk of infectious complications compared with enteral feeding, which is in part explained by impaired mucosal immune function during PN. Adding glutamine (GLN) to PN has improved outcome in some clinical patient groups. Although GLN improves acquired mucosal immunity, its effect on innate mucosal immunity (defensins, mucus, lysozymes) has not been investigated. Methods: Forty-eight hours following venous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 10), PN (n = 12), or PN + GLN (n = 13) for 5 days. Small intestine tissue and luminal fluid were collected for mucin 2 (MUC2), lysozyme, cryptdin 4 analysis, and luminal interleukin (IL)-4, IL-10, and IL-13 level measurement. Tissue was also harvested for ex vivo intestinal segment culture to assess tissue susceptibility to enteroinvasive Escherichia coli. Results: In both luminal and tissue samples, PN reduced MUC2 and lysozyme (P < .0001, respectively) compared with chow, whereas GLN addition increased MUC2 and lysozyme (luminal, P < .05; tissue, P < .0001, respectively) compared with PN alone. PN significantly suppressed cryptdin 4 expression, while GLN supplementation significantly enhanced expression. IL-4, IL-10, and IL-13 decreased significantly with PN compared with chow, whereas GLN significantly increased these cytokines compared with PN. Functionally, bacterial invasion increased with PN compared with chow (P < .05), while GLN significantly decreased enteroinvasion to chow levels (P < .05). Conclusions: GLN-supplemented PN improves innate immunity and resistance to bacterial mucosal invasion lost with PN alone. This work confirms a clinical rationale for providing glutamine for the protection of the intestinal mucosa. C1 [Wang, Xinying; Pierre, Joseph F.; Heneghan, Aaron F.; Busch, Rebecca A.; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Wang, Xinying] Nanjing Univ, Dept Surg, Jinling Hosp, Sch Med, Nanjing 210008, Jiangsu, Peoples R China. [Pierre, Joseph F.; Heneghan, Aaron F.; Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Kudsk, KA (reprint author), Univ Wisconsin, Clin Sci Ctr G5 341, 600 Highland Ave, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [I01BX001672]; NIH Surgical Oncology Research Training Program [T32CA090217-13] FX The project described was supported by Award Number I01BX001672 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development and by NIH Surgical Oncology Research Training Program T32CA090217-13. The contents of this article do not represent the views of the Veterans Affairs or the United States government. NR 46 TC 4 Z9 8 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD AUG PY 2015 VL 39 IS 6 BP 688 EP 697 DI 10.1177/0148607114535265 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CN5DM UT WOS:000358450000008 PM 24836948 ER PT J AU Tsao, H Begolka, WS AF Tsao, Hensin Begolka, Wendy Smith CA Amer Acad Dermatology Ad Hoc Task TI Reply to: "The ABCDs of melanoma-A complicated morphologic message not intended for the general public'' SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Boston, MA USA. [Begolka, Wendy Smith] Amer Acad Dermatol, Schaumburg, IL 60173 USA. RP Begolka, WS (reprint author), Amer Acad Dermatol, 930 East Woodfield Rd, Schaumburg, IL 60173 USA. EM wsmithbegolka@aad.org NR 4 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2015 VL 73 IS 2 BP E61 EP E61 DI 10.1016/j.jaad.2015.04.025 PG 1 WC Dermatology SC Dermatology GA CM9FN UT WOS:000358012900007 PM 26183999 ER PT J AU Parisi, TJ Ferre, IM Rubash, HE AF Parisi, Thomas J. Ferre, Isabella M. Rubash, Harry E. TI The Basics of the Sunshine Act: How It Pertains to the Practicing Orthopaedic Surgeon SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Article ID INDUSTRY PAYMENTS; PHYSICIANS AB The Physician Payments Sunshine Act is a disclosure law requiring all drug, medical device, and biologics companies to report transfers of value to physicians and teaching hospitals. It was passed into law in 2010 as part of the Affordable Care Act. The first set of data was released via an online public database on September 30, 2014, with subsequent annual reports to come. Three categories of payments are recorded: general payments, ownership interests, and research payments. With few exceptions, any transfer of value greater than $10 is reported. The first dataset of 4.4 million payments totaling more than $3.5 billion was released amidst controversy and technical problems. Identified data constituted $1.3 billion in transfer payments; de-identified data constituted $2.2 billion in payments. Data regarding an additional $1.1 billion in payments were not published, in part because of unresolved disputes. The largest amount of funding went to research payments. The highest proportion of general payments went to licensing and royalty payments. Orthopaedic surgeons comprised 3.5% of the physicians represented, and they were responsible for more than 20% of total payments. The full impact of the Sunshine Act will not be clear until several years after its implementation. C1 [Parisi, Thomas J.; Ferre, Isabella M.; Rubash, Harry E.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Parisi, TJ (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. NR 26 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD AUG PY 2015 VL 23 IS 8 BP 455 EP 467 DI 10.5435/JAAOS-D-14-00426 PG 13 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CN4RG UT WOS:000358417300001 PM 26209143 ER PT J AU Christino, MA Fantry, AJ Vopat, BG AF Christino, Melissa A. Fantry, Amanda J. Vopat, Bryan G. TI Psychological Aspects of Recovery Following Anterior Cruciate Ligament Reconstruction SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Review ID NATIONAL-FOOTBALL-LEAGUE; SELF-EFFICACY; PREINJURY LEVEL; HEALTH LOCUS; INJURY; RETURN; SPORT; REHABILITATION; SURGERY; OUTCOMES AB Recovery following anterior cruciate ligament reconstruction is an arduous process that requires a significant mental and physical commitment to rehabilitation. Orthopaedic research in recent years has focused on optimizing anterior cruciate ligament surgical techniques; however, despite stable anterior cruciate ligament reconstructions, many athletes still never achieve their preinjury ability or even return to sport. Psychological factors associated with patient perceptions and functional outcomes following anterior cruciate ligament reconstruction are important to acknowledge and understand. Issues related to emotional disturbance, motivation, self-esteem, locus of control, and self-efficacy can have profound effects on patients' compliance, athletic identity, and readiness to return to sport. The psychological aspects of recovery play a critical role in functional outcomes, and a better understanding of these concepts is essential to optimize the treatment of patients undergoing anterior cruciate ligament reconstruction, particularly those who plan to return to sport. Identifying at-risk patients, encouraging a multidisciplinary approach to patient care, and providing early referral to a sports psychologist may improve patient outcomes and increase return-to-play rates among athletes. C1 [Christino, Melissa A.] Boston Childrens Hosp, Boston, MA 02115 USA. [Fantry, Amanda J.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Vopat, Bryan G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Christino, MA (reprint author), Boston Childrens Hosp, Boston, MA 02115 USA. FU DePuy FX Dr. Vopat or an immediate family member serves as a paid consultant to DePuy. Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Christino and Dr. Fantry. NR 54 TC 4 Z9 4 U1 3 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD AUG PY 2015 VL 23 IS 8 BP 501 EP 509 DI 10.5435/JAAOS-D-14-00173 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CN4RG UT WOS:000358417300006 PM 26209145 ER PT J AU Skelley, NW Harwood, JL Hogan, MV Provencher, MT Milbrandt, TA Kim, YJ AF Skelley, Nathan W. Harwood, Jared L. Hogan, MaCalus V. Provencher, Matthew T. Milbrandt, Todd A. Kim, Young-jo TI The AAOS Resident Assembly SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Editorial Material C1 [Skelley, Nathan W.] Washington Univ, Dept Orthopaed Surg, St Louis, MO 63110 USA. [Harwood, Jared L.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Hogan, MaCalus V.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Provencher, Matthew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Milbrandt, Todd A.] Mayo Clin, Rochester, MN USA. [Kim, Young-jo] Harvard Univ, Boston, MA 02115 USA. RP Skelley, NW (reprint author), Washington Univ, Dept Orthopaed Surg, St Louis, MO 63110 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 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD AUG PY 2015 VL 23 IS 8 BP E11 EP E12 DI 10.5435/JAAOS-D-15-00287 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CN4RI UT WOS:000358417500002 PM 26209147 ER PT J AU Cambria, RP Conrad, MF Matsumoto, AH Fillinger, M Pochettino, A Carvalho, S Patel, V Matsumura, J AF Cambria, Richard P. Conrad, Mark F. Matsumoto, Alan H. Fillinger, Mark Pochettino, Alberto Carvalho, Stephanie Patel, Virendra Matsumura, Jon TI Multicenter clinical trial of the conformable stent graft for the treatment of acute, complicated type B dissection SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID ACUTE AORTIC DISSECTION; COMPOSITE DEVICE DESIGN; INTERNATIONAL REGISTRY; ENDOVASCULAR TREATMENT; REPAIR; PLACEMENT; IRAD; OUTCOMES; THERAPY AB Objective: The treatment of acute, complicated type B aortic dissection has evolved in the past several decades. Thoracic endovascular aortic repair when anatomy is suitable, has been regarded as the preferable treatment to seal the primary entry tear, redirect and re-establish adequate true lumen flow, and thereby promote aortic remodeling. This study was designed to determine the safety and efficacy of a conformable thoracic endoprosthesis device for patients with acute, complicated type B aortic dissection, defined as malperfusion or rupture or both. Methods: Between January 2010 and January 2012, 50 patients with complicated type B aortic dissection from 26 sites in the United States were included in this prospective, multicenter, nonrandomized single-arm study. The primary safety end point was all-cause mortality through 30 days after treatment, and the primary efficacy end point was exclusion of the primary entry tear (Core Laboratory adjudicated) at 1-month follow-up. Secondary end points included false lumen thrombosis, dissection-based reintervention rate, and aortic rupture. Results: All device implants were successfully completed. Six patients (12%) required additional device implantations <= 1 year from the index procedure. There was no conversion to open repair at 1 year. Exclusion of the primary entry tear at 30 days occurred in 97.5% of patients. All-cause mortality through 30 days was 8%. Survival was 88% at 1 year and 85% at 2 years. At 1 year after treatment, 35.1% of patients had experienced a decrease of >= 5 mm in overall diameter in the treated segment of the aorta. From pretreatment to the 36-month follow-up, the average minimum true lumen area increased by 206.3 mm(2), and the average maximum false lumen area decreased by 313.4 mm(2). The 30-day stroke rate was 18%; none were fatal, and one permanent deficit occurred. Four patients (8%) experienced spinal cord ischemia of any severity but without any permanent or significant deficits. New aortic dissection (3 retrograde, 2 de novo) occurred in five patients (10%). The secondary intervention rate was 18%. Conclusions: Treatment with the conformable thoracic endovascular aortic repair device produced favorable perioperative and intermediate level clinical and anatomic outcomes. In particular, an operative mortality of 8% in this cohort is comparable to that noted in a Society for Vascular Surgery objective performance criteria publication. Late survival in our cohort compares favorably with historical data referable to complicated type B dissection. C1 [Cambria, Richard P.; Conrad, Mark F.; Carvalho, Stephanie; Patel, Virendra] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Matsumoto, Alan H.] Univ Virginia Hlth Syst, Dept Radiol, Charlottesville, VA USA. [Fillinger, Mark] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. [Pochettino, Alberto] Univ Penn, Div Cardiac Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Matsumura, Jon] Univ Wisconsin, Div Vasc Surg, Madison, WI 53706 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Thorac Aort Ctr, 15 Parkman St, Boston, MA 02114 USA. EM rcambria@partners.org NR 21 TC 1 Z9 1 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2015 VL 62 IS 2 BP 271 EP 278 DI 10.1016/j.jvs.2015.03.026 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CN4WT UT WOS:000358431900001 PM 26211376 ER PT J AU Kougias, P Collins, R Pastorek, N Sharath, S Barshes, NR McCulloch, K Pisimisis, G Berger, DH AF Kougias, Panos Collins, Robert Pastorek, Nicholas Sharath, Sherene Barshes, Neal R. McCulloch, Katie Pisimisis, George Berger, David H. TI Comparison of domain-specific cognitive function after carotid endarterectomy and stenting SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Vascular Annual Meeting of the Society-for-Vascular-Surgery / Spring Meeting of the Vascular-and-Endovascular-Surgery-Society CY JUN 04-07, 2014 CL Boston, MA SP Soc Vasc Surg, Vasc & Endovascular Surg Soc ID HIGH-RISK PATIENTS; ARTERY STENOSIS; SURGERY; PERFORMANCE; DECLINE; ANGIOPLASTY; DEMENTIA; BRAIN AB Background: Observational data indicate that carotid artery stenting (CAS) is associated with higher incidence of subclinical cerebral microemboli than carotid endarterectomy (CEA). We hypothesized that CEA would be associated with superior performance on detailed domain-specific cognitive testing compared with CAS. Methods: Patients with >80% asymptomatic carotid artery stenosis were randomized to CEA or CAS with side of stenosis balanced across condition. A robust battery of tests was used to assess the cognitive domains of attention, memory, mood, visual-spatial skills, motor ability, processing speed, and executive functioning <= 10 days preoperatively and postoperatively at 6 weeks and 6 months. Tests were administered using standardized conditions and were scored by individuals blinded to treatment allocation. Results: Baseline cognitive performance was similar between CAS (n=29) and CEA (n=31) groups (P > .05). Relative to baseline, verbal and visual memory and attention functions substantially improved in the CAS and CEA groups at 6 months (multiple cognitive tests achieved statistical significance). Compared with CEA, cognitive processing speed (Stroop Color test: 9.0 vs 7.3, P = .04; and Stroop Word test: 9.0 vs 7.4, P = .05) was superior in the CAS group at 6 weeks. Executive functioning (phonemic verbal fluency: 10.6 vs 8.4, P = .043) and motor function (Grooved Pegboard of nondominant extremity: 45.7 vs 38.9, P = .022) were also superior in the CAS group at 6 months. Tests of attention, memory, and visual-spatial skills were similar between CAS and CEA patients at 6 weeks and 6 months. Conclusions: Carotid revascularization improves memory and attention within the first 6 postoperative months. Compared with CEA, CAS produces improvements in cognitive processing speed, executive functioning, and motor function. C1 [Kougias, Panos; Collins, Robert; Pastorek, Nicholas; Sharath, Sherene; Barshes, Neal R.; Pisimisis, George; Berger, David H.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Kougias, Panos; Barshes, Neal R.; Pisimisis, George] Baylor Coll Med, Div Vasc Surg, Houston, TX 77030 USA. [Collins, Robert] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Pastorek, Nicholas] Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [Berger, David H.] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. [McCulloch, Katie] Univ Houston, Dept Psychol, Houston, TX 77004 USA. RP Kougias, P (reprint author), Houston VAMC, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd,OCL 112, Houston, TX 77030 USA. EM pkougias@bcm.edu NR 25 TC 4 Z9 4 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2015 VL 62 IS 2 BP 355 EP 361 DI 10.1016/j.jvs.2015.02.057 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CN4WT UT WOS:000358431900014 PM 26211378 ER PT J AU Saraidaridis, JT Ergul, E Patel, VI Stone, DH Cambria, RP Conrad, MF AF Saraidaridis, Julia T. Ergul, Emel Patel, Virendra I. Stone, David H. Cambria, Richard P. Conrad, Mark F. TI The Society for Vascular Surgery's objective performance goals for lower extremity revascularization are not generalizable to many open surgical bypass patients encountered in contemporary surgical practice SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 41st Joint Annual Meeting of the New-England-Society-for-Vascular-Surgery (NESVS) and Eastern-Vascular-Society (EVS) CY SEP 11-14, 2014 CL Boston, MA SP New England Soc Vasc Surg, Eastern Vasc Soc ID CRITICAL LIMB ISCHEMIA; PERIPHERAL ARTERIAL-DISEASE; STAGE RENAL-DISEASE; ADJUNCTIVE PARENTERAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; PROSTAGLANDIN E-1 ANALOG; IMPROVE 6-MONTH OUTCOMES; CHRONIC-KIDNEY-DISEASE; SAPHENOUS-VEIN; DISTAL REVASCULARIZATION AB Objective: In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPG) for lower extremity bypass (LEB) in patients with critical limb ischemia (CLI) based on pooled data from previously performed prospective studies in an effort to provide a benchmark and historical control for future trials. However, patients with a prosthetic conduit and end-stage renal disease were excluded from this cohort. In contemporary practice, many patients do not meet the criteria for SVS OPG inclusion, making generalization of the SVS OPG difficult. The goal of this study was to establish safety and efficacy measures for patients who were excluded from the original SVS OPG analysis. Methods: All patients who underwent LEB for CLI in the Vascular Study Group of New England (VSGNE) from 2003 to 2013 were identified. Patients were stratified into OPG-eligible and non-OPG-eligible cohorts. Outcomes included 30-day major adverse limb events, 30-day major adverse cardiovascular events, 1-year survival, and 1-year freedom from amputation. The SVS OPG methodology was used to create new performance goals for the non-OPG-eligible patients. Results: We identified 3609 patients: 2360 OPG(65%) vs1249 non-OPG(35%), and overall results were stratified as a function of OPG status. The 30-day major adverse limb event rate was 5.0% (5.5% non-OPG vs 4.4% OPG; P = .34), and the 30-day major adverse cardiovascular event ratewas 7.3% (9.2% non-OPGvs 6.2% OPG; P = . 001). At 1 year, survival was 84% (75.9% non-OPG vs 88.3% OPG; P < .001), and freedom from amputation was 86.9% (80.9% non-OPG vs 90.1% OPG; P <.001). Conclusions: The SVS OPG were attainable in New England for the population of patients who would have met SVS OPG study cohort inclusion criteria. However, 35% of the patients who underwent LEB for CLI in the last 10 years fell outside of these criteria by having end-stage renal disease or requiring a prosthetic conduit. We therefore suggest new benchmarks for these high-risk populations. C1 [Saraidaridis, Julia T.; Ergul, Emel; Patel, Virendra I.; Cambria, Richard P.; Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc Surg, Boston, MA 02114 USA. [Stone, David H.] Dartmouth Hitchcock Hosp, Dept Vasc Surg, Lebanon, NH USA. RP Conrad, MF (reprint author), Massachusetts Gen Hosp, Dept Vasc Surg, 55 Fruit St, Boston, MA 02114 USA. EM mconrad@partners.org NR 31 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2015 VL 62 IS 2 BP 392 EP 400 DI 10.1016/j.jvs.2015.03.043 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CN4WT UT WOS:000358431900022 PM 26033008 ER PT J AU Azarbal, AF Harris, S Mitchell, EL Liem, TK Landry, GJ McLafferty, RB Edwards, J Moneta, GL AF Azarbal, Amir F. Harris, Sheena Mitchell, Erica L. Liem, Timothy K. Landry, Gregory J. McLafferty, Robert B. Edwards, James Moneta, Greg L. TI Nasal methicillin-resistant Staphylococcus aureus colonization is associated with increased wound occurrence after major lower extremity amputation SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID LOWER-LIMB AMPUTATION; RISK-FACTORS; ANTIBIOTIC-PROPHYLAXIS; SURGICAL AMPUTATIONS; MUPIROCIN OINTMENT; EARLY FAILURE; INFECTION; ERADICATION; CARRIAGE; DECOLONIZATION AB Objective: Wound occurrence (WO) after major lower extremity amputation (MLEA) can be due to wound infection or sterile dehiscence. We sought to determine the association of nasal methicillin-resistant Staphylococcus aureus (MRSA) colonization and other patient factors with overall WO, WO due to wound infection, and WO due to sterile dehiscence. Methods: The medical records of all patients undergoing MLEA from August 1, 2011, to November 1, 2013, were reviewed. Demographic data, hemoglobin A1c level, albumin concentration, dialysis dependence, peripheral vascular disease (PVD), nasal MRSA colonization, and diabetes mellitus (DM) were examined as variables. The overall WO rate was determined, and the cause of WO was categorized as either a sterile dehiscence or a wound infection. Results: Eighty-three patients underwent 96 MLEAs during a 27-month period. The rates of overall WO, WO due to infection, and WO due to sterile dehiscence were 39%, 19%, and 19%, respectively (1% developed a traumatic wound). On univariate analysis, PVD, MRSA colonization, DM, and dialysis dependence were all associated with higher rates of overall WO (P < .05). On multivariate analysis, MRSA colonization was associated with higher rates of overall WO (P =.03) and WO due to wound infection (11% vs 45%; P < .01). DM and PVD were associated with higher rates of overall WO and WO due to sterile dehiscence on both univariate and multivariate analysis (P < .05). Conclusions: Nasal MRSA colonization is associated with higher rates of overall WO and WO due to wound infection. DM and PVD are associated with higher rates of overall WO and WO due to sterile dehiscence but are not associated with WO due to wound infection. Further studies addressing the effect of nasal MRSA eradication on postoperative wound outcomes after MLEA are warranted. C1 [Azarbal, Amir F.; Harris, Sheena; Mitchell, Erica L.; Liem, Timothy K.; Landry, Gregory J.; McLafferty, Robert B.; Edwards, James; Moneta, Greg L.] Oregon Hlth & Sci Univ, Div Vasc Surg, Dept Surg, Portland, OR 97201 USA. [Azarbal, Amir F.; Mitchell, Erica L.; Liem, Timothy K.; Landry, Gregory J.; McLafferty, Robert B.; Edwards, James; Moneta, Greg L.] Portland VA Med Ctr, Operat Care Div, Portland, OR USA. RP Azarbal, AF (reprint author), Mail Code OP-11,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM azarbala@ohsu.edu NR 22 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2015 VL 62 IS 2 BP 401 EP 405 DI 10.1016/j.jvs.2015.02.052 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CN4WT UT WOS:000358431900023 PM 25935268 ER PT J AU Gombos, RB Kolodkin-Gal, D Eslamizar, L Owuor, JO Mazzola, E Gonzalez, AM Korioth-Schmitz, B Gelman, RS Montefiori, DC Haynes, BF Schmitz, JE AF Gombos, Randi B. Kolodkin-Gal, Dror Eslamizar, Leila Owuor, Joshua O. Mazzola, Emanuele Gonzalez, Ana M. Korioth-Schmitz, Birgit Gelman, Rebecca S. Montefiori, David C. Haynes, Barton F. Schmitz, Joern E. TI Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CONFORMATIONAL EPITOPE; ANTIRETROVIRAL THERAPY; VIROLOGICAL SYNAPSES; MONOCLONAL-ANTIBODY; NONHUMAN-PRIMATES; ENVELOPE PROTEIN; HUMANIZED MICE; SMALL-MOLECULE; BINDING-SITE AB To date, most therapeutic and vaccine candidates for human immunodeficiency virus type 1 (HIV-1) are evaluated preclinically for efficacy against cell-free viral challenges. However, cell-associated HIV-1 is suggested to be a major contributor to sexual transmission by mucosal routes. To determine if neutralizing antibodies or inhibitors block cell-free and cell-associated virus transmission of diverse HIV-1 strains with different efficiencies, we tested 12 different antibodies and five inhibitors against four green fluorescent protein (GFP)-labeled HIV-1 envelope (Env) variants from transmitted/founder (T/F) or chronic infection isolates. We evaluated antibody/inhibitor-mediated virus neutralization using either TZM-bl target cells, in which infectivity was determined by virus-driven luciferase expression, or A3R5 lymphoblastoid target cells, in which infectivity was evaluated by GFP expression. In both the TZM-bl and A3R5 assays, cell-free virus or infected CD4(+) lymphocytes were used as targets for neutralization. We further hypothesized that the combined use of specific neutralizing antibodies targeting HIV-1 Env would more effectively prevent cell-associated virus transmission than the use of individual antibodies. The tested antibody combinations included two gp120-directed antibodies, VRC01 and PG9, or VRC01 with the gp41-directed antibody 10E8. Our results demonstrated that cell-associated virus was less sensitive to neutralizing antibodies and inhibitors, particularly using the A3R5 neutralization assay, and the potencies of these neutralizing agents differed among Env variants. A combination of different neutralizing antibodies that target specific sites on gp120 led to a significant reduction in cell-associated virus transmission. These assays will help identify ideal combinations of broadly neutralizing antibodies to use for passive preventive antibody administration and further characterize targets for the most effective neutralizing antibodies/inhibitors. IMPORTANCE Prevention of the transmission of human immunodeficiency virus type 1 (HIV-1) remains a prominent goal of HIV research. The relative contribution of HIV-1 within an infected cell versus cell-free HIV-1 to virus transmission remains debated. It has been suggested that cell-associated virus is more efficient at transmitting HIV-1 and more difficult to neutralize than cell-free virus. Several broadly neutralizing antibodies and retroviral inhibitors are currently being studied as potential therapies against HIV-1 transmission. The present study demonstrates a decrease in neutralizing antibody and inhibitor efficiencies against cell-associated compared to cell-free HIV-1 transmission among different strains of HIV-1. We also observed a significant reduction in virus transmission using a combination of two different neutralizing antibodies that target specific sites on the outermost region of HIV-1, the virus envelope. Therefore, our findings support the use of antibody combinations against both cell-free and cell-associated virus in future candidate therapy regimens. C1 [Gombos, Randi B.; Kolodkin-Gal, Dror; Eslamizar, Leila; Owuor, Joshua O.; Gonzalez, Ana M.; Korioth-Schmitz, Birgit; Schmitz, Joern E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Kolodkin-Gal, Dror] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Mazzola, Emanuele; Gelman, Rebecca S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mazzola, Emanuele; Gelman, Rebecca S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Montefiori, David C.; Haynes, Barton F.] Duke Univ, Med Ctr, Human Vaccine Inst, Durham, NC USA. [Montefiori, David C.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Gombos, RB (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM rgombos@outlook.com RI Korioth-Schmitz, Birgit/M-7816-2015 OI Korioth-Schmitz, Birgit/0000-0002-5271-9223 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID); Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) grant [UM1-AI100645]; NIH [P30-AI060354]; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; NIDDK; NIGMS; FIC; OAR FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID) and by the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) grant no. UM1-AI100645. This publication was made possible with help from the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30-AI060354), which is supported by the following NIH cofunding and participating institutes and centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NIDDK, NIGMS, FIC, and OAR. NR 76 TC 1 Z9 1 U1 2 U2 12 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 AUG PY 2015 VL 89 IS 15 BP 7813 EP 7828 DI 10.1128/JVI.00783-15 PG 16 WC Virology SC Virology GA CN2UP UT WOS:000358277800030 PM 25995259 ER PT J AU Vigano, S Negron, J Ouyang, Z Rosenberg, ES Walker, BD Lichterfeld, M Yu, XG AF Vigano, Selena Negron, Jordi Ouyang, Zhengyu Rosenberg, Eric S. Walker, Bruce D. Lichterfeld, Mathias Yu, Xu G. TI Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 INFECTION; VIRUS; LYMPHOCYTES; CONTROLLERS; TRANSPLANTATION; NONPROGRESSORS; PROLIFERATION; DETERMINANTS; ELIMINATION; EXPRESSION AB HIV-1-specific CD8 T cells can influence HIV-1 disease progression during untreated HIV-1 infection, but the functional and phenotypic properties of HIV-1-specific CD8 T cells in individuals treated with suppressive antiretroviral therapy remain less well understood. Here we show that a subgroup of HIV-1-specific CD8 T cells with stem cell-like properties, termed T memory stem cells (T-SCM cells), is enriched in patients receiving suppressive antiretroviral therapy compared with their levels in untreated progressors or controllers. In addition, a prolonged duration of antiretroviral therapy was associated with a progressive increase in the relative proportions of these stem cell-like HIV-1-specific CD8 T cells. Interestingly, the proportions of HIV-1-specific CD8 T-SCM cells and total HIV-1-specific CD8 TSCM cells were associated with the CD4 T cell counts during treatment with antiretroviral therapy but not with CD4 T cell counts, viral loads, or immune activation parameters in untreated patients, including controllers. HIV-1-specific CD8 T-SCM cells had increased abilities to secrete interleukin-2 in response to viral antigen, while secretion of gamma interferon (IFN-gamma) was more limited in comparison to alternative HIV-1-specific CD8 T cell subsets; however, only proportions of IFN-gamma-secreting HIV-1-specific CD8 T-SCM cells were associated with CD4 T cell counts during antiretroviral therapy. Together, these data suggest that HIV-1-specific CD8 T-SCM cells represent a long-lasting component of the cellular immune response to HIV-1 that persists in an antigen-independent fashion during antiretroviral therapy but seems unable to survive and expand under conditions of ongoing viral replication during untreated infection. IMPORTANCE Memory CD8 T cells that imitate the functional properties of stem cells to maintain lifelong cellular immunity have been hypothesized for many years, but only recently have such cells, termed T memory stem cells (T-SCM cells), been physically identified and isolated in humans, mice, and nonhuman primates. Here, we investigated whether cellular immune responses against HIV-1 include such T memory stem cells. Our data show that HIV-1-specific CD8 T memory stem cells are detectable during all stages of HIV-1 infection but occur most visibly at times of prolonged viral antigen suppression by antiretroviral combination therapy. These cells may therefore be particularly relevant for designing antiviral immune defense strategies against the residual reservoir of HIV-1-infected cells that persists despite treatment and leads to viral rebound upon treatment discontinuation. C1 [Vigano, Selena; Negron, Jordi; Ouyang, Zhengyu; Walker, Bruce D.; Lichterfeld, Mathias; Yu, Xu G.] MGH MIT & Harvard, Ragon Inst, Cambridge, MA 02139 USA. [Rosenberg, Eric S.; Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lichterfeld, Mathias] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Yu, XG (reprint author), MGH MIT & Harvard, Ragon Inst, Cambridge, MA 02139 USA. EM xyu@partners.org FU U.S. National Institutes of Health [AI078799, AI089339, HL121890, AI098484, HL126554, AI116228, AI087452, AI098487, AI106468]; Bill and Melinda Gates Foundation [OPP 1066973]; Mark and Lisa Swartz Foundation; Ragon Institute of MGH, MIT, and Harvard; International HIV Controller Consortium FX This work was supported by the U.S. National Institutes of Health (grants AI078799, AI089339, HL121890, AI098484, HL126554, AI116228, and AI087452 to X.G.Y. and grants AI098487 and AI106468 to M.L.). PBMC sample collection was supported by the Bill and Melinda Gates Foundation (OPP 1066973), the Mark and Lisa Swartz Foundation, the Ragon Institute of MGH, MIT, and Harvard, and the International HIV Controller Consortium. NR 41 TC 8 Z9 9 U1 4 U2 8 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 AUG PY 2015 VL 89 IS 15 BP 7829 EP 7840 DI 10.1128/JVI.00789-15 PG 12 WC Virology SC Virology GA CN2UP UT WOS:000358277800031 PM 25995260 ER PT J AU Thobakgale, CF Prendergast, A Crawford, H Mkhwanazi, N Ramduth, D Reddy, S Molina, C Mncube, Z Leslie, A Prado, J Chonco, F Mphatshwe, W Tudor-Williams, G Jeena, P Blanckenberg, N Dong, K Kiepiela, P Coovadia, H Ndung'u, T Walker, BD Goulder, PJR AF Thobakgale, Christina F. Prendergast, Andrew Crawford, Hayley Mkhwanazi, Nompumelelo Ramduth, Danni Reddy, Sharon Molina, Claudia Mncube, Zenele Leslie, Alasdair Prado, Julia Chonco, Fundi Mphatshwe, Wendy Tudor-Williams, Gareth Jeena, Prakash Blanckenberg, Natasha Dong, Krista Kiepiela, Photini Coovadia, Hoosen Ndung'u, Thumbi Walker, Bruce D. Goulder, Philip J. R. TI Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection (vol 83, pg 10234, 2009) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Thobakgale, Christina F.; Mkhwanazi, Nompumelelo; Ramduth, Danni; Reddy, Sharon; Mncube, Zenele; Chonco, Fundi; Mphatshwe, Wendy; Jeena, Prakash; Blanckenberg, Natasha; Dong, Krista; Kiepiela, Photini; Coovadia, Hoosen; Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip J. R.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Prendergast, Andrew; Crawford, Hayley; Molina, Claudia; Leslie, Alasdair; Prado, Julia; Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Tudor-Williams, Gareth] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, Div Med, London, England. [Walker, Bruce D.] Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA 02129 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20185 USA. RP Thobakgale, CF (reprint author), Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. FU Wellcome Trust [104748] NR 1 TC 0 Z9 0 U1 0 U2 1 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 AUG PY 2015 VL 89 IS 15 BP 8101 EP 8101 DI 10.1128/JVI.00876-15 PG 1 WC Virology SC Virology GA CN2UP UT WOS:000358277800056 PM 26157156 ER PT J AU Go, EP Herschhorn, A Gu, C Castillo-Menendez, L Zhang, SJ Mao, YD Chen, HY Ding, HT Wakefield, JK Hua, D Liao, HX Kappes, JC Sodroski, J Desaire, H AF Go, Eden P. Herschhorn, Alon Gu, Christopher Castillo-Menendez, Luis Zhang, Shijian Mao, Youdong Chen, Haiyan Ding, Haitao Wakefield, John K. Hua, David Liao, Hua-Xin Kappes, John C. Sodroski, Joseph Desaire, Heather TI Comparative Analysis of the Glycosylation Profiles of Membrane-Anchored HIV-1 Envelope Glycoprotein Trimers and Soluble gp140 SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; O-LINKED GLYCOSYLATION; SITE-SPECIFIC ANALYSIS; NEUTRALIZING ANTIBODIES; SYNTHETIC GLYCOPEPTIDES; CYTOPLASMIC DOMAIN; CELL-SURFACE; GP120; RECOGNITION; PROTEINS AB The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, which consists of the gp120 and gp41 subunits, is the focus of multiple strategies for vaccine development. Extensive Env glycosylation provides HIV-1 with protection from the immune system, yet the glycans are also essential components of binding epitopes for numerous broadly neutralizing antibodies. Recent studies have shown that when Env is isolated from virions, its glycosylation profile differs significantly from that of soluble forms of Env (gp120 or gp140) predominantly used in vaccine discovery research. Here we show that exogenous membrane-anchored Envs, which can be produced in large quantities in mammalian cells, also display a virion-like glycan profile, where the glycoprotein is extensively decorated with high-mannose glycans. Additionally, because we characterized the glycosylation with a high-fidelity profiling method, glycopeptide analysis, an unprecedented level of molecular detail regarding membrane Env glycosylation and its heterogeneity is presented. Each glycosylation site was characterized individually, with about 500 glycoforms characterized per Env protein. While many of the sites contain exclusively high-mannose glycans, others retain complex glycans, resulting in a glycan profile that cannot currently be mimicked on soluble gp120 or gp140 preparations. These site-level studies are important for understanding antibody-glycan interactions on native Env trimers. Additionally, we report a newly observed O-linked glycosylation site, T606, and we show that the full O-linked glycosylation profile of membrane-associated Env is similar to that of soluble gp140. These findings provide new insight into Env glycosylation and clarify key molecular-level differences between membrane-anchored Env and soluble gp140. IMPORTANCE A vaccine that protects against human immunodeficiency virus type 1 (HIV-1) infection should elicit antibodies that bind to the surface envelope glycoproteins on the membrane of the virus. The envelope glycoproteins have an extensive coat of carbohydrates (glycans), some of which are recognized by virus-neutralizing antibodies and some of which protect the virus from neutralizing antibodies. We found that the HIV-1 membrane envelope glycoproteins have a unique pattern of carbohydrates, with many high-mannose glycans and also, in some places, complex glycans. This pattern was very different from the carbohydrate profile seen for a more easily produced soluble version of the envelope glycoprotein. Our results provide a detailed characterization of the glycans on the natural membrane envelope glycoproteins of HIV-1, a carbohydrate profile that would be desirable to mimic with a vaccine. C1 [Go, Eden P.; Hua, David; Desaire, Heather] Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. [Chen, Haiyan; Liao, Hua-Xin] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Herschhorn, Alon; Gu, Christopher; Castillo-Menendez, Luis; Zhang, Shijian; Mao, Youdong; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Microbiol & Immunobiol,Dept Canc Immunol & A, Boston, MA 02115 USA. [Ding, Haitao; Wakefield, John K.; Kappes, John C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. RP Desaire, H (reprint author), Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. EM hdesaire@ku.edu RI Zhang, Shijian/P-9353-2015 OI Zhang, Shijian/0000-0002-2017-6754 FU National Institutes of Health [GM103547, AI094797, GM095639, AI024755, AI100645]; Virology, Genetic Sequencing and Flow Cytometry Cores of the UAB Center for AIDS Research (NIH) [P30 AI27767] FX This work was supported by National Institutes of Health grants GM103547 and AI094797 to H. Desaire, GM095639 to J. C. Kappes, and AI024755 and AI100645 to J. Sodroski. The work was also supported by the Virology, Genetic Sequencing and Flow Cytometry Cores of the UAB Center for AIDS Research (NIH, P30 AI27767). NR 61 TC 22 Z9 22 U1 0 U2 12 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 AUG PY 2015 VL 89 IS 16 BP 8245 EP 8257 DI 10.1128/JVI.00628-15 PG 13 WC Virology SC Virology GA CN2UT UT WOS:000358278200014 PM 26018173 ER PT J AU Remenschneider, AK Kozin, ED Curtin, H Santos, F AF Remenschneider, Aaron K. Kozin, Elliott D. Curtin, Hugh Santos, Felipe TI Histopathology of idiopathic lateral skull base defects SO LARYNGOSCOPE LA English DT Article DE Cerebrospinal fluid leak; temporal bone pathology; arachnoid granulation; encephalocele; Mondini; scala communis; tympanomeningeal fissure; patent fallopian canal; petromastoid canal ID TEMPORAL BONE; ARACHNOID GRANULATIONS; COCHLEAR IMPLANTATION; RECURRENT MENINGITIS; CSF LEAKS; CHILDREN; CLASSIFICATION; MALFORMATIONS; ENCEPHALOCELE; MANAGEMENT AB Objectives/HypothesisThe objective of this study was to utilize techniques of otopathology to gain insight into the pathogenesis, sites of origin, and associated findings in idiopathic lateral skull base defects. Study DesignHistopathologic analysis of temporal bones from an otopathology repository. MethodsSpecimens from a human temporal bone repository were investigated for clinical or otopathologic evidence of occult bony dehiscence indicating communication between the subarachnoid space and air cells of the temporal bone. Specimens were examined by light microscopy, organized by fistula site, and histopathologically described. Premortem patient demographics and clinical history was reviewed. ResultsSpecimens from 52 individuals met inclusion criteria. Three distinct fistula pathways were determined: transdural, labyrinthine, and perilabyrinthine. Transdural fistulae occur most commonly as the result of arachnoid granulations along the middle or posterior fossa dura (n=30) and are frequently incidental findings in specimens of older individuals (median age at death: 81 years). Labyrinthine fistulae (n=10) were noted with cochlear malformations when modiolar atresia permits cerebrospinal fluid (CSF) flow into a common intracochlear scala and oval window perilymphatic fistula results. Perilabyrinthine fistulae (n=7) were observed through three congenitally unfused tracts: the tympanomeningeal fissure, the petromastoid canal, or an extension of the subarachnoid space into the fallopian canal. ConclusionsIdiopathic lateral skull base defects occur in three distinct anatomic locations with consistent histopathologic findings. In the absence of clear radiographic localization, patient age and associated cochlear defects may assist in the determination of the site of CSF leak. These data have implications for surgical approaches of CSF fistula repair. Level of EvidenceNA Laryngoscope, 125:1798-1806, 2015 C1 [Remenschneider, Aaron K.; Kozin, Elliott D.; Santos, Felipe] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Curtin, Hugh] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Remenschneider, Aaron K.; Kozin, Elliott D.; Curtin, Hugh; Santos, Felipe] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Santos, F (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM felipe_santos@meei.harvard.edu RI Kozin, Elliott/J-1225-2014; OI Kozin, Elliott/0000-0002-0305-0682; Santos, Felipe/0000-0002-3523-665X NR 29 TC 2 Z9 2 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2015 VL 125 IS 8 BP 1798 EP 1806 DI 10.1002/lary.25366 PG 9 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CN4DJ UT WOS:000358379700017 PM 26059539 ER PT J AU Kozin, ED Sethi, RKV Remenschneider, AK Kaplan, AB del Portal, DA Gray, ST Shrime, MG Lee, DJ AF Kozin, Elliott D. Sethi, Rosh K. V. Remenschneider, Aaron K. Kaplan, Alyson B. del Portal, Daniel A. Gray, Stacey T. Shrime, Mark G. Lee, Daniel J. TI Epidemiology of otologic diagnoses in United States emergency departments SO LARYNGOSCOPE LA English DT Article DE Otology; emergency department; specialized emergency care; resource utilization ID PAROXYSMAL POSITIONAL VERTIGO; CLINICAL-PRACTICE GUIDELINE; ACUTE OTITIS-MEDIA; DIZZINESS PRESENTATIONS; NONURGENT CONDITIONS; RETAIL CLINICS; CARE; VISITS; COSTS; PATTERNS AB Objectives/HypothesisOtologic complaints may place a significant burden on emergency departments (EDs) in the United States; however, few studies have comprehensively examined this discrete patient population. We aimed to identify utilization of EDs by patients with primary otologic complaints. Study DesignRetrospective analysis of the Nationwide Emergency Department Sample (NEDS) from 2009 through 2011. MethodsThe NEDS database was queried for patient encounters with a primary otologic diagnosis based on International Classification of Diseases, Ninth Revision codes (380-389). Weighted estimates for demographics, diagnostic characteristics, socioeconomic status, and trends over time were extracted. Predictors of mortality and admission were determined by multivariable logistic regression. ResultsA weighted total of 8,611,282 visits between 2009 and 2011 were attributed to otologic diagnoses, representing 2.21% of all ED visits. Stratified by patient age, otologic diagnoses encompassed 1.01% and 6.79% of all adult and pediatric ED visits, respectively. The majority of patients were treated and released (98.17%). The average age of patients presenting with an otologic complaint was 17.9 years (standard error=0.23). Overall, 62.7% of patients who presented with an otologic complaint were 0 to 17 years old. The most common diagnoses among all age groups included otitis media not otherwise specified (NOS) (60.6%), infected otitis externa NOS (11.8%), and otalgia NOS (6.8%). ConclusionsWe provide a comprehensive overview of otologic complaints that are an overlooked diagnostic category in public health research. NEDS data demonstrate a significant number of visits related to otologic complaints, especially in the pediatric population, that are nonemergent. Level of Evidence4 Laryngoscope, 125:1926-1933, 2015 C1 [Kozin, Elliott D.; Sethi, Rosh K. V.; Remenschneider, Aaron K.; Gray, Stacey T.; Shrime, Mark G.; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kozin, Elliott D.; Sethi, Rosh K. V.; Remenschneider, Aaron K.; Kaplan, Alyson B.; Gray, Stacey T.; Shrime, Mark G.; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [del Portal, Daniel A.] Temple Univ, Sch Med, Dept Emergency Med, Philadelphia, PA 19122 USA. [Shrime, Mark G.] Harvard Interfac Initiat Hlth Policy, Cambridge, MA USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu RI Kozin, Elliott/J-1225-2014 OI Kozin, Elliott/0000-0002-0305-0682 FU NIDCD NIH HHS [T32 DC000020] NR 42 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2015 VL 125 IS 8 BP 1926 EP 1933 DI 10.1002/lary.25197 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CN4DJ UT WOS:000358379700040 PM 25702897 ER PT J AU Kandil, E Mohamed, SE Deniwar, A Mohamed, H Friedlander, P Aslam, R Saeed, A Musa, I Randolph, G AF Kandil, Emad Mohamed, Salah Eldin Deniwar, Ahmed Mohamed, Hossam Friedlander, Paul Aslam, Rizwan Saeed, Ahmad Musa, Ibrahim Randolph, Gregory TI Electrophysiologic identification and monitoring of the external branch of superior laryngeal nerve during thyroidectomy SO LARYNGOSCOPE LA English DT Article DE External branch of superior laryngeal nerve; intraoperative nerve monitoring; recurrent laryngeal nerve; neural monitoring; thyroidectomy ID SURGICAL ANATOMY; SURGERY; RECURRENT; INJURY; NECK AB ObjectiveThe aim of the study is to examine the correlation between weight, gender, and race with external branch of superior laryngeal nerve (EBSLN) visualization. Furthermore, we compared normative EBSLN neural-monitoring values to those of the recurrent laryngeal nerve (RLN). Study DesignRetrospective study. SettingNorth American tertiary academic hospital. Subjects and MethodsA retrospective, institutional review board-approved review was carried out on patients undergoing thyroid surgery by a single surgeon over 3.5 years. Preoperative and postoperative laryngoscopy was done on all patients in accordance with recently published American Academy of Otolaryngology voice optimization at thyroidectomy guidelines, and patients' clinical and operative relevant data were collected. ResultsA total of 447 nerves were at risk in 371 thyroidectomy patients. Of these nerves at risk, 237 (53.02%) were visualized and stimulated. The average amplitude and latency for the EBSLN were significantly lower when compared to the amplitude and the latency of RLN stimulation (P<0.0001, P<0.0001, respectively). There was no gender or racial disparity. Out of our study population, the EBSLN was identified in 64.56% in nonobese patients, whereas it was only 40.00% in obese patients (P<0.001). Additionally, of the 56 patients in whom the EBSLN was visualized on one side and who further underwent bilateral neck exploration, 41 (73%) had visualization of the nerve on the contralateral side as well. ConclusionEBSLN is less likely to be visualized in obese patients; however, there was no gender or racial disparity. Stimulation of EBSLN was felt to be a useful adjunct during superior pole dissection to assure the nerve integrity. Level of Evidence4. Laryngoscope, 125:1996-2000, 2015 C1 [Kandil, Emad; Mohamed, Salah Eldin; Deniwar, Ahmed; Mohamed, Hossam; Saeed, Ahmad; Musa, Ibrahim] Tulane Univ, Sch Med, Dept Surg, Div Endocrine & Oncol Surg, New Orleans, LA 70124 USA. [Friedlander, Paul; Aslam, Rizwan] Tulane Univ, Sch Med, Dept Otolaryngol Surg, Div Endocrine & Oncol Surg, New Orleans, LA 70124 USA. [Randolph, Gregory] Harvard Univ, Massachusetts Gen Hosp, Div Surg Oncol, Endocrine Surg Serv,Med Sch, Cambridge, MA 02138 USA. RP Kandil, E (reprint author), Tulane Univ, Sch Med, Surg Oncol, 1430 Tulane Ave, New Orleans, LA 70124 USA. EM ekandil@tulane.edu FU Tulane University Medical Center FX This research and work was fully supported by Tulane University Medical Center. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 31 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2015 VL 125 IS 8 BP 1996 EP 2000 DI 10.1002/lary.25139 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CN4DJ UT WOS:000358379700052 PM 25942675 ER PT J AU Lin, YC Dionigi, G Randolph, GW Lu, IC Chang, PY Tsai, SY Kim, HY Lee, HY Tufano, RP Sun, H Liu, XL Chiang, FY Wu, CW AF Lin, Yi-Chu Dionigi, Gianlorenzo Randolph, Gregory W. Lu, I-Cheng Chang, Pi-Ying Tsai, Shan-Yin Kim, Hoon Yub Lee, Hye Yoon Tufano, Ralph P. Sun, Hui Liu, Xiaoli Chiang, Feng-Yu Wu, Che-Wei TI Electrophysiologic monitoring correlates of recurrent laryngeal nerve heat thermal injury in a porcine model SO LARYNGOSCOPE LA English DT Article DE Recurrent laryngeal nerve; continuous intraoperative neuromonitoring; thyroid surgery; nerve thermal injury; energy-based devices ID TOTAL THYROIDECTOMY; PARATHYROID REOPERATIONS; HARMONIC SCALPEL; SURGERY; IDENTIFICATION; PRESERVATION; STIMULATION; MECHANISMS; PARALYSIS; DIAGNOSIS AB Objectives/HypothesisThermal injury to the recurrent laryngeal nerve (RLN) may not be visually apparent and may go unrecognized intraoperatively. This study aimed to investigate the heat thermal tolerance of RLN and evaluate the electrophysiologic correlates of electromyographic (EMG) signal change during an acute RLN heat damage. Study DesignProspective porcine model with continuous intraoperative neuromonitoring (CIONM). MethodsTen pigs (20 RLNs) undergoing CIONM had their EMG tracings recorded and correlated with heated normal saline (NS) irrigation of varying temperature and duration. ResultsIn the initial pilot study, the EMG was without change during incremental heated NS irrigation (40/45/50/55 degrees C for 60 seconds), but adverse EMG combined events (CE) (amplitude decrease with a concordant latency increase) occurred and degraded to loss of signal (LOS) (by 17.51.3 seconds) when the temperature was elevated to 60 degrees C (n=4). Another 16 RLNs were evaluated to further compare the EMG pattern after various degrees of thermal stress (60/70 degrees C for 30/20 seconds). Electromyographic recordings showed CEs and LOS in all RLNs, and only six of eight RLNs with 60 degrees C exposure showed slight EMG amplitude recovery (16%-35%) after 20 minutes. None of the injured nerve segments were visually apparent, but all were detectable by IONM. ConclusionSixty degrees Celsius is a critical temperature to cause RLN thermal injury. Continuous intraoperative neuromonitoring can be used as a tool for the early detection of acute thermal stress and may guide use of energy-based devices during thyroid procedures. Level of EvidenceN/A. Laryngoscope, 125:E283-E290, 2015 C1 [Lin, Yi-Chu; Chiang, Feng-Yu; Wu, Che-Wei] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Grad Inst Clin Med,Fac Med,Coll Med, Kaohsiung 807, Taiwan. [Lu, I-Cheng; Chang, Pi-Ying] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Anesthesiol, Kaohsiung 807, Taiwan. [Tsai, Shan-Yin] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Pathol, Kaohsiung 807, Taiwan. [Dionigi, Gianlorenzo] Univ Insubria Como Varese, Div Surg 1, Dept Surg Sci & Human Morphol, Res Ctr Endocrine Surg, Varese, Italy. Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm,Div Thyroid & Para, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Surg Serv,Div Surg Oncol, Boston, MA USA. [Tufano, Ralph P.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Div Head & Neck Endocrine Surg, Baltimore, MD USA. [Kim, Hoon Yub; Lee, Hye Yoon] Korea Univ, Coll Med, Korea Univ Hosp, Dept Surg,KUMC Thyroid Ctr, Seoul 136705, South Korea. [Sun, Hui; Liu, Xiaoli] Jilin Univ, China Japan Union Hosp, Dept Thyroid & Parathyroid Surg, Changchun 130023, Jilin Province, Peoples R China. [Sun, Hui; Liu, Xiaoli] Jilin Prov Key Lab Surg Translat Med, Changchun, Jilin Province, Peoples R China. RP Chiang, FY (reprint author), Kaohsiung Med Univ, Coll Med, Fac Med, Dept Otorhinolaryngol Head & Neck Surg, 100,Tzyou First Rd, Kaohsiung 807, Taiwan. EM fychiang@kmu.edu.tw; cwwu@kmu.edu.tw OI dionigi, gianlorenzo/0000-0003-0864-6087; Wu, Che-Wei/0000-0003-1052-5348 FU Kaohsiung Medical University Hospital [KMUH 103-3T07, 103-3R36]; Ministry of Science and Technology, Taiwan [MOST 103-2314-B-037-037-MY2] FX This study was supported by grants from the Kaohsiung Medical University Hospital (KMUH 103-3T07, 103-3R36) and the Ministry of Science and Technology, Taiwan (MOST 103-2314-B-037-037-MY2). The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 31 TC 4 Z9 4 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2015 VL 125 IS 8 BP E283 EP E290 DI 10.1002/lary.25362 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA CN4DJ UT WOS:000358379700004 PM 26010439 ER PT J AU Wang, TY McElroy, A Halaney, D Vela, D Fung, E Hossain, S Phipps, J Wang, BQ Yin, BW Feldman, MD Milner, TE AF Wang, Tianyi McElroy, Austin Halaney, David Vela, Deborah Fung, Edmund Hossain, Shafat Phipps, Jennifer Wang, Bingqing Yin, Biwei Feldman, Marc D. Milner, Thomas E. TI Detection of plaque structure and composition using OCT combined with two-photon luminescence (TPL) imaging SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE atherosclerotic plaque; lipid; oxidized-LDL; calcium; collagen; elastin fiber; hybrid imaging; optical coherence tomography; two-photon luminescence imaging; photonic crystal fiber ID OPTICAL COHERENCE TOMOGRAPHY; THIN-CAP FIBROATHEROMA; CORONARY-ARTERY; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS; RUPTURED PLAQUES; VIVO VALIDATION; FREQUENCY; MICROSCOPY; CELL AB Background and ObjectivesAtherosclerosis and plaque rupture leads to myocardial infarction and stroke. A novel hybrid optical coherence tomography (OCT) and two-photon luminescence (TPL) fiber-based imaging system was developed to characterize tissue constituents in the context of plaque morphology. Study Design/Materials and MethodsEx vivo coronary arteries (34 regions of interest) from three human hearts with atherosclerotic plaques were examined by OCT-TPL imaging. Histological sections (4m in thickness) were stained with Oil Red O for lipid, Von Kossa for calcium, and Verhoeff-Masson Tri-Elastic for collagen/elastin fibers and compared with imaging results. ResultsBiochemical components in plaques including lipid, oxidized-LDL, and calcium, as well as a non-tissue component (metal) are distinguished by multi-channel TPL images with statistical significance (P<0.001). TPL imaging provides complementary optical contrast to OCT (two-photon absorption/emission vs scattering). Merged OCT-TPL images demonstrate the distribution of lipid deposits in registration with detailed plaque surface profile. ConclusionsResults suggest that multi-channel TPL imaging can effectively identify lipid sub-types and different plaque components. Furthermore, fiber-based hybrid OCT-TPL imaging simultaneously detects plaque structure and composition, improving the efficacy of vulnerable plaque detection and characterization. Lasers Surg. Med. 47:485-494, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Wang, Tianyi; McElroy, Austin; Fung, Edmund; Hossain, Shafat; Wang, Bingqing; Yin, Biwei; Milner, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Halaney, David; Phipps, Jennifer; Feldman, Marc D.] Univ Texas Hlth Sci Ctr San Antonio, Div Cardiol, San Antonio, TX 78229 USA. [Halaney, David; Feldman, Marc D.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Vela, Deborah] Texas Heart Inst, Houston, TX 77025 USA. RP Wang, TY (reprint author), Dept Biomed Engn, 1 Univ Stn C0800, Austin, TX 78712 USA. EM Tianyi.Wang@utexas.edu OI Halaney, David/0000-0003-4437-0516 FU ASLMS Research Grant; Veterans Health Administration Merit Grant [I01 BX000397]; American Heart Association Grant [13POST17080074]; Clayton Foundation for Biomedical Research; University of Texas FX Contract grant sponsor: ASLMS Research Grant; Contract grant sponsor: Veterans Health Administration Merit Grant; Contract grant number: I01 BX000397; Contract grant sponsor: American Heart Association Grant; Contract grant number: 13POST17080074; Contract grant sponsor: Clayton Foundation for Biomedical Research; Contract grant sponsor: University of Texas. NR 49 TC 1 Z9 1 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2015 VL 47 IS 6 BP 485 EP 494 DI 10.1002/lsm.22366 PG 10 WC Dermatology; Surgery SC Dermatology; Surgery GA CN4CF UT WOS:000358375800005 PM 26018531 ER PT J AU Chen, GD Lai, XQ Ko, DSC Qiu, J Wang, CX Han, M Li, J Huang, G He, XS Chen, LZ AF Chen, Guo-Dong Lai, Xing-Qiang Ko, Dicken Shiu-Chung Qiu, Jiang Wang, Chang-Xi Han, Ming Li, Jun Huang, Gang He, Xiao-Shun Chen, Li-Zhong TI Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: A retrospective cohort study SO NEPHROLOGY LA English DT Article DE anti-T lymphocyte globulin; donation after cardiac death; kidney transplantation; rabbit anti-thymocyte globulin ID RENAL-TRANSPLANTATION; INDUCTION THERAPY; ATGAM INDUCTION; THYMOGLOBULIN; EXPERIENCE; RECIPIENTS; FRESENIUS; DONORS AB AimTo compare the efficacy and safety between rabbit anti-thymocyte globulin (Thymoglobulin) and anti-T lymphocyte globulin (ATG-Fresenius, ATG-F) in donation after cardiac death (DCD) kidney transplantation. MethodsWe retrospectively analyzed 255 cases of DCD kidney transplantation performed at our hospital from February 2007 to October 2013. The patients were divided into two groups based on their induction therapies with Thymoglobulin (n=188) or ATG-F (n=67). Clinical data were collected and compared between the two groups. ResultsDelayed graft function (DGF) occurred in 36 (19.1%) patients in the Thymoglobulin group versus 17 (25.4%) patients in the ATG-F group (P=0.281). However, if we subgroup the patients with increased risk factors for DGF, the DGF rate was 9/40 (22.5%) in the Thymoglobulin group versus 9/16 (56.3%) in the ATG-F group (P=0.015). Duration of DGF was significantly shorter in the Thymoglobulin group (11.7 days vs. 16.1 days). The acute rejection rate was significantly lower in the Thymoglobulin group (9.6% vs. 19.4%, P=0.035). One-year graft and patient survival were both comparable between the Thymoglobulin and ATG-F groups. The adjusted odds ratio of DGF was 4.283 (1.137-16.13) between the ATG-F and Thymoglobulin groups in patients with increased risk factors for DGF. ConclusionCompared with ATG-F, Thymoglobulin may reduce duration of DGF and acute rejection rate after DCD kidney transplantation. Moreover, Thymoglobulin significantly reduced DGF in patients with increased risk factors for DGF. Summary at a Glance This study suggests that Thymoglobulin may have an advantage in reducing delayed graft function (DGF) in patients at higher risk for DGF in donation after cardiac death kidney transplantation. C1 [Chen, Guo-Dong; Lai, Xing-Qiang; Qiu, Jiang; Wang, Chang-Xi; Han, Ming; Li, Jun; Huang, Gang; He, Xiao-Shun; Chen, Li-Zhong] Sun Yat Sen Univ, Affiliated Hosp 1, Organ Transplant Ctr, Guangzhou 510080, Guangdong, Peoples R China. [Ko, Dicken Shiu-Chung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Ko, Dicken Shiu-Chung] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Chen, LZ (reprint author), Sun Yat Sen Univ, Affiliated Hosp 1, Organ Transplant Ctr, 58 Zhongshan Rd 2, Guangzhou 510080, Guangdong, Peoples R China. EM clz1@medmail.com.cn FU National Natural Science Fund Youth Science project [81302549]; Youth Medical Teacher Project of Sun Yat-sen University [14ykpy11]; National Natural Science Fund project [81470976]; Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology [2013A061401007]; Special Fund for Science Research by Ministry of Health [201302009] FX This study was supported by the National Natural Science Fund Youth Science project (81302549), Youth Medical Teacher Project of Sun Yat-sen University (14ykpy11), National Natural Science Fund project (81470976), the Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology (2013A061401007), the Special Fund for Science Research by Ministry of Health (201302009). NR 12 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1320-5358 EI 1440-1797 J9 NEPHROLOGY JI Nephrology PD AUG PY 2015 VL 20 IS 8 BP 539 EP 543 DI 10.1111/nep.12469 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA CN5ED UT WOS:000358451700005 PM 25808082 ER PT J AU Xu, WX Shubina, M Goldberg, SI Turchin, A AF Xu, Wenxin Shubina, Maria Goldberg, Saveli I. Turchin, Alexander TI Body mass index and all-cause mortality in patients with hypertension SO OBESITY LA English DT Article ID OBESITY PARADOX; BONFERRONI PROCEDURE; METABOLIC SYNDROME; PROSPECTIVE COHORT; MULTIPLE TESTS; TIME-SCALE; VALIDATION; DATABASE; DISEASE; OVERWEIGHT AB ObjectiveTo characterize the relationship between body mass index (BMI) and all-cause mortality among adults with hypertension. MethodsWe conducted a retrospective cohort study of adults with hypertension from The Health Improvement Network primary care research database in the United Kingdom. Mortality rates within each BMI category were compared after adjustment for age, sex, pre existing medical conditions, smoking, alcohol use, and socioeconomic status. ResultsDuring a median follow-up period of 8.0 years, 34,354 deaths occurred (8.8%) among the 388,724 study patients. In multivariable analysis that included interaction terms between smoking, heavy alcohol use, preexisting cardiovascular disease and chronic obstructive pulmonary disease (COPD), and BMI category to account for these conditions' association with increased mortality at lower BMI levels, a U-shaped relationship was observed between BMI and mortality, with no difference in mortality in overweight (25.0-29.9 kg/m(2)) versus normal (18.5-24.9 kg/m(2)) BMI (risk ratio 1.00, 95% confidence interval 0.95 to 1.04, P=0.80). In multivariable analysis that used narrower BMI categories, lowest mortality was observed between BMI of 23.0 and 26.9 kg/m(2). ConclusionsPatients with hypertension who have no history of smoking, heavy alcohol use, cardiovascular disease, or COPD have lowest mortality between BMI of 23.0 and 26.9 kg/m(2). C1 [Xu, Wenxin; Turchin, Alexander] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Xu, Wenxin] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Shubina, Maria; Turchin, Alexander] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Goldberg, Saveli I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Turchin, Alexander] Harvard Clin Res Inst, Boston, MA USA. RP Turchin, A (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA. EM aturchin@partners.org FU Harvard Medical School Center for Primary Care FX This study was funded in part by the Harvard Medical School Center for Primary Care. This organization had no 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 article for publication. NR 34 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD AUG PY 2015 VL 23 IS 8 BP 1712 EP 1720 DI 10.1002/oby.21129 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CN3JG UT WOS:000358321300027 PM 26179058 ER PT J AU Yanos, BR Saules, KK Schuh, LM Sogg, S AF Yanos, Brenton R. Saules, Karen K. Schuh, Leslie M. Sogg, Stephanie TI Predictors of Lowest Weight and Long-Term Weight Regain Among Roux-en-Y Gastric Bypass Patients SO OBESITY SURGERY LA English DT Article DE Bariatric surgery; Roux-en-Y gastric bypass; Weight loss; Weight regain; Nocturnal eating; Depression; Alcohol use; Physical activity; Comorbidity ID FOOD ADDICTION SCALE; VERTICAL BANDED GASTROPLASTY; BARIATRIC SURGERY; MORBID-OBESITY; FOLLOW-UP; LOSS MAINTENANCE; EATING BEHAVIOR; POPULATION; VALIDATION; VALIDITY AB Weight loss surgery (WLS) outcomes are poorly understood. This study aimed to evaluate the relationship of well-documented (e.g., health, diet, physical activity) and theoretically relevant variables (e.g., substance use and "food addiction") with both weight nadir and weight regain (WR) following WLS. A sample of 97 Roux-en-Y gastric bypass patients (M (time since surgery) = 8.86 years) were surveyed about pre- and post-WLS weight, health, self-management behaviors, alcohol problems, and clinical symptoms. Patients lost a mean of 42 % (SD = 10.71 %) of total weight at weight nadir, but 26 % (SD = 19.66 %) of the lost weight was regained by the time of the survey. Correlates of lower weight nadir and WR differed considerably, with minor overlap. Weight nadir was associated with pre-WLS drug use and post-WLS medical comorbidities. WR, on the other hand, was associated with post-WLS adherence to dietary and physical activity modification. Post-WLS nocturnal eating, depression, and problematic alcohol use were also associated with WR. With all associated variables in regression models, number of post-WLS medical comorbidities (beta = -.313, p < 0.01) and post-WLS depression (beta = 0.325, p < 0.01) accounted for the most variance and remained as significant predictors of weight nadir and WR, respectively. While weight nadir was associated with relatively few and largely nonmodifiable variables, WR was significantly associated with adherence-related behaviors, mood symptoms, and pathological patterns of food and alcohol use, all of which are potentially modifiable. These findings underscore the importance of long-term behavioral and psychosocial monitoring after surgery. C1 [Yanos, Brenton R.; Saules, Karen K.] Eastern Michigan Univ, Ypsilanti, MI 48197 USA. [Schuh, Leslie M.] St Vincent Carmel Bariatr Ctr Excellence, Carmel, IN USA. [Sogg, Stephanie] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saules, KK (reprint author), Eastern Michigan Univ, Ypsilanti, MI 48197 USA. EM byanos1@emich.edu; ksaules@emich.edu; lmschuh@stvincent.org; SSOGG@mgh.harvard.edu NR 54 TC 8 Z9 8 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 EI 1708-0428 J9 OBES SURG JI Obes. Surg. PD AUG PY 2015 VL 25 IS 8 BP 1364 EP 1370 DI 10.1007/s11695-014-1536-z PG 7 WC Surgery SC Surgery GA CN1GM UT WOS:000358166600149 PM 25519772 ER PT J AU Stefanopoulos, A Economopoulos, KP Kalles, V AF Stefanopoulos, Anastasios Economopoulos, Konstantinos P. Kalles, Vasileios TI Single Incision Laparoscopic Sleeve Gastrectomy: a Review SO OBESITY SURGERY LA English DT Review DE Single incision; SILS; Sleeve gastrectomy; Single port; Bariatric surgery ID Y GASTRIC BYPASS; MORBID-OBESITY; WEIGHT-LOSS; TECHNICAL CONSIDERATIONS; INITIAL-EXPERIENCE; FOLLOW-UP; PORT; SURGERY; SILS; SERIES AB We aim to summarize the existing evidence on the use of single incision sleeve gastrectomy (SILSG) for morbid obesity. A thorough literature search for studies reporting outcomes of SILSG was performed. Data on patient demographics, operative details, and surgical outcomes were analyzed. Sixteen studies incorporating 945 patients (90.6 % women) with a mean age of 37 years were included in the analysis. A commercially available single-port device was used in 89.7 % of the cases. The mean operative time was 64.7 min, with two cases (0.2 %) of intraoperative and 27 cases (2.8 %) of postoperative complications. There were no perioperative deaths reported, while the mean postoperative hospital stay was 2.5 days. SILSG is a feasible and safe approach, with low complication and mortality rates in carefully selected patients. C1 [Stefanopoulos, Anastasios; Economopoulos, Konstantinos P.; Kalles, Vasileios] Soc Jr Doctors, Athens, Greece. [Economopoulos, Konstantinos P.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kalles, Vasileios] Naval & Vet Hosp Athens, Dept Surg 2, Athens, Greece. RP Stefanopoulos, A (reprint author), Soc Jr Doctors, Athens, Greece. EM anastkstef@gmail.com; keconomopoulos@mgh.harvard.edu; vassilis_kalles@yahoo.gr OI Economopoulos, Konstantinos/0000-0003-4856-0405 NR 45 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 EI 1708-0428 J9 OBES SURG JI Obes. Surg. PD AUG PY 2015 VL 25 IS 8 BP 1502 EP 1510 DI 10.1007/s11695-015-1709-4 PG 9 WC Surgery SC Surgery GA CN1GM UT WOS:000358166600170 PM 25986425 ER PT J AU Bateman, BT Huybrechts, KF Maeda, A Desai, R Patorno, E Seely, EW Ecker, JL Allen-Coleman, C Mogun, H Hernandez-Diaz, S Fischer, MA AF Bateman, Brian T. Huybrechts, Krista F. Maeda, Ayumi Desai, Rishi Patorno, Elisabetta Seely, Ellen W. Ecker, Jeffrey L. Allen-Coleman, Cora Mogun, Helen Hernandez-Diaz, Sonia Fischer, Michael A. TI Calcium Channel Blocker Exposure in Late Pregnancy and the Risk of Neonatal Seizures SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PRETERM LABOR; POSTPARTUM HEMORRHAGE; ANTIDEPRESSANT USE; UNITED-STATES; POPULATION; NIFEDIPINE; WOMEN; TOCOLYSIS; OUTCOMES AB OBJECTIVE: To assess whether maternal calcium channel blocker exposure during late pregnancy is independently associated with neonatal seizures after carefully controlling for confounding factors. METHODS: Data were derived from the Medicaid Analytic eXtract for the years 2000-2007 and included 2,529,636 completed pregnancies. We compared the risk of neonatal seizures among neonates who were born to women who took calcium channel blockers in the final month of pregnancy to the risk in neonates born to women who did not use calcium channel blockers. Confounding was addressed through the use of propensity score matching. RESULTS: A total of 22,908 (0.91%) pregnancies included exposure to calcium channel blockers during the final month of pregnancy. Neonatal seizures occurred in 53 (0.23%) neonates born to mothers exposed to calcium channel blockers and in 4,609 (0.18%) neonates of unexposed women (unadjusted odds ratio [OR] 1.26, 95% confidence interval [CI] 0.96-1.65). After accounting for confounders, there was no increase in risk of neonatal seizures associated with calcium channel blocker exposure (OR 0.95, 95% CI 0.70-1.30). This null finding was robust across multiple sensitivity analysis. CONCLUSION: In this large, carefully controlled, population-based cohort study, there was no significant increase in the risk of neonatal seizures in neonates attributable to maternal calcium channel blocker exposure in late pregnancy. The results suggest that calcium channel blockers can be used by obstetricians in late pregnancy without excess concern about this neonatal complication. C1 [Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. Brigham & Womens Hosp, Div Endocrinol Diabet & Metab, Boston, MA 02120 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Bateman, BT (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM bbateman@partners.org FU Eunice Kennedy Shriver National Institute of Child Health; Human Development of the National Institutes of Health (Bethesda, Maryland) [K08HD075831]; National Heart Lung and Blood Institute at the National Institutes of Health [K24HL096141]; Agency for Healthcare Research and Quality [R01HS018533] FX Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (Bethesda, Maryland) under Award Number K08HD075831 (B.T.B.) and the National Heart Lung and Blood Institute at the National Institutes of Health under grant number K24HL096141 (E.W.S.). The Medicaid Analytic eXtract (MAX) pregnancy cohort was supported by the Agency for Healthcare Research and Quality (Grant R01HS018533). NR 28 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2015 VL 126 IS 2 BP 271 EP 278 DI 10.1097/AOG.0000000000000908 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN2WP UT WOS:000358283500001 PM 26241414 ER PT J AU Thompson, JL Kuklina, EV Bateman, BT Callaghan, WM James, AH Grotegut, CA AF Thompson, Jennifer L. Kuklina, Elena V. Bateman, Brian T. Callaghan, William M. James, Andra H. Grotegut, Chad A. TI Medical and Obstetric Outcomes Among Pregnant Women With Congenital Heart Disease SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MATERNAL MORBIDITY; UNITED-STATES; HOSPITALIZATIONS; DELIVERY AB OBJECTIVE: To estimate nationwide trends in the prevalence of maternal congenital heart disease (CHD) and determine whether women with CHD are more likely than women without maternal CHD to have medical and obstetric complications. METHODS: The 2000-2010 Nationwide Inpatient Sample was queried for International Classification of Diseases, 9th Revision, Clinical Modification codes to identify delivery hospitalizations of women with and without CHD. Trends in the prevalence of CHD were determined and then rates of complications were reported for CHD per 10,000 delivery hospitalizations. For Nationwide Inpatient Sample 2008-2010, logistic regression was used to examine associations between CHD and complications. RESULTS: From 2000 to 2010, there was a significant linear increase in the prevalence of CHD from 6.4 to 9.0 per 10,000 delivery hospitalizations (P<.001). Multivariable logistic regression demonstrated that all selected medical complications, including mortality (17.8 compared with 0.7/10,000 deliveries, adjusted odds ratio [OR] 22.10, 95% confidence interval [CI] 13.96-34.97), mechanical ventilation (91.9 compared with 6.9/10,000, adjusted OR 9.94, 95% CI 7.99-12.37), and a composite cardiovascular outcome (614 compared with 34.3/10,000, adjusted OR 10.54, 95% CI 9.55-11.64) were more likely to occur among delivery hospitalizations with maternal CHD than without. Obstetric complications were also common among women with CHD. Delivery hospitalizations with maternal CHD that also included codes for pulmonary circulatory disorders had higher rates of medical complications compared with hospitalizations with maternal CHD without pulmonary circulatory disorders. CONCLUSION: The number of delivery hospitalizations with maternal CHD in the United States is increasing, and although we were not able to determine whether correction of the cardiac lesion affected outcomes, these hospitalizations have a high burden of medical and obstetric complications. C1 [Grotegut, Chad A.] Duke Univ, Div Maternal Fetal Med, Durham, NC 27710 USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Harvard Univ, Brigham & Womens Hosp, Massachusetts Gen Hosp,Div Pharmacoepidemiol & Ph, Dept Anesthesia Crit Care & Pain Management,Dept, Boston, MA 02115 USA. RP Grotegut, CA (reprint author), Duke Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, DUMC Box 3967, Durham, NC 27710 USA. EM chad.grotegut@duke.edu FU Intramural CDC HHS [CC999999] NR 25 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2015 VL 126 IS 2 BP 346 EP 354 DI 10.1097/AOG.0000000000000973 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN2WY UT WOS:000358284500003 PM 26241425 ER PT J AU Guthrie, KA LaCroix, AZ Ensrud, KE Joffe, H Newton, KM Reed, SD Caan, B Carpenter, JS Cohen, LS Freeman, EW Larson, JC Manson, JE Rexrode, K Skaar, TC Sternfeld, B Anderson, GL AF Guthrie, Katherine A. LaCroix, Andrea Z. Ensrud, Kristine E. Joffe, Hadine Newton, Katherine M. Reed, Susan D. Caan, Bette Carpenter, Janet S. Cohen, Lee S. Freeman, Ellen W. Larson, Joseph C. Manson, JoAnn E. Rexrode, Kathy Skaar, Todd C. Sternfeld, Barbara Anderson, Garnet L. TI Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LOW-DOSE ESTRADIOL; HOT FLASHES; POSTMENOPAUSAL WOMEN; DOUBLE-BLIND; MENOPAUSAL SYMPTOMS; CLINICAL-TRIAL; BREAST-CANCER; PHASE-III; EFFICACY AB OBJECTIVE: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials. METHODS: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time. RESULTS: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements. CONCLUSION: These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes. C1 Fred Hutchinson Canc Res Ctr, MsFLASH Data Coordinating Ctr, Seattle, WA 98104 USA. Grp Hlth Res Inst, Seattle, WA USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Minnesota, VA Med Center, Minneapolis, MN USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. Indiana Univ, Dept Med, Div Clin Pharmacol, Indianapolis, IN USA. Univ Penn, Sch Med, Dept Obstet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Gynecol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Guthrie, KA (reprint author), 1100 Fairview Ave N,POB 19024,M3-C102, Seattle, WA 98109 USA. EM kguthrie@fredhutch.org OI Anderson, Garnet/0000-0001-5087-7837; Rexrode, Kathryn/0000-0003-3387-8429 FU Cephalon/Teva; Bayer Pharmaceuticals; AstraZeneca; Bristol-Myers Squibb/Otsuka; Cephalon, Inc.; Ortho-McNeil Janssen; Sunovion Pharmaceuticals, Inc.; Takeda/Lundbeck; Forest Laboratories, Inc.; Bionovo FX Dr. Ensrud serves as a consultant on a Data Monitoring Committee for Merck Sharpe & Dohme. Dr. Joffe has received grant funding from Cephalon/Teva, has been a consultant for Noven Pharmaceuticals and Merck, and has served on an advisory board for Merck. Dr. Reed has received research funding from Bayer Pharmaceuticals. Dr. Cohen has received research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Cephalon, Inc., Ortho-McNeil Janssen, Sunovion Pharmaceuticals, Inc., and Takeda/Lundbeck. Dr. Freeman has received grants paid to the University of Pennsylvania by Forest Laboratories, Inc., and Bionovo. The other authors did not report any potential conflicts of interest. NR 37 TC 6 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2015 VL 126 IS 2 BP 413 EP 422 DI 10.1097/AOG.0000000000000927 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN2WY UT WOS:000358284500012 PM 26241433 ER PT J AU Ho, AC Humayun, MS Dorn, JD da Cruz, L Dagnelie, G Handa, J Barale, PO Sahel, JA Stanga, PE Hafezi, F Safran, AB Salzmann, J Santos, A Birch, D Spencer, R Cideciyan, AV de Juan, E Duncan, JL Eliott, D Fawzi, A de Koo, LCO Brown, GC Haller, JA Regillo, CD Del Priore, LV Arditi, A Geruschat, DR Greenberg, RJ AF Ho, Allen C. Humayun, Mark S. Dorn, Jessy D. da Cruz, Lyndon Dagnelie, Gislin Handa, James Barale, Pierre-Olivier Sahel, Jose-Alain Stanga, Paulo E. Hafezi, Farhad Safran, Avinoam B. Salzmann, Joel Santos, Arturo Birch, David Spencer, Rand Cideciyan, Artur V. de Juan, Eugene Duncan, Jacque L. Eliott, Dean Fawzi, Amani de Koo, Lisa C. Olmos Brown, Gary C. Haller, Julia A. Regillo, Carl D. Del Priore, Lucian V. Arditi, Aries Geruschat, Duane R. Greenberg, Robert J. CA Argus II Study Grp TI Long-Term Results from an Epiretinal Prosthesis to Restore Sight to the Blind SO OPHTHALMOLOGY LA English DT Article ID II RETINAL PROSTHESIS; GENE-THERAPY; STIMULATION; SURGERY; VISION; TACKS AB Purpose: Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. Design: The study is a multicenter, single-arm, prospective clinical trial. Participants: There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). Methods: The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Results: A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device-or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. Conclusions: The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals. (C) 2015 by the American Academy of Ophthalmology. C1 [Ho, Allen C.; Brown, Gary C.; Haller, Julia A.; Regillo, Carl D.] Wills Eye Hosp & Res Inst, Philadelphia, PA 19108 USA. [Humayun, Mark S.; Hafezi, Farhad; Eliott, Dean; Fawzi, Amani; de Koo, Lisa C. Olmos] Univ So Calif, Los Angeles, CA USA. [Dorn, Jessy D.; Greenberg, Robert J.] Second Sight Med Prod, Sylmar, CA USA. [da Cruz, Lyndon] Moorfields Eye Hosp NHS Fdn Trust, London, England. [da Cruz, Lyndon] NHIR Moorfields Biomed Res Ctr, London, England. [Dagnelie, Gislin; Handa, James; Haller, Julia A.; Geruschat, Duane R.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Barale, Pierre-Olivier; Sahel, Jose-Alain] Ctr Hosp Natl Ophtalmol Quinze Vingts, Paris, France. [Stanga, Paulo E.] Manchester Royal Eye Hosp, Manchester M13 9WH, Lancs, England. [Stanga, Paulo E.] Wellcome Trust Manchester CRF, Natl Inst Hlth Res, Manchester Vis Regenerat Lab, Manchester, Lancs, England. [Stanga, Paulo E.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Stanga, Paulo E.] Univ Manchester, Ctr Ophthalmol & Vis Res, Inst Human Dev, Manchester, Lancs, England. [Hafezi, Farhad; Safran, Avinoam B.; Salzmann, Joel] Hop Univ Geneva, Geneva, Switzerland. [Sahel, Jose-Alain; Hafezi, Farhad] ELZA Inst, Zurich, Switzerland. [Safran, Avinoam B.] UPMC, Univ Paris 04, Paris, France. [Safran, Avinoam B.] Inst Vis, Paris, France. [Santos, Arturo] Ctr Retina Med & Quirurg SC, Guadalajara, Jalisco, Mexico. [Santos, Arturo] Tecnol Monterrey, Guadalajara, Jalisco, Mexico. [Birch, David] Retina Fdn Southwest, Dallas, TX USA. [Spencer, Rand] Texas Retina Associates, Dallas, TX USA. [Cideciyan, Artur V.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [de Juan, Eugene; Duncan, Jacque L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Eliott, Dean] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Fawzi, Amani] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Del Priore, Lucian V.] Columbia Univ, New York, NY USA. [Del Priore, Lucian V.] Storm Eye Inst, Charleston, SC 29425 USA. [Arditi, Aries] Lighthouse Guild, New York, NY USA. [Arditi, Aries] Visibil Metr LLC, Chappaqua, NY USA. RP Ho, AC (reprint author), Wills Eye Hosp & Res Inst, 840 Walnut St,Suite 1020, Philadelphia, PA 19108 USA. EM acho@midatlanticretina.com RI Sahel, Jose-Alain/F-3172-2017; OI Olmos de Koo, Lisa/0000-0002-8146-4653; fawzi, amani/0000-0002-9568-3558 FU National Institutes of Health [5R01EY012893-10, 1RC3EY020778-01]; National Eye Institute, Research/Development of Artificial Retinas for the Blind [07/2000-02/2011]; Second Sight Medical Products, Inc. FX Funded by National Institutes of Health grant no. 5R01EY012893-10 (R.J.G., principal investigator) 07/2000-02/2011 National Eye Institute, Research/Development of Artificial Retinas for the Blind and National Institutes of Health grant no. 1RC3EY020778-01 (R.J.G., principal investigator), Development and Testing of Low Vision Assessment Tools for Retinal Prostheses. The clinical trial was sponsored by Second Sight Medical Products, Inc. The sponsor participated in the design and conduct of the study; data management, analysis, and interpretation; and preparation and review of the manuscript. NR 18 TC 42 Z9 43 U1 5 U2 35 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2015 VL 122 IS 8 BP 1547 EP 1554 DI 10.1016/j.ophtha.2015.04.032 PG 8 WC Ophthalmology SC Ophthalmology GA CN3JV UT WOS:000358322900011 PM 26162233 ER PT J AU Saboo, US Amparo, F Abud, TB Schaumberg, DA Dana, R AF Saboo, Ujwala S. Amparo, Francisco Abud, Tulio B. Schaumberg, Debra A. Dana, Reza TI Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease SO OPHTHALMOLOGY LA English DT Article ID VISUAL FUNCTION QUESTIONNAIRE; DRY EYE SYNDROME; STEM-CELL TRANSPLANTATION; PSYCHOMETRIC PROPERTIES; NEI-VFQ; IMPACT; PERFORMANCE; REPEATABILITY; VALIDATION; NEI-VFQ-25 AB Purpose: To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). Design: Prospective study. Participants: Eighty-four patients diagnosed with chronic ocular GVHD. Methods: We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. Main Outcome Measures: We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. Results: The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5 +/- 17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). Conclusions: Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. (C) 2015 by the American Academy of Ophthalmology. C1 [Saboo, Ujwala S.; Amparo, Francisco; Abud, Tulio B.; Dana, Reza] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. [Schaumberg, Debra A.] Univ Utah, Sch Med, John A Moran Eye Ctr, Moran Ctr Translat Med, Salt Lake City, UT USA. [Schaumberg, Debra A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Dana, R (reprint author), Massachusetts Eye & Ear Infirm, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu FU National Eye Institute, National Institutes of Health [K24-EY019098]; Research to Prevent Blindness FX Supported by the National Eye Institute, National Institutes of Health (grant K24-EY019098), and Research to Prevent Blindness. The funding organizations had no role in the design or conduct of this research. NR 42 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2015 VL 122 IS 8 BP 1669 EP 1674 DI 10.1016/j.ophtha.2015.04.011 PG 6 WC Ophthalmology SC Ophthalmology GA CN3JV UT WOS:000358322900028 PM 26001816 ER PT J AU Ambroggio, L Test, M Metlay, JP Graf, TR Blosky, MA Macaluso, M Shah, SS AF Ambroggio, Lilliam Test, Matthew Metlay, Joshua P. Graf, Thomas R. Blosky, Mary Ann Macaluso, Maurizio Shah, Samir S. TI Comparative Effectiveness of Beta-lactam Versus Macrolide Monotherapy in Children with Pneumonia Diagnosed in the Outpatient Setting SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pneumonia; child; pediatric ID COMMUNITY-ACQUIRED PNEUMONIA; PROPENSITY SCORES AB Background: Most children diagnosed with community-acquired pneumonia (CAP) are treated in the outpatient setting. The objective of this study was to determine the comparative clinical effectiveness of beta-lactam monotherapy and macrolide monotherapy in this population. Study Design: Children, 1-18 years old, with a clinical diagnosis of CAP at an outpatient practice affiliated (n = 71) with Geisinger Health System during January 1, 2008 to January 31, 2010 were eligible. The primary exposure was receipt of beta-lactam or macrolide monotherapy. The primary outcome was treatment failure defined as change in antibiotic prescription within 14 days of the initial pneumonia diagnosis. Propensity scores were used to determine the likelihood of receiving macrolide monotherapy. Treatment groups were matched 1:1, based on propensity score, age group and asthma status. Multivariable conditional logistic regression models estimated the association between macrolide monotherapy and treatment failures. Results: Of 1999 children with CAP, 1164 were matched. In the matched cohorts, 24% of children had asthma. Patients who received macrolide monotherapy had no statistical difference in treatment failure regardless of age when compared with patients who received beta-lactam monotherapy. Conclusion: Our findings suggest that children diagnosed with CAP in the outpatient setting and treated with beta-lactam or macrolide monotherapy have the same likelihood to fail treatment regardless of age. C1 [Ambroggio, Lilliam; Test, Matthew; Shah, Samir S.] Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, Cincinnati, OH 45229 USA. [Ambroggio, Lilliam; Macaluso, Maurizio] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Graf, Thomas R.; Blosky, Mary Ann] Geisinger Hlth Syst, Populat Hlth, Danville, PA USA. [Ambroggio, Lilliam; Macaluso, Maurizio; Shah, Samir S.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Shah, Samir S.] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. RP Ambroggio, L (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Hosp Med, 3333 Burnet Ave ML 9016, Cincinnati, OH 45229 USA. EM lilliam.ambroggio@cchmc.org RI Macaluso, Maurizio/J-2076-2015; OI Macaluso, Maurizio/0000-0002-2977-9690; Ambroggio, Lilliam/0000-0002-6242-607X FU Ruth L. Kirschestein National Research Service Award [NRSA T32HP10027-14-00]; National Institute of Allergy and Infectious Diseases [K01 73729, K24AI073957]; Robert Wood Johnson Foundation FX Funding for this study was provided to L.A. from the Ruth L. Kirschestein National Research Service Award (NRSA T32HP10027-14-00), provided to S.S.S from the National Institute of Allergy and Infectious Diseases (K01 73729) and Robert Wood Johnson Foundation under its Physician Faculty Scholar Award and provided to J.P.M. from the National Institute of Allergy and Infectious Diseases (K24AI073957). The authors have no conflicts of interest or funding relationships relevant to this article to disclose. NR 15 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2015 VL 34 IS 8 BP 839 EP 842 DI 10.1097/INF.0000000000000740 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA CN4PE UT WOS:000358411500007 PM 25955834 ER PT J AU Gharedaghi, MH Rahimian, R Dehpour, AR Yousefzadeh-Fard, Y Mohammadi-Farani, A AF Gharedaghi, Mohammad Hadi Rahimian, Reza Dehpour, Ahmad Reza Yousefzadeh-Fard, Yashar Mohammadi-Farani, Ahmad TI Dinitrobenzene sulphonic acid-induced colitis impairs spatial recognition memory in mice: roles of N-methyl D-aspartate receptors and nitric oxide SO PSYCHOPHARMACOLOGY LA English DT Article DE Dinitrobenzene sulfonic acid-induced colitis; Y-maze paradigm; Memory; N-methyl D-aspartate; MK-801; Memantine; Nitric oxide; Aminoguanidine; Passive avoidance test; Mice ID INFLAMMATORY-BOWEL-DISEASE; EXCITATORY AMINO-ACIDS; LONG-TERM POTENTIATION; TOLL-LIKE RECEPTOR-4; PERIPHERAL INFLAMMATION; INTESTINAL INFLAMMATION; SYNTHASE EXPRESSION; ULCERATIVE-COLITIS; ANTAGONIST BLOCKS; GLUTAMATE UPTAKE AB Many peripheral diseases are associated with a decline in cognitive function. In this regard, there have been reports of patients with inflammatory bowel disease and an otherwise unexplained memory impairment. We sought to assess the memory performance of mice with colitis. We also investigated the roles of N-methyl d-aspartate (NMDA) receptors and nitric oxide (NO) as possible mediators of colitis-induced amnesia. To induce colitis, male NMRI mice were intrarectally injected with a solution containing dinitrobenzene sulfonic acid (DNBS; 4 mg in 100 mu l) under anesthesia. Three days after intrarectal DNBS instillation, spatial recognition and associative memories were assessed by the Y-maze and passive avoidance tasks, respectively. The NMDA antagonists, MK-801 and memantine, and the inducible NO synthase (iNOS) inhibitor, aminoguanidine, were injected intraperitoneally 45 min before the Y-maze task. Induction of colitis by DNBS impaired spatial recognition memory in the Y-maze task but had no effect on step through latencies in the passive avoidance test. Colitis-induced amnesia was reversed by administering specific doses of MK-801 and memantine (30 mu g/kg and 1 mg/kg, respectively) suggesting dysregulated NMDA receptor activation as an underlying mechanism. No effect was seen with lower and higher doses of these drugs, resulting in a bell-shaped dose response curve. Colitis-induced amnesia was also inhibited by aminoguanidine (50 mg/kg), implicating a role for iNOS activation and neuroinflammation in this phenomenon. DNBS-induced colitis impairs memory through NMDA receptor overstimulation and NO overproduction. C1 [Gharedaghi, Mohammad Hadi; Rahimian, Reza; Dehpour, Ahmad Reza; Yousefzadeh-Fard, Yashar] Univ Tehran Med Sci, Sch Med, Dept Pharmacol, Tehran, Iran. [Gharedaghi, Mohammad Hadi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Dehpour, Ahmad Reza] Univ Tehran Med Sci, Expt Med Res Ctr, Tehran, Iran. [Yousefzadeh-Fard, Yashar] Columbia Univ, Dept Psychiat, Div Mol Imaging & Neuropathol, New York State Psychiat Inst,Med Ctr, New York, NY USA. [Mohammadi-Farani, Ahmad] Kermanshah Univ Med Sci, Novel Drug Delivery Res Ctr, Kermanshah, Iran. [Mohammadi-Farani, Ahmad] Kermanshah Univ Med Sci, Fac Pharm, Dept Pharmacol Toxicol & Med Serv, Kermanshah, Iran. RP Dehpour, AR (reprint author), Univ Tehran Med Sci, Sch Med, Dept Pharmacol, POB 13145-784, Tehran, Iran. EM dehpour@yahoo.com; amohammadifa@kums.ac.ir OI dehpour, ahmad reza/0000-0002-8001-5565 FU Kermanshah University of Medical Sciences FX This study was supported by a grant from the Vice Chancellor of Research of Kermanshah University of Medical Sciences. The protocol for this study was approved by our institution's animal use and care committee (Department of Pharmacology, Kermanshah University of Medical Sciences, Kermanshah, Iran), and the experiments were performed in accordance with Iranian laws. NR 68 TC 3 Z9 3 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2015 VL 232 IS 16 BP 3081 EP 3090 DI 10.1007/s00213-015-3950-x PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CN4QF UT WOS:000358414400018 PM 25971874 ER PT J AU Colman, MW Karim, SM Lozano-Calderon, SA Pedlow, FX Raskin, KA Hornicek, FJ Schwab, JH AF Colman, Matthew W. Karim, Syed M. Lozano-Calderon, Santiago A. Pedlow, Frank X. Raskin, Kevin A. Hornicek, Francis J. Schwab, Joseph H. TI Quality of life after en bloc resection of tumors in the mobile spine SO SPINE JOURNAL LA English DT Article DE Spondylectomy; Quality of life; Mobile spine; PROMIS; Malignant; Tumor; En bloc ID OSWESTRY DISABILITY INDEX; SOLITARY METASTASES; SURGICAL TECHNIQUE; CERVICAL-SPINE; BONE-TUMORS; SURGERY; PAIN; SPONDYLECTOMY; OUTCOMES; FUSION AB BACKGROUND CONTEXT: Little has been reported regarding the patient-centered quality-of-life (QOL) outcomes after en bloc spondylectomy (ES). Despite lower local recurrence rates, it is unknown whether outcomes justify the surgical morbidity. PURPOSE: The purpose of this study was to report on patient QOL after ES as measured by validated instruments and to identify factors that may predict better postoperative QOL. STUDY DESIGN: This is a retrospective case-control study (Level III). PATIENT SAMPLE: Thirty-five consecutive patients with mobile spine tumors were included. Twenty-seven patients underwent en bloc resection, whereas 8 patients received definitive radiation and no surgery. Minimum follow-up was 6 months (median, 32 months). OUTCOME MEASURES: The outcome measures were European Quality Group 5-Dimensional Questionnaire (EQ5D), four Patient-Reported Outcome Measurement Information System (PROMIS) short-form metrics, Neck Disability Index, and Oswestry Disability Index (ODI). METHODS: We performed statistical comparisons between the surgery and radiation groups, of the general US population, and within the study group itself to identify predictors of higher QOL scores. RESULTS: We identified a significant difference in QOL between the surgery and radiation groups in only one instrument, PROMIS pain interference, with surgery having more pain interference (15.7 vs. 10.1, p=.04). For most metrics, including EQ5D, pain interference, pain behavior, and ODI, scores were around one standard deviation worse than the US population mean. Multivariable linear regression for each instrument demonstrated that preoperative factors such as better performance status, tumor location in the cervical spine, lack of mechanical back or neck pain, and shorter fusion span were independently predictive of better QOL scores. Postoperative factors such as poor performance status, chronic narcotic use, and local recurrence were more dominant than preoperative factors in predicting worse QOL. CONCLUSIONS: Patients may experience more pain interference after surgery as opposed to definitive radiotherapy, but we did not identify a difference for most metrics. Quality of life in our study group was significantly worse than the general population for most metrics. Cervical tumors, lack of mechanical pain, better baseline performance status, and less extensive surgery predict better QOL after surgery. (C) 2015 Elsevier Inc. All rights reserved. C1 [Colman, Matthew W.] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL USA. [Karim, Syed M.; Lozano-Calderon, Santiago A.; Pedlow, Frank X.; Raskin, Kevin A.; Hornicek, Francis J.; Schwab, Joseph H.] Massachusetts Gen Hosp, Dept Orthoped Surg, Harvard Combined Dept Orthoped, Boston, MA 02114 USA. RP Colman, MW (reprint author), Rush Univ, Med Ctr, Dept Orthoped Surg, 1611 W Harrison St,Ste 300, Chicago, IL USA. EM matthew.colman@rushortho.com FU Biomet FX MWC: Nothing to disclose. SMK: Nothing to disclose. SAL-C: Nothing to disclose. FXP: Nothing to disclose. KAR: Nothing to disclose. FJH: Royalties: Amyirsys Publishing (A); Consulting: Stryker (B); Board of Directors: ISOLS and AATB (Nonfinancial); Scientific Advisory Board/Other Office: DTRF (Nonfinancial); Fellowship Support: Biomet. JHS: Consulting: Stryker (C), Biom'up (B). NR 42 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD AUG 1 PY 2015 VL 15 IS 8 BP 1728 EP 1737 DI 10.1016/j.spinee.2015.03.042 PG 10 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA CN4XZ UT WOS:000358435200006 PM 25862510 ER PT J AU Esain, V Kwan, W Carroll, KJ Cortes, M Liu, SY Frechette, GM Sheward, LMV Nissim, S Goessling, W North, TE AF Esain, Virginie Kwan, Wanda Carroll, Kelli J. Cortes, Mauricio Liu, Sarah Y. Frechette, Gregory M. Sheward, Lea M. V. Nissim, Sahar Goessling, Wolfram North, Trista E. TI Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity SO STEM CELLS LA English DT Article DE Hematopoietic stem cells; Cell migration; Cannabinoids; Prostaglandin E2; Zebrafish; Proliferation ID PERIPHERAL-BLOOD EOSINOPHILS; INCREASES COX-2 EXPRESSION; HUMAN NEUROGLIOMA CELLS; ZEBRAFISH DANIO-RERIO; MATRIX-METALLOPROTEINASE-9 EXPRESSION; CYCLOOXYGENASE-2 EXPRESSION; STEM/PROGENITOR CELLS; THYMUS COLONIZATION; SIGNALING PATHWAYS; MOLECULAR-CLONING AB Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized. Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development. During HSC specification in the aorta-gonad-mesonephros (AGM) region, CNR2 stimulation by AM1241 increased runx1;cmyb(+) HSPCs, through heightened proliferation, whereas CNR2 antagonism decreased HSPC number; FACS analysis and absolute HSC counts confirmed and quantified these effects. Epistatic investigations showed AM1241 significantly upregulated PGE2 synthesis in a Ptgs2-dependent manner to increase AGM HSCs. During the phases of HSC production and colonization of secondary niches, AM1241 accelerated migration to the caudal hematopoietic tissue (CHT), the site of embryonic HSC expansion, and the thymus; however these effects occurred independently of PGE2. Using a candidate approach for HSC migration and retention factors, P-selectin was identified as the functional target of CNR2 regulation. Epistatic analyses confirmed migration of HSCs into the CHT and thymus was dependent on CNR2-regulated P-selectin activity. Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways. C1 [Esain, Virginie; Kwan, Wanda; Carroll, Kelli J.; Cortes, Mauricio; Liu, Sarah Y.; Frechette, Gregory M.; Sheward, Lea M. V.; North, Trista E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Nissim, Sahar; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Nissim, Sahar; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. [Nissim, Sahar; Goessling, Wolfram] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram; North, Trista E.] Harvard Stem Cell Inst, Cambridge, MA USA. RP North, TE (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, Ctr Life Sci 638, 3 Blackfan Circle, Boston, MA 02115 USA. EM tnorth@bidmc.harvard.edu OI Goessling, Wolfram/0000-0001-9972-1569 FU Philippe Foundation; NIDDK [K01DK080226, R03DK096156-01] FX We thank P.Crosier and K. Crosier (University of Auckland) for runx1P2:eGFP fish, D. Traver (UCSD) for the CD45:dsRed line, and K. Poss (Duke University) for flk1:dsRed transgenics. We also thank Daniel Tenen and Kristin K. Brown (BIDMC) for advices on cannabinoid signaling and the Western blot analysis, respectively. FACS analyses were conducted with assistance from the BIDMC/HSCI FACS Core. This investigation was supported by the Philippe Foundation (V.E.) and the NIDDK:K01DK080226 and R03DK096156-01 (T.E.N.). NR 100 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD AUG PY 2015 VL 33 IS 8 BP 2596 EP 2612 DI 10.1002/stem.2044 PG 17 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA CN1UP UT WOS:000358206000020 PM 25931248 ER PT J AU Denneson, LM Teo, AR Ganzini, L Helmer, DA Bair, MJ Dobscha, SK AF Denneson, Lauren M. Teo, Alan R. Ganzini, Linda Helmer, Drew A. Bair, Matthew J. Dobscha, Steven K. TI Military Veterans' Experiences with Suicidal Ideation: Implications for Intervention and Prevention SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID OEF/OIF VETERANS; CARE; IRAQ; DECEDENTS; MORTALITY; CULTURE; OREGON; SYSTEM; LIFE AB We sought to understand Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans' experiences with suicidal ideation. Semi-structured interviews with 34 OEF/OIF veterans addressed circumstances leading up to disclosure of suicidal ideation during brief clinical assessments. We used an iterative, inductive and deductive thematic analysis approach. Results revealed three pervasive, persistent domains that reinforce the uniqueness of veteran suicidal thoughts: military culture, difficult deployment experiences, and postdeployment adjustment challenges. Within postdeployment, we identified four themes that serve as intervention targets: adjusting to civilian culture, changes to sense of self, feeling overwhelmed by stressors, and lacking life purpose or meaning. C1 [Denneson, Lauren M.; Teo, Alan R.; Ganzini, Linda; Dobscha, Steven K.] Portland VA Med Ctr, Portland CIVIC, Portland, OR 97207 USA. [Denneson, Lauren M.; Teo, Alan R.; Ganzini, Linda; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Helmer, Drew A.] VA New Jersey Hlth Care Syst, War Related Illness & Injury Study Ctr, E Orange, NJ USA. [Helmer, Drew A.] Rutgers State Univ, New Jersey Med Sch, Dept Med, Newark, NJ 07102 USA. [Bair, Matthew J.] Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. RP Denneson, LM (reprint author), Portland VA Med Ctr, POB 1034 R&D66, Portland, OR 97207 USA. EM lauren.denneson@va.gov FU Department of Veterans Affairs, Veterans Health Administration and Health Services Research and Development Service [DHI-08-096] FX This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service Project DHI-08-096. Dr. Denneson is a core investigator in the Center to Improve Veteran Involvement in Care (CIVIC) at the Portland VA Medical Center. 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 U.S. Government. We gratefully acknowledge Monica Huffman, MA, for assisting with conducting interviews and Megan Crutchfield, MPH, for participant recruitment. NR 34 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD AUG PY 2015 VL 45 IS 4 BP 399 EP 414 DI 10.1111/sltb.12136 PG 16 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CN2KY UT WOS:000358251100002 PM 25367753 ER PT J AU Kim, SM Baek, JH Han, DH Lee, YS Yurgelun-Todd, DA AF Kim, Sun Mi Baek, Ji Hyun Han, Doug Hyun Lee, Young Sik Yurgelun-Todd, Deborah A. TI Psychosocial-Environmental Risk Factors for Suicide Attempts in Adolescents with Suicidal Ideation: Findings from a Sample of 73,238 Adolescents SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; KOREAN ADOLESCENTS; PROTECTIVE-FACTORS; BEHAVIOR; ASSOCIATION; GENDER; PREVENTION; DEPRESSION; THERAPY; YOUTH AB We determined risk factors that discriminate between suicide attempt (SA) adolescents and suicidal ideation only (SI only) adolescents using data from the 2010 Korea Youth Risk Behavior Web-based Survey (12-19years; N=73,238). In males, heavy alcohol use, drug use, and high perceived sadness/hopelessness showed significant effects on the presence of SA versus the presence of SI only. In females, along with these variables, low academic achievement, poor perceived health status, high perceived stress, and unhealthy coping strategy were also significantly related to the presence of SA versus SI only. Therefore, clinical interventions targeting adolescents' psychological distress are warranted to prevent suicide. C1 [Kim, Sun Mi; Baek, Ji Hyun; Lee, Young Sik] Chung Ang Univ, Coll Med, Dept Psychiat, Seoul 156755, South Korea. [Baek, Ji Hyun] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. [Baek, Ji Hyun] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Yurgelun-Todd, Deborah A.] Univ Utah, Inst Brain, Salt Lake City, UT USA. RP Lee, YS (reprint author), Chung Ang Univ, Med Ctr, Dept Psychiat, 102 Heukseok Ro, Seoul 156755, South Korea. EM hawkeyelys@hanmail.net NR 34 TC 0 Z9 0 U1 3 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD AUG PY 2015 VL 45 IS 4 BP 477 EP 487 DI 10.1111/sltb.12143 PG 11 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CN2KY UT WOS:000358251100007 PM 25443162 ER PT J AU Jensen, ET Shah, ND Hoffman, K Sonnenberg, A Genta, RM Dellon, ES AF Jensen, E. T. Shah, N. D. Hoffman, K. Sonnenberg, A. Genta, R. M. Dellon, E. S. TI Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INCREASING INCIDENCE; PATHOLOGY DATABASE; ELIMINATION DIET; UNITED-STATES; CHILDREN; ADULTS; EPIDEMIOLOGY; PREVALENCE; AEROALLERGENS; MANAGEMENT AB BackgroundSeasonal variation has been reported in diagnosis of eosinophilic oesophagitis (EoE), but results are not consistent across studies and there are no national-level data in the USA. AimTo determine if there is seasonal variation in diagnosis of oesophageal eosinophilia and EoE in the USA, while accounting for factors such as climate zone and geographic variation. MethodsThis was a cross-sectional study using a USA national pathology database. Patients with oesophageal eosinophilia (15 eosinophils per high-power field) comprised the primary case definition and were compared to those with normal oesophageal biopsies. We calculated the crude and adjusted odds of oesophageal eosinophilia by season, as well as by day of the year. Sensitivity analyses were performed using more restrictive case definitions of EoE, and after stratification by climate zone. ResultsExactly, 14524 cases with oesophageal eosinophilia and 90459 normal controls were analysed. The adjusted odds of oesophageal eosinophilia were higher in the late spring and summer months, with the highest odds in July (aOR: 1.13; 95% CI: 1.03-1.24). These findings persisted with increasing levels of oesophageal eosinophilia, as well as across EoE case definitions. Seasonal variation was strongest in temperate and cold climates, and peak diagnosis varied by climate zone. ConclusionsThere is a mild but consistent seasonal variation in the diagnosis of oesophageal eosinophilia and EoE, with cases more frequently diagnosed during summer months. These findings take into account climate and geographic differences, suggesting that aeroallergens may contribute to disease development or flare. C1 [Jensen, E. T.; Shah, N. D.; Dellon, E. S.] Univ North Carolina Sch Med, Div Gastroenterol & Hepatol, Dept Med, Ctr Esophageal Dis & Swallowing, Chapel Hill, NC USA. [Jensen, E. T.] Univ North Carolina Sch Med, Div Gastroenterol & Hepatol, Dept Med, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA. [Hoffman, K.; Dellon, E. S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hoffman, K.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Sonnenberg, A.] Portland VA Med Ctr, Portland, OR USA. [Sonnenberg, A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Genta, R. M.] Miraca Life Sci Res Inst, Irving, TX USA. [Genta, R. M.] Univ Texas SW Med Ctr Dallas, Dallas Vet Affairs Med Ctr, Dallas, TX 75390 USA. RP Dellon, ES (reprint author), UNC CH, CB 7080,Bioinformat Bldg,130 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM edellon@med.unc.edu RI Jensen, Elizabeth/L-1466-2016 FU NIH [K23DK090073] FX Declaration of funding interests: This research was conducted with support, in part, by NIH award K23DK090073 (ESD). NR 39 TC 9 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL 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 AUG PY 2015 VL 42 IS 4 BP 461 EP 469 DI 10.1111/apt.13273 PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA CM7TU UT WOS:000357900200007 PM 26059636 ER PT J AU Bloch, SL McKenna, MJ Adams, J Friis, M AF Bloch, Sune Land McKenna, Michael John Adams, Joe Friis, Morten TI Labyrinthitis Ossificans: On the Mechanism of Perilabyrinthine Bone Remodeling SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE lining cells; anti-resorptive barriers; osteoprotegerin; osteocytes; cartilage remnants ID OTIC CAPSULE; OSTEOCYTES; VIABILITY AB Introduction: It has been suggested that remodeling of the otic capsule is highly suppressed by the action of anti-resorptive signals emanating from structures of the inner ear space. Labyrinthitis ossificans (LO) is a severe complication to bacterial meningitis and is characterized by destruction of inner ear structures by the formation of new bone. The aim of this study was to explore the impact of LO on bone remodeling of the otic capsule. Material and Methods: In 11 human temporal bones with extensive LO and 10 control specimens, the degree of bone remodeling was explored indirectly by estimating the viability of osteocytes in perilabyrinthine bone and the mastoid. Results: The viability of osteocytes was significantly lower in the perilabyrinthine bone compared to the mastoid in both groups. However, the loss of perilabyrinthine osteocytes was the same in the 2 groups, and the presence of cartilage remnants appeared to be the same. Conclusion: This study indicates that the factors affecting bone remodeling of the otic capsule and the degeneration of osteocytes are not altered by wholesale destruction of inner ear soft tissue and its replacement by bone. Therefore, alternative mechanisms may be implicated in the suppression of capsular bone remodeling. C1 [Bloch, Sune Land; Friis, Morten] Univ Copenhagen, Rigshosp, Dept Otolaryngol Head & Neck Surg & Audiol, DK-2100 Copenhagen, Denmark. [McKenna, Michael John; Adams, Joe] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Bloch, SL (reprint author), Univ Copenhagen, Rigshosp, Dept Otolaryngol Head & Neck Surg & Audiol, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. EM sunebloch@hotmail.com FU Schioldann's Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors thank Schioldann's Foundation for supporting this study. NR 17 TC 0 Z9 0 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD AUG PY 2015 VL 124 IS 8 BP 649 EP 654 DI 10.1177/0003489415573960 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA CM8NG UT WOS:000357957900009 PM 25757630 ER PT J AU Stone, JH Carruthers, MN Topazian, MD Khosroshahi, A Witzig, TE Wallace, ZS Hart, PA Deshpande, V Smyrk, TC Chari, S AF Stone, John H. Carruthers, Mollie N. Topazian, Mark D. Khosroshahi, Arezou Witzig, Thomas E. Wallace, Zachary S. Hart, Phillip A. Deshpande, Vikram Smyrk, Thomas C. Chari, Suresh TI Response to: 'Is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years' by Yamamoto et al SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID VASCULITIS C1 [Stone, John H.] Massachusetts Gen Hosp, Dept Rheumatol, Allergy & Immunol Div, Boston, MA 02114 USA. [Carruthers, Mollie N.] Massachusetts Gen Hosp, Dept Rheumatol, Boston, MA 02114 USA. [Topazian, Mark D.; Hart, Phillip A.; Chari, Suresh] Mayo Clin, Dept Gastroenterol & Hepatol, Rochester, MN USA. [Khosroshahi, Arezou] Emory Univ, Sch Med, Dept Rheumatol, Atlanta, GA USA. [Witzig, Thomas E.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Wallace, Zachary S.] Massachusetts Gen Hosp, Rheumatol Unit, Boston, MA 02114 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Smyrk, Thomas C.] Mayo Clin, Dept Pathol, Rochester, MN USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Dept Rheumatol, Allergy & Immunol Div, Boston, MA 02114 USA. EM jhstone@partners.org RI Hart, Phil/A-9842-2016 OI Hart, Phil/0000-0003-4346-6196 NR 8 TC 2 Z9 2 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2015 VL 74 IS 8 AR E47 DI 10.1136/annrheumdis-2015-207625 PG 2 WC Rheumatology SC Rheumatology GA CM4VQ UT WOS:000357683600010 PM 26160908 ER PT J AU Erlendsson, AM Taudorf, EH Eriksson, AH Haak, CS Zibert, J Paasch, U Anderson, RR Haedersdal, M AF Erlendsson, A. M. Taudorf, E. H. Eriksson, A. H. Haak, C. S. Zibert, J. R. Paasch, U. Anderson, R. R. Haedersdal, M. TI Ablative fractional laser alters biodistribution of ingenol mebutate in the skin SO ARCHIVES OF DERMATOLOGICAL RESEARCH LA English DT Article DE Ablative fractional laser; Laser; Laser-assisted drug delivery; Drug delivery; Ingenol mebutate; Biodistribution; Non-melanoma skin cancer; Actinic keratosis ID ASSISTED DRUG-DELIVERY; PROTEIN-KINASE-C; METHYL AMINOLEVULINATE; MACROMOLECULES; 3-ANGELATE; PATTERNS; SYSTEMS; IMPACT; CANCER; GEL AB Topically applied ingenol mebutate (IngMeb) is approved for field-treatment of actinic keratosis and is currently being investigated for treatment of non-melanoma skin cancer (NMSC). Ablative fractional lasers (AFXLs) generate microscopic ablation zones (MAZs) in the skin, which may help induce a deep penetration needed for effective treatment of NMSC. Using Franz diffusion cells, uptake and bio-distribution were investigated over 21 h in intact (n = 9) and AFXL-exposed porcine skin (n = 58). A 2940-nm fractional Er:YAG laser generated intraepidermal (11.2 mJ/MAZ; 66 mu m deep, 177 mu m wide) and intradermal (128 mJ/MAZ; 570 mu m deep, 262 wide) MAZ's with 16, 97, and 195 MAZs/cm(2). Surface ablation densities corresponded to 0.5, 2.5, and 5 % for intraepidermal MAZs, and corresponded to 1, 5, and 10.5 % for intradermal MAZs. Liquid-chromatography-mass-spectrometry quantified deposition of IngMeb in stratum corneum, epidermis, dermis, and receiver chamber. In intact skin, IngMeb readily penetrated to the epidermal layer (1,314 ng, 41 % of the applied IngMeb), while dermal deposition was limited (508 ng, 16 %). In AFXL-exposed skin, a profound dermal deposition of IngMeb was achieved, while less accumulated in SC and epidermis. Uptake depended entirely on laser density; increasing coverage from 0 % to 0.5 %, 1 %, 2.5 %, 5 %, and 10.5 % enhanced dermal uptake 1.6-, 2.1-, 3.1-, 3.4-, and 3.9-fold, respectively (p < 0.0001). Channel depth did not influence drug uptake; at 5 % density, dermal deposition with intraepidermal and intradermal MAZs was analogous (1801 vs. 1744; p = 0.447). In conclusion, IngMeb readily distributes to superficial layers of intact skin, whereas dermal uptake is limited. Independent of channel depth, AFXL enhances dermal drug deposition, providing for customized topical delivery and potential use of IngMeb for treatment of NMSC. C1 [Erlendsson, A. M.; Taudorf, E. H.; Haak, C. S.; Haedersdal, M.] Univ Copenhagen, Bispebjerg Univ Hosp, Dept Dermatol, Copenhagen, Denmark. [Erlendsson, A. M.; Haak, C. S.; Anderson, R. R.; Haedersdal, M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Eriksson, A. H.; Zibert, J. R.] LEO Pharma AS, Ballerup, Denmark. [Paasch, U.] Univ Leipzig, Dept Dermatol Venerol & Allergol, D-04109 Leipzig, Germany. RP Erlendsson, AM (reprint author), Univ Copenhagen, Bispebjerg Univ Hosp, Dept Dermatol, Copenhagen, Denmark. EM andres.erlendsson@gmail.com FU LEO Pharma A/S; Pantec Biosolutions FX AM Erlendsson received PhD Scholarship from LEO Pharma A/S. M Haedersdal received research grants from LEO Pharma A/S and Pantec Biosolutions. AH Eriksson and JR Zibert are employees at LEO Pharma A/S. NR 26 TC 7 Z9 7 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-3696 EI 1432-069X J9 ARCH DERMATOL RES JI Arch. Dermatol. Res. PD AUG PY 2015 VL 307 IS 6 BP 515 EP 522 DI 10.1007/s00403-015-1561-3 PG 8 WC Dermatology SC Dermatology GA CN0TO UT WOS:000358126800006 PM 25832754 ER PT J AU Daud, A Joshua, AM Ribas, A Robert, C Hodi, FS Wolchok, J Hwu, WJ Weber, JS Gangadhar, TC Joseph, R Dronca, R Patnaik, A Zarour, H Kefford, R Lindia, J Li, XN Ebbinghaus, S Kang, SP Hamid, O AF Daud, A. Joshua, A. M. Ribas, A. Robert, C. Hodi, F. S. Wolchok, J. Hwu, W-J Weber, J. S. Gangadhar, T. C. Joseph, R. Dronca, R. Patnaik, A. Zarour, H. Kefford, R. Lindia, J. Li, X. N. Ebbinghaus, S. Kang, S. P. Hamid, O. TI A POOLED ANALYSIS OF 655 PATIENTS WITH ADVANCED MELANOMA ENROLLED IN KEYNOTE-001: LONG-TERM EFFICACY OF PEMBROLIZUMAB (MK-3475) SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Daud, A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Joshua, A. M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Ribas, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Robert, C.] Gustave Roussy, Villeuif, France. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolchok, J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hwu, W-J] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Weber, J. S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Gangadhar, T. C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Joseph, R.] Mayo Clin, Jacksonville, FL USA. [Dronca, R.] Mayo Clin, Rochester, MN USA. [Patnaik, A.] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Zarour, H.] Univ Pittsburgh, Pittsburgh, PA USA. [Kefford, R.] Macquarie Univ, Sydney, NSW 2109, Australia. [Kefford, R.] Westmead Hosp, Sydney, NSW, Australia. [Lindia, J.; Li, X. N.; Ebbinghaus, S.; Kang, S. P.] Merck & Co Inc, Kenilworth, NJ USA. [Hamid, O.] Angeles Clin & Res Inst, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD AUG PY 2015 VL 11 SU 3 SI SI BP 43 EP 43 PG 1 WC Oncology SC Oncology GA CM8NB UT WOS:000357957300008 ER PT J AU Spencer, A Lipton, A Smith, MR Fizazi, K Stopeck, A Shore, N Zhu, L Warner, D AF Spencer, A. Lipton, A. Smith, M. R. Fizazi, K. Stopeck, A. Shore, N. Zhu, L. Warner, D. TI BONE TURNOVER MARKER (BTM) LEVELS AND CLINICAL OUTCOMES IN ADVANCED CANCER PATIENTS TREATED WITH ANTIRESORPTIVE BONE THERAPIES SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Spencer, A.] Monash Univ, Dept Clin Haematol, Melbourne, Vic 3004, Australia. [Lipton, A.] Penn State Hematol Oncol, Hershey, PA USA. [Smith, M. R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fizazi, K.] Univ Paris 11, Inst Gustave Roussy, Dept Canc Med, Villejuif, France. [Stopeck, A.] Stony Brook Canc Ctr, Dept Internal Med, New York, NY USA. [Shore, N.] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Zhu, L.; Warner, D.] Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD AUG PY 2015 VL 11 SU 3 SI SI BP 44 EP 44 PG 1 WC Oncology SC Oncology GA CM8NB UT WOS:000357957300010 ER PT J AU Wolchok, JD Chiarion-Sileni, V Gonzalez, R Rutkowski, P Grob, JJ Cowey, CL Lao, CD Schadendorf, D Ferrucci, PF Smylie, M Dummer, R Hill, A Haanen, J Maio, M McArthur, G Yang, A Rollin, L Horak, C Larkin, J Hodi, FS AF Wolchok, J. D. Chiarion-Sileni, V. Gonzalez, R. Rutkowski, P. Grob, J. J. Cowey, C. L. Lao, C. D. Schadendorf, D. Ferrucci, P. F. Smylie, M. Dummer, R. Hill, A. Haanen, J. Maio, M. McArthur, G. Yang, A. Rollin, L. Horak, C. Larkin, J. Hodi, F. S. TI CHECKMATE 067: A PHASE III RANDOMIZED DOUBLE-BLIND STUDY OF NIVOLUMAB (NIVO) MONOTHERAPY OR NIVO COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI MONOTHERAPY IN PREVIOUSLY UNTREATED PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL) SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wolchok, J. D.] Weill Cornell Med Coll, New York, NY USA. [Chiarion-Sileni, V.] Oncol Inst Veneto IRCCS, Padua, Italy. [Gonzalez, R.] Univ Colorado Canc Ctr, Denver, CO USA. [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Grob, J. J.] Hosp Timone, Marseille, France. [Cowey, C. L.] Texas Oncology Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Lao, C. D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Schadendorf, D.] Univ Essen Gesamthsch, Dept Dermatol, Essen, Germany. [Ferrucci, P. F.] European Inst Oncol, Milan, Italy. [Smylie, M.] Cross Canc Inst, Edmonton, AB, Canada. [Dummer, R.] Univ Spital, Zurich, Switzerland. [Hill, A.] Tasman Oncol Res, Gold Coast, Australia. [Haanen, J.] Netherlands Canc Inst, Amsterdam, Netherlands. [Maio, M.] Univ Hosp Siena, Siena, Italy. [McArthur, G.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Yang, A.; Horak, C.] Bristol Myers Squibb Co, Princeton, NJ USA. [Rollin, L.] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Larkin, J.] Royal Marsden Hosp, London SW3 6JJ, England. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD AUG PY 2015 VL 11 SU 3 SI SI BP 68 EP 68 PG 1 WC Oncology SC Oncology GA CM8NB UT WOS:000357957300069 ER PT J AU Shiramizu, B Goldman, S Smith, L Agsalda-Garcia, M Galardy, P Perkins, SL Frazer, JK Sanger, W Anderson, JR Gross, TG Weinstein, H Harrison, L Barth, MJ Mussolin, L Cairo, MS AF Shiramizu, Bruce Goldman, Stanton Smith, Lynette Agsalda-Garcia, Melissa Galardy, Paul Perkins, Sherrie L. Frazer, J. Kimble Sanger, Warren Anderson, James R. Gross, Thomas G. Weinstein, Howard Harrison, Lauren Barth, Matthew J. Mussolin, Lara Cairo, Mitchell S. TI Impact of persistent minimal residual disease post-consolidation therapy in children and adolescents with advanced Burkitt leukaemia: a Children's Oncology Group Pilot Study Report SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE children; central nervous system; leukaemia ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; RISK; CHEMOTHERAPY; CHILDHOOD; RITUXIMAB; STAGE AB Patient-specific primers from 10 children/adolescents with Burkitt leukaemia (BL) +/- central nervous system disease who were treated with French-British-American/Lymphome Malins de Burkitt 96 C1 plus rituximab were developed from diagnostic blood/bone marrow. Minimal residual disease (MRD) was assessed by real-time polymerase chain reaction at the end of induction (EOI) and consolidation (EOC). Seventy per cent (7/10) and 71% (5/7) were MRD-positive at EOI and EOC, respectively, with no disease recurrences. MRD after induction and consolidation did not predict relapse and subsequent therapy appeared to eliminate MRD. Thus, assessing MRD at a later time point is warranted in future trials to determine its clinical significance. C1 [Shiramizu, Bruce; Agsalda-Garcia, Melissa] Univ Hawaii, Div Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Goldman, Stanton] Med City Childrens Hosp, Div Pediat Hematol Oncol, Dallas, TX USA. [Smith, Lynette; Anderson, James R.] Univ Nebraska, Coll Publ Hlth, Dept Biostat, Omaha, NE 68182 USA. [Galardy, Paul] Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. [Perkins, Sherrie L.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Frazer, J. Kimble] Univ Oklahoma, Hlth Sci Ctr, Sect Pediat Hematol Oncol, Oklahoma City, OK USA. [Sanger, Warren] Univ Nebraska Med Ctr, Dept Cytogenet, Omaha, NE USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, DHHS, Rockville, MD USA. [Weinstein, Howard] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Hematol Oncol, Boston, MA USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Barth, Matthew J.] Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. [Mussolin, Lara] Univ Padua, Fdn Citta Speranza, Ist Ric Pediat, Padua, Italy. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Shiramizu, B (reprint author), Univ Hawaii Manoa, John A Burns Sch Med, Dept Pediat, Pediat Hematol Oncol, 651 Ilalo St, Honolulu, HI 96813 USA. EM bshirami@hawaii.edu OI Frazer, John Kimble/0000-0003-2936-2817 FU Division of Cancer Treatment, National Cancer Institute; National Institutes of Health; Department of Health and Human Services (COG) [CA98543-09, CA98413-09]; Pediatric Cancer Research Foundation [U54MD007584]; Thrasher Research Fund; St. Baldrick's Foundation FX The authors would like to acknowledge Angelo Rosolen, MD, PhD, a leader in childhood and adolescent NHL MRD studies who passed away during the past year. The study was supported by Division of Cancer Treatment, National Cancer Institute, and National Institutes of Health, Department of Health and Human Services (COG) (CA98543-09 and CA98413-09), Pediatric Cancer Research Foundation (M.S.C), U54MD007584 (B.S.), Thrasher Research Fund (B.S.), St. Baldrick's Foundation (B.S.) NR 11 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2015 VL 170 IS 3 BP 367 EP 371 DI 10.1111/bjh.13443 PG 5 WC Hematology SC Hematology GA CM9DS UT WOS:000358007400007 PM 25858645 ER PT J AU Saez, JC Cisterna, BA Vargas, A Cardozo, CP AF Saez, Juan C. Cisterna, Bruno A. Vargas, Anibal Cardozo, Christopher P. TI Regulation of pannexin and connexin channels and their functional role in skeletal muscles SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Pannexons; Connexons; Myoblasts; Myotubes; Striate muscles; Myogenesis; Denervation ID GAP-JUNCTION PROTEINS; MYOBLAST DIFFERENTIATION; PHARMACOLOGICAL-PROPERTIES; CELLS; ATP; HEMICHANNELS; EXPRESSION; MYOGENESIS; ACTIVATION; RECEPTORS AB Myogenic precursor cells express connexins (Cx) and pannexins (Panx), proteins that form different membrane channels involved in cell-cell communication. Cx channels connect either the cytoplasm of adjacent cells, called gap junction channels (GJC), or link the cytoplasm with the extracellular space, termed hemichannels (HC), while Panx channels only support the latter. In myoblasts, Panx1 HCs play a critical role in myogenic differentiation, and Cx GJCs and possibly Cx HCs coordinate metabolic responses during later steps of myogenesis. After innervation, myofibers do not express Cxs, but still express Panx1. In myotubes and innervated myofibers, Panx1 HCs allow release of adenosine triphosphate and thus they might be involved in skeletal muscle plasticity. In addition, Panx1 HCs present in adult myofibers mediate adenosine triphosphate release and glucose uptake required for potentiation of muscle contraction. Under pathological conditions, such as upon denervation and spinal cord injury, levels of Panx1 are upregulated. However, Panx1(-/-) mice show similar degree of atrophy as denervated wild-type muscles. Skeletal muscles also express Cx HCs in the sarcolemma after denervation or spinal cord injury, plus other non-selective membrane channels, including purinergic P2X7 receptors and transient receptor potential type V2 channels. The absence of Cx43 and Cx45 is sufficient to drastically reduce denervation atrophy. Moreover, inflammatory cytokines also induce the expression of Cxs in myofibers, suggesting the expression of these Cxs as a common factor for myofiber degeneration under diverse pathological conditions. Inhibitors of skeletal muscle Cx HCs could be promising tools to prevent muscle wasting induced by conditions associated with synaptic dysfunction and inflammation. C1 [Saez, Juan C.; Cisterna, Bruno A.; Vargas, Anibal] Pontificia Univ Catolica Chile, Dept Fisiol, Santiago, Chile. [Saez, Juan C.; Cisterna, Bruno A.; Vargas, Anibal] Univ Valparaiso, Inst Milenio, Ctr Interdisciplinario Neurociencias Valparaiso, Valparaiso, Chile. [Cardozo, Christopher P.] James J Peters Vet Affairs Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10039 USA. [Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10039 USA. [Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10039 USA. RP Saez, JC (reprint author), Pontificia Univ Catolica Chile, Dept Fisiol, Alameda 340, Santiago, Chile. EM jsaez@bio.puc.cl FU FONDECYT [1150291]; ICM-Economia Centro Interdisciplinario de Neurociencias de Valparaiso [P09-022-F]; Department of Veterans Affairs Rehabilitation Research and Development Service [B9212C]; James J. Peters VA Medical Center; CONICYT FX This work was partially funded by FONDECYT grants 1150291 (to Juan C. Saez), ICM-Economia P09-022-F Centro Interdisciplinario de Neurociencias de Valparaiso (to Juan C. Saez) and the Department of Veterans Affairs Rehabilitation Research and Development Service (B9212C) and the James J. Peters VA Medical Center. Bruno A. Cisterna and Anibal Vargas acknowledge the support of a CONICYT fellowship. NR 47 TC 1 Z9 2 U1 2 U2 6 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD AUG PY 2015 VL 72 IS 15 BP 2929 EP 2935 DI 10.1007/s00018-015-1968-1 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN0FD UT WOS:000358088600011 PM 26084874 ER PT J AU Cheney, MD Zhang, DJ Chen, MH Loffredo, MJ Richie, JP D'Amico, AV AF Cheney, Matthew D. Zhang, Danjie Chen, Ming-Hui Loffredo, Marian J. Richie, Jerome P. D'Amico, Anthony V. TI Greatest Percentage Involved Core Length and Risk of Clinically Significant Prostate-Specific Antigen Failure After Radical Prostatectomy SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Biopsy; Doubling time; Percent positive biopies; Prognosis; Prostate cancer ID CANCER-SPECIFIC MORTALITY; BEAM RADIATION-THERAPY; STAGE MIGRATION; NEEDLE-BIOPSY; NATURAL-HISTORY; COMPETING RISK; PROGRESSION; MEN; RADIOTHERAPY; DIAGNOSIS AB Radical prostatectomy (RP) has been increasingly used for high-risk prostate cancer (PC). Of 402 men who had undergone RP, an increasing greatest percentage of involved biopsy core length was significantly associated with an increased risk of clinically significant prostate-specific antigen failure, particularly in men with unfavorable intermediate- or high-risk PC. Men planning to undergo RP should be considered for randomized neoadjuvant trials of metastatic treatments that prolong survival. Background: Radical prostatectomy (RP) can cure men with unfavorable intermediate- or high-risk prostate cancer (PC). However, some will experience short prostate-specific antigen (PSA) doubling time (PSADT) failure that requires additional treatment with increased toxicity. The present study investigated whether the greatest percentage of involved biopsy core length (GPC) can preoperatively identify men at risk of short PSADT failure. Patients and Methods: A total of 503 men with biopsy-proven PC underwent RP at an academic institution from January 2005 to December 2008. Men with incomplete pathologic information, those who had received neoadjuvant or adjuvant hormonal therapy or chemotherapy, and those who had undergone adjuvant radiation therapy were excluded. The median follow-up period was 4.89 years (interquartile range, 1.97-5.68 years). A competing risk regression was used to assess whether an increasing GPC value was associated with an increased PSADT at < 10-month failure risk, adjusting for age, percentage of positive biopsy results, and risk group. Results: Of the 402 men, 34 (8.46%) developed PSA failure, 17 (50.0%) of whom had a PSADT of < 10 months. An increasing GPC value was significantly associated with an increased PSADT of < 10-month failure risk (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01-1.06; P = .015). Men with a GPC > 30% (median) versus < 30% and unfavorable intermediate- or high-risk PC (P = .011), but not low or favorable intermediate-risk PC (P = .57), had a significantly greater incidence of PSADT < 10-month failure estimates (30% vs. 0% at 5 years). Conclusion: Men planning to undergo RP for unfavorable intermediate- or high-risk PC with a GPC of > 30% should be considered for randomized trials evaluating the effect on survival of the neoadjuvant use of treatment that extends survival in those with castrate-resistant metastatic PC. C1 [Cheney, Matthew D.] Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Cheney, Matthew D.; Loffredo, Marian J.; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Danjie; Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Richie, Jerome P.] Brigham & Womens Hosp, Dept Urol, Boston, MA 02115 USA. RP Cheney, MD (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM mcheney@lroc.harvard.edu NR 30 TC 1 Z9 1 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2015 VL 13 IS 4 BP 338 EP 343 DI 10.1016/j.clgc.2015.02.012 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CM7NF UT WOS:000357880000034 PM 25862320 ER PT J AU Margalit, DN Jordahl, KM Werner, L Wang, XD Lee, MGS Penney, KL Batista, JL Martin, NE Chan, JM Kantoff, PW Stampfer, MJ Nguyen, PL Mucci, LA AF Margalit, Danielle N. Jordahl, Kristina M. Werner, Lillian Wang, Xiaodong Lee, Mary Gwo-Shu Penney, Kathryn L. Batista, Julie L. Martin, Neil E. Chan, June M. Kantoff, Philip W. Stampfer, Meir J. Nguyen, Paul L. Mucci, Lorelei A. TI GermLine Variation in Superoxide Dismutase-2 (SOD2) and Survival Outcomes After Radiation Therapy for Prostate Cancer: Results of a Test and Validation Set Analysis SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Antioxidant; Free radicals; Predictive biomarkers; Reactive oxygen species; SOD2 ID SINGLE NUCLEOTIDE POLYMORPHISMS; BREAST-CANCER; CARDIOVASCULAR-DISEASE; PHYSICIANS HEALTH; OXIDATIVE STRESS; BETA-CAROTENE; VITAMINS E; RISK; GENE; RADIOTHERAPY AB In this study, we investigated whether patient-specific differences in the antioxidant gene, superoxide dismutase-2 (SOD2), affect the efficacy of radiation therapy for prostate cancer. We identified a link between common mutations in the SOD2 gene and prostate cancer recurrence after radiation for prostate cancer in a group of predominantly low-risk prostate cancer patients but not in a higher-risk cohort. Background: Genetic variants in antioxidant pathways might decrease the efficacy of radiation therapy (RT) by suppressing the generation of reactive oxygen species. We studied the association between single nucleotide polymorphisms (SNPs) in the antioxidant gene superoxide dismutase-2 (SOD2) and cancer-specific outcomes after RT. Patients and Methods: Among 816 prostate cancer patients who received radiation as primary therapy from the Physicians' Health Study and the Health Professionals Follow-up Study, we evaluated the association of 7 tagging SNPs in SOD2 with lethal prostate cancer (death from prostate cancer or distant metastasis among living patients). We sought to validate findings in a separate cohort of 612 prostate cancer patients treated with RT with a greater proportion of intermediate and high-risk Gleason scores at the Dana-Farber Cancer Institute. Genetic effects were analyzed using a codominant model, using the genotype homozygous for the major allele as baseline. Results: Among patients who underwent RT in the test cohort, there was a significant association between 3 of the 7 SOD2 SNPs and lethal prostate cancer: rs6917589 (overall P = .006), rs2758331 (P = .04) and the functional valine to alanine polymorphism in rs4880 (P = .04). These SNPs were not associated with outcome among men who had undergone prostatectomy. The associations were not replicated in the validation cohort. Conclusion: Germline genetic variation in the SOD2 gene might be a predictive biomarker of response to RT for prostate cancer but is not consistently associated with outcome after RT across prostate cancer cohorts with different clinical characteristics. C1 [Margalit, Danielle N.; Martin, Neil E.; Nguyen, Paul L.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Jordahl, Kristina M.; Penney, Kathryn L.; Batista, Julie L.; Stampfer, Meir J.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Wang, Xiaodong; Lee, Mary Gwo-Shu; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Penney, Kathryn L.; Batista, Julie L.; Stampfer, Meir J.; Mucci, Lorelei A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Penney, Kathryn L.; Batista, Julie L.; Stampfer, Meir J.; Nguyen, Paul L.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, June M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Margalit, DN (reprint author), Dana 2,450 Brookline Ave, Boston, MA 02215 USA. EM dmargalit@lroc.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU National Institutes of Health [T32 CA09001, CA-34944, CA-40360, CA-097193, CA055075, CA131945, CA136578, CA141298, CA176726, HL-26490, HL-34595]; Department of Defense Prostate Cancer Research Program [W81XWH-12-1-0072]; DFCI Mazzone Awards Program; Prostate Cancer Foundation; [CA-106947] FX This work was supported by the National Institutes of Health (T32 CA09001 to DNM and JLB, Principal Investigator MJS; CA-34944, CA-40360, CA-097193, CA055075, CA131945, CA136578, CA141298, CA176726, HL-26490, and HL-34595 for the PHS), the Department of Defense Prostate Cancer Research Program (W81XWH-12-1-0072 to JLB), CA-106947 for the HPFS, the DFCI Mazzone Awards Program to J.L.B., and the Prostate Cancer Foundation (to LAM, KLP, NEM). NR 25 TC 1 Z9 1 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2015 VL 13 IS 4 BP 370 EP U280 DI 10.1016/j.clgc.2014.12.018 PG 9 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CM7NF UT WOS:000357880000039 PM 25662905 ER PT J AU Chandra, RA Chen, MH Zhang, DJ Loffredo, M D'Amico, AV AF Chandra, Ravi A. Chen, Ming-Hui Zhang, Danjie Loffredo, Marian D'Amico, Anthony V. TI Age, Comorbidity, and the Risk of Prostate Cancer-Specific Mortality in Men With Biopsy Gleason Score 4+3: Implications on Patient Selection for Multiparametric MRI SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Intermediate risk; MRI; Occult cancer; Older age: Prostate cancer ID RANDOMIZED CONTROLLED-TRIAL; TERM ANDROGEN DEPRIVATION; BEAM RADIATION-THERAPY; SUPPRESSION; RADIOTHERAPY; SYSTEM AB Some men with Gleason score 7 prostate cancer (PC) have occult Gleason score 8 to 10 disease and experience undertreatment. We evaluated adjusted PC-specific mortality risk for older men with Gleason score 4+3 PC and all men with Gleason score 8 to 10 PC, finding no significant difference. This suggests the presence of occult Gleason score 8 to 10 PC, which multiparametric prostate magnetic resonance imaging might disclose, and thus avoid patient undertreatment. Background: Some men with biopsy Gleason score (GS) 7 prostate cancer (PC) harbor occult GS 8 to 10 PC and might be undertreated with short-term androgen deprivation therapy (ADT) and radiation therapy (RT). With advancing age associated with occult high-grade PC, we evaluated PC-specific mortality (PCSM) risk after RT and short-term ADT for older men with GS 4+3 PC and men of any age with GS 8 to 10 PC. Patients and Methods: The study cohort comprised 206 men with unfavorable-risk PC treated with RT or RT and 6 months of ADT on a randomized trial between 1995 and 2001. Competing risks regression was used to compare PCSM risk for men with GS 8 to 10 PC to men with GS <= 3+4, GS 4+3 and age <= 73 years (median age), and GS 4+3 and age > 73 years, adjusting for PC risk factors, comorbidity, and treatment. Results: After a median follow-up of 14.3 years, 135 men died (65.53%), 24 (17.78%) of PC. Men age > 73 years with GS 4+3 PC did not have significantly lower PCSM risk compared with men with GS 8 to 10 (adjusted hazard ratio [AHR], 1.08; 95% confidence interval [CI], 0.29-4.06; P = .91); whereas unhealthy men (AHR, 0.20; 95% CI, 0.04-0.93; P = .04) and men age <= 73 years with GS 4+3 (AHR, 0.09; 95% CI, 0.01-1.03; P = .05) fared better. Conclusion: Men age > 73 years with biopsy GS 4+3 did not have a significant difference in PCSM risk than men with GS 8 to 10, supporting further study of multiparametric magnetic resonance imaging in such men with no or minimal comorbidity before determining ADT duration. C1 [Chandra, Ravi A.] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Loffredo, Marian; D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Loffredo, Marian; D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Chandra, RA (reprint author), Harvard Radiat Oncol Program, 75 Francis St,L2, Boston, MA 02115 USA. EM rchandra@lroc.harvard.edu NR 31 TC 4 Z9 4 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2015 VL 13 IS 4 BP 400 EP 405 DI 10.1016/j.clgc.2015.03.001 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CM7NF UT WOS:000357880000043 PM 25862319 ER PT J AU Graff, JN Beer, TM Liu, B Sonpavde, G Taioli, E AF Graff, Julie N. Beer, Tomasz M. Liu, Bian Sonpavde, Guru Taioli, Emanuela TI Pooled Analysis of C-Reactive Protein Levels and Mortality in Prostate Cancer Patients SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Epidemiological methods; Outcome; Prognostic markers; Systemic inflammation; Urological cancer ID SYSTEMIC INFLAMMATORY RESPONSE; PREDICTING SURVIVAL; METAANALYSIS; ASSOCIATION; RESECTION; ADENOCARCINOMA; HETEROGENEITY; STATISTICS; THERAPY; COHORT AB This was a pooled analysis of studies on C-reactive protein (CRP) and prostate cancer mortality. Two hundred thirty-five patients were included. CRP was significantly associated with mortality; the best predictor cutoff was CRP < 12 mg/L. CRP is a routine assay that could be tested at diagnosis to improve prognostication of prostate cancer patients. Introduction: Previous studies have reported that higher C-reactive protein (CRP) levels are significantly associated with worse outcome in prostate cancer patients. The size of each individual study was not large enough to allow sufficient statistical power to draw conclusions. We conducted a pooled analysis of individual data of published studies to evaluate the association between increased CRP level and risk of death in prostate cancer, and to find the best CRP cutoff that could predict mortality. Materials and Methods: Original research studies on prostate cancer survival and CRP levels were identified (n = 6). Corresponding authors were contacted and invited to share individual data. Two data sets were received (235 patients). The combined hazard ratio (HR) was calculated and adjusted for age, prostate-specific antigen, hemoglobin, and alkaline phosphatase. The best cutoff of CRP was explored using X-title software version 3.6.1. Results: High CRP level was statistically significantly associated with mortality (meta-HR, 1.83 [95% confidence interval (CI), 1.51-2.21]), without evidence of heterogeneity among studies. At pooled analysis, adjusted pooled HR for CRP < 5 versus > 5 mg/L was 1.44 (95% CI, 1.02-20.4). The best CRP cutoff was 12 mg/ L: the adjusted HRpooled for CRP < 12 versus >= 12 mg/L was 1.53 (95% CI, 1.01-2.32). Conclusion: Increased CRP levels are associated with overall survival in prostate cancer patients. Because CRP is an affordable and readily available assay, it might hold promise in improving prognostication and potentially to predict the activity of specific therapeutic agents. C1 [Graff, Julie N.] Portland VA Med Ctr, Portland, OR USA. [Graff, Julie N.; Beer, Tomasz M.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Liu, Bian; Taioli, Emanuela] Hofstra North Shore LIJ Sch Med, Manhasset, NY 11021 USA. [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Taioli, E (reprint author), Hofstra North Shore LIJ Sch Med, 175 Community Dr,Rm 203, Manhasset, NY 11021 USA. EM taiolema@gmail.com FU DOD [PC120302]; NIH [U01 OH010396] FX This work was partially supported by DOD PC120302 and NIH U01 OH010396 to E.T. NR 31 TC 2 Z9 2 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2015 VL 13 IS 4 BP E217 EP E221 DI 10.1016/j.clgc.2015.01.011 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CM7NF UT WOS:000357880000004 PM 25735198 ER PT J AU Mckay, RR Mamlouk, K Montgomery, B Taplin, ME AF McKay, Rana R. Mamlouk, Khalid Montgomery, Bruce Taplin, Mary-Ellen TI Treatment With Galeterone in an Elderly Man With Castration-Resistant Prostate Cancer: A Case Report SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Androgen receptor; Androgen signaling; Anti-androgen; CYP17 inhibitor; Hormone therapy ID RECEPTOR SPLICE VARIANTS; ABIRATERONE ACETATE; INCREASED SURVIVAL; CLINICAL ACTIVITY; ENZALUTAMIDE; CHEMOTHERAPY; TRIALS; MECHANISMS; OLDER; AGE C1 [McKay, Rana R.; Taplin, Mary-Ellen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mamlouk, Khalid] Tokai Pharmaceut Inc, Cambridge, MA USA. [Montgomery, Bruce] Univ Washington, Seattle, WA 98195 USA. RP Mckay, RR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM rmckay5@partners.org FU Tokai Pharmaceuticals, Cambridge Massachusetts; Fairweather Family Fund; Uribe Family Fund at the DanaFarber Cancer Center FX The galeterone clinical trial was funded by Tokai Pharmaceuticals, Cambridge Massachusetts. M.-E.T. received Tokai Pharmaceutical support for advisory board and research support from the Fairweather Family Fund and Uribe Family Fund at the Dana-Farber Cancer Center. The remaining authors have no conflicts of interest. NR 22 TC 0 Z9 0 U1 0 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2015 VL 13 IS 4 BP E325 EP E328 DI 10.1016/j.clgc.2014.12.015 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CM7NF UT WOS:000357880000020 PM 25600761 ER PT J AU Larson, JJ Lynch, S Tarver, LB Mitchell, L Frosch, E Solomon, B AF Larson, Justine Julia Lynch, Sean Tarver, Leslie Bishop Mitchell, Laura Frosch, Emily Solomon, Barry TI Do Parents Expect Pediatricians to Pay Attention to Behavioral Health? SO CLINICAL PEDIATRICS LA English DT Article DE community mental health services; pediatrics; behavioral medicine ID PRIMARY-CARE; DISORDERS; CHILDREN AB Background and Objective. This study is a qualitative analysis examining caregivers' expectations for pediatricians with regard to behavioral health care. Methods. Fifty-five parents/caregivers of children seen in an urban primary care clinic participated in semistructured interviews. Participants were parents or guardians of children between the ages of 2 and 17 years, referred from the pediatric clinic to the mental health center. Interviews were analyzed using grounded theory methods. Results. Pertinent themes were the following: expected range of care, components of an effective primary care provider (PCP) relationship, action of the PCP, and parent reaction to PCP intervention. Forty-seven percent of caregivers saw the PCP role as strictly for physical health care; 53% expected the PCP to have a role in both physical and behavioral health. Responses were overwhelmingly positive from caregivers when the PCP asked about or conducted a behavioral health intervention. Conclusion. Caregivers did not consistently expect but responded positively to PCPs engaging around behavioral health concerns. C1 [Larson, Justine Julia; Frosch, Emily; Solomon, Barry] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lynch, Sean] Univ Florida, Jacksonville, FL USA. [Tarver, Leslie Bishop] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mitchell, Laura] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Larson, JJ (reprint author), 515 Philadelphia Ave, Takoma Pk, MD 20912 USA. EM justinelarson72@gmail.com FU Center for Mental Health Services in Pediatric Primary Care; National Institutes of Mental Health [P20MH086048] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported through a pilot grant from the Center for Mental Health Services in Pediatric Primary Care. National Institutes of Mental Health Grant No. P20MH086048. NR 25 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 EI 1938-2707 J9 CLIN PEDIATR JI Clin. Pediatr. PD AUG PY 2015 VL 54 IS 9 BP 888 EP 893 DI 10.1177/0009922815569199 PG 6 WC Pediatrics SC Pediatrics GA CM8EA UT WOS:000357928800010 PM 25644647 ER PT J AU Eddy, KT Thomas, JJ Keshaviah, A Edkins, K Krishna, M Murray, HB Hastings, E Franko, DL Herzog, DB AF Eddy, Kamryn T. Thomas, Jennifer J. Keshaviah, Aparna Edkins, Katherine Krishna, Meera Murray, Helen B. Hastings, Elizabeth Franko, Debra L. Herzog, David B. TI Reply to "Comment on "Re-examining premature mortality in anorexia nervosa: A meta-analysis redux" by Keshaviah et al. [Comprehensive Psychiatry 55 (2014) 1773-1784]" SO COMPREHENSIVE PSYCHIATRY LA English DT Editorial Material ID EATING-DISORDERS; DENMARK C1 [Eddy, Kamryn T.; Thomas, Jennifer J.; Keshaviah, Aparna; Edkins, Katherine; Krishna, Meera; Murray, Helen B.; Hastings, Elizabeth; Franko, Debra L.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.; Herzog, David B.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Hastings, Elizabeth] Amundsen, Burlington, MA USA. [Franko, Debra L.] Northeastern Univ, Boston, MA 02115 USA. RP Eddy, KT (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. EM keddy@mgh.harvard.edu NR 6 TC 0 Z9 0 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD AUG PY 2015 VL 61 BP 133 EP 134 DI 10.1016/j.comppsych.2015.05.012 PG 2 WC Psychiatry SC Psychiatry GA CM7XC UT WOS:000357908800019 PM 26095864 ER PT J AU Lauer, A Greenberg, SM Gurol, ME AF Lauer, Arne Greenberg, Steven M. Gurol, M. Edip TI Statins in Intracerebral Hemorrhage SO CURRENT ATHEROSCLEROSIS REPORTS LA English DT Article DE Statins; 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; Intracerebral hemorrhage; Cerebral amyloid angiopathy; CAA; Brain bleed; Hypercholesterolemia; Low-density lipoprotein; Cholesterol; LDL; Deep hypertensive hemorrhage ID CEREBRAL AMYLOID ANGIOPATHY; DENSITY-LIPOPROTEIN CHOLESTEROL; SERUM TOTAL CHOLESTEROL; STROKE PREVENTION; ISCHEMIC-STROKE; APOLIPOPROTEIN-E; RISK-FACTORS; INTRACRANIAL HEMORRHAGE; REDUCTASE INHIBITORS; AGGRESSIVE REDUCTION AB While statins play an indisputable role in primary and secondary prevention of ischemic cardiovascular and cerebrovascular disease, a concern exists regarding a possible association between low lipoprotein levels and statin use on the risk of intracerebral hemorrhage (ICH). While these data may incline physicians to discontinue statins after ICH, an increasing amount of preclinical and clinical evidence suggests that statins might have a beneficial effect on outcome and recovery in this context that goes beyond lipid lowering effects. Different etiologies of ICH and the related risk of recurrence should also be taken into account when deciding about statin use/avoidance in patients with high risk of ICH. The problem is compounded by paucity of data from randomized controlled trials and well-designed prospective observational studies. This review will discuss the existing evidence on potential interactions between statins and risk of ICH as well as outcomes in order to provide practical recommendations for clinical decision-making. C1 [Lauer, Arne; Greenberg, Steven M.; Gurol, M. Edip] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. RP Gurol, ME (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. EM alauer@partners.org; sgreenberg@mgh.harvard.edu; edip@mail.harvard.edu RI Gurol, Edip/J-2279-2014 OI Gurol, Edip/0000-0002-2169-4457 FU NIH [K23 NS083711, R01 NS070834, R01 AG026484] FX Study Support: This work was made possible by the following NIH grants: K23 NS083711, R01 NS070834, R01 AG026484. NR 64 TC 6 Z9 6 U1 2 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1523-3804 EI 1534-6242 J9 CURR ATHEROSCLER REP JI Curr. Atheroscleros. Rep. PD AUG PY 2015 VL 17 IS 8 AR 46 DI 10.1007/s11883-015-0526-5 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CL7CF UT WOS:000357127000002 PM 26092038 ER PT J AU Powers, MA Bardsley, J Cypress, M Duker, P Funnell, MM Fischl, AH Maryniuk, MD Siminerio, L Vivian, E AF Powers, Margaret A. Bardsley, Joan Cypress, Marjorie Duker, Paulina Funnell, Martha M. Fischl, Amy Hess Maryniuk, Melinda D. Siminerio, Linda Vivian, Eva TI Diabetes Self-management Education and Support in Type 2 Diabetes: A Joint Position Statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics SO DIABETES EDUCATOR LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; GLYCEMIC CONTROL; CLINICAL-OUTCOMES; DECISION-MAKING; METAANALYSIS; CARE; ADULTS; PEOPLE; NEEDS C1 [Powers, Margaret A.] Int Diabet Ctr, Minneapolis, MN 55416 USA. [Bardsley, Joan] MedStar Hlth Res Inst, Hyattsville, MD USA. [Bardsley, Joan] MedStar Nursing, Hyattsville, MD USA. [Cypress, Marjorie] ABQ Hlth Partners, Albuquerque, NM USA. [Duker, Paulina] LifeScan, Dubai, U Arab Emirates. [Funnell, Martha M.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Fischl, Amy Hess] Univ Chicago, Chicago, IL 60637 USA. [Maryniuk, Melinda D.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Siminerio, Linda] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Vivian, Eva] Univ Wisconsin, Madison, WI USA. RP Powers, MA (reprint author), Int Diabet Ctr, Pk Nicollet, Minneapolis, MN 55416 USA. EM margaret.powers@parknicollet.com FU American Association of Diabetes Educators; American Diabetes Association; Academy of Nutrition and Dietetics FX The authors gratefully acknowledge the commitment and support of the collaborating organizations-the American Association of Diabetes Educators, the American Diabetes Association, and the Academy of Nutrition and Dietetics; their colleagues, including members of the Executive Committee of the National Diabetes Education Program, who participated in discussions and reviews about this inaugural position statement; and patients who teach and inspire them. The authors also thank Erika Gebel Berg (American Diabetes Association) for her invaluable editorial contribution. NR 82 TC 19 Z9 19 U1 4 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD AUG PY 2015 VL 41 IS 4 BP 417 EP 430 DI 10.1177/0145721715588904 PG 14 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA CM9IV UT WOS:000358023000002 PM 26047627 ER PT J AU Laskiewicz, L Mirzabeigi, M Faquin, W Lithgow, M AF Laskiewicz, Lisa Mirzabeigi, Marjan Faquin, William Lithgow, Marie TI Cytologic Features of Sebaceous Epithelial-Myoepithelial Carcinoma of the Salivary Gland A Brief Report of a Rare Variant SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Letter ID HISTOLOGIC VARIANT C1 [Laskiewicz, Lisa; Mirzabeigi, Marjan; Lithgow, Marie] Univ Massachusetts, Mem Med Ctr, Dept Pathol, Worcester, MA 01605 USA. [Faquin, William] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Lithgow, M (reprint author), Univ Massachusetts, Mem Med Ctr, Dept Pathol, Biotech 3,1 Innovat Dr, Worcester, MA 01605 USA. EM marie.lithgow@umassmemorial.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-1039 EI 1097-0339 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD AUG PY 2015 VL 43 IS 8 BP 676 EP 679 DI 10.1002/dc.23235 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA CM8RF UT WOS:000357969000018 PM 25417919 ER PT J AU Genta, RM Sonnenberg, A AF Genta, Robert M. Sonnenberg, Amnon TI The yield of colonic biopsy in the evaluation of chronic unexplained diarrhea SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Article DE adenomatous polyps; colon biopsy; histopathology of the intestine; inflammatory bowel disease; microscopic colitis ID HELICOBACTER-PYLORI; ESOPHAGEAL EOSINOPHILIA; PATHOLOGY DATABASE; COLONOSCOPY; RISK AB Background and aimsIn clinical practice, colonoscopy is widely used for the workup of chronic unexplained diarrhea. The aim of this study was to determine the yield of colonic biopsy in such an endeavor.MethodsIn a computerized database of 130204 patients evaluated for chronic diarrhea, we tested the influence of biopsy site, number of tissue fragments, patient symptoms, and indication on the outcome of histopathologic evaluation.ResultsThe population comprised 69% women and 31% men aged (meanSD) 52.8 +/- 17.4 years. In 19% of patients, histopathological analysis revealed various types of mucosal lesion, the most common being microscopic colitis (8.6%), ulcerative colitis (2.2%), Crohn's disease (0.6%), active colitis (5.0%), diverticulitis (0.1%), and colonic ischemia (0.5%). In 29% of patients, the colonoscopy also revealed the presence of colon polyps. Endoscopists tended to take significantly more tissue samples from endoscopically visible lesions than for random biopsies of macroscopically normal-appearing mucosa.ConclusionOverall, these associations suggest that specific diagnoses lead to more biopsies, rather than more biopsies leading to more diagnoses. Colonoscopy is a successful tool in the workup of chronic diarrhea, yielding a definitive diagnosis in almost one-fifth of all patients. As an added benefit, it also contributes to cancer prevention through the incidental findings of colonic neoplasm. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved. C1 [Genta, Robert M.] Miraca Life Sci, Irving, TX USA. [Genta, Robert M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr P3 GI, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 11 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0954-691X EI 1473-5687 J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD AUG PY 2015 VL 27 IS 8 BP 963 EP 967 DI 10.1097/MEG.0000000000000365 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM4HZ UT WOS:000357646700014 PM 26114907 ER PT J AU Rogus-Pulia, NM Pierce, M Mittal, BB Zecker, SG Logemann, J AF Rogus-Pulia, Nicole M. Pierce, Margaret Mittal, Bharat B. Zecker, Steven G. Logemann, Jeri TI Bolus effects on patient awareness of swallowing difficulty and swallow physiology after chemoradiation for head and neck cancer SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE dysphagia; chemoradiation; head and neck cancer; perception; bolus; volume; consistency ID UPPER ESOPHAGEAL SPHINCTER; ORAL-CANCER; OROPHARYNGEAL CANCER; TONGUE STRENGTH; PHARYNGEAL; DYSPHAGIA; VOLUME; RADIOTHERAPY; VARIABLES; AGE AB BackgroundPatients treated for head and neck cancer frequently develop dysphagia. Bolus characteristics are altered during fluoroscopic swallowing studies to observe the impact on swallowing function. The purpose of this study was to determine bolus volume and consistency effects on oropharyngeal swallowing physiology and patient awareness of swallowing difficulty. MethodsTwenty-one patients with head and neck cancer were assessed pre-chemoradiation and post-chemoradiation. The Modified Barium Swallow Study (MBSS) was utilized to examine swallow physiology. Each patient provided perceptual ratings of swallowing difficulty after each swallow of varying bolus types. ResultsOral transit times were significantly longer with pudding boluses. There were trends for higher residue percentages as well as perceptual ratings for pudding and cookie boluses. One correlation between perceptual ratings and physiology was significant. ConclusionPatient awareness of swallowing difficulty and aspects of swallowing physiology vary with bolus consistency. Patient awareness does not correlate with observed changes in swallowing physiology. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 1122-1129, 2015 C1 [Rogus-Pulia, Nicole M.] Univ Wisconsin, William S Middleton Mem Vet Hosp, Div Gastroenterol & Hepatol, Dept Med,Sch Med & Publ Hlth, Madison, WI USA. [Pierce, Margaret] NW Mem Hosp, Dept Radiat Oncol, Chicago, IL 60611 USA. [Mittal, Bharat B.] Northwestern Univ, Dept Radiat Oncol, Feinberg Sch Med, Chicago, IL 60611 USA. [Zecker, Steven G.; Logemann, Jeri] Northwestern Univ, Dept Commun Sci & Disorders, Evanston, IL 60611 USA. RP Rogus-Pulia, NM (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace,Madison GRECC 11G, Madison, WI 53705 USA. EM nicolepulia@gmail.com NR 41 TC 4 Z9 4 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD AUG PY 2015 VL 37 IS 8 BP 1122 EP 1129 DI 10.1002/hed.23720 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CM8JM UT WOS:000357946400011 PM 24841209 ER PT J AU Bhatt, AB Yeh, DD AF Bhatt, Ami B. Yeh, Doreen Defaria TI Long-term outcomes in coarctation of the aorta: an evolving story of success and new challenges SO HEART LA English DT Editorial Material ID LEFT-VENTRICULAR MASS; REPAIRED COARCTATION; CHILDREN C1 [Bhatt, Ami B.; Yeh, Doreen Defaria] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. RP Bhatt, AB (reprint author), Massachusetts Gen Hosp, Dept Cardiol, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM abhatt@partners.org NR 10 TC 1 Z9 1 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 AUG PY 2015 VL 101 IS 15 BP 1173 EP 1175 DI 10.1136/heartjnl-2015-307641 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM5LO UT WOS:000357729600002 PM 26025083 ER PT J AU Barakat, LA Juthani-Mehta, M Allore, H Trentalange, M Tate, J Rimland, D Pisani, M Akgun, KM Goetz, MB Butt, AA Rodriguez-Barradas, M Duggal, M Crothers, K Justice, AC Quagliarello, VJ AF Barakat, L. A. Juthani-Mehta, M. Allore, H. Trentalange, M. Tate, J. Rimland, D. Pisani, M. Akguen, K. M. Goetz, M. B. Butt, A. A. Rodriguez-Barradas, M. Duggal, M. Crothers, K. Justice, A. C. Quagliarello, V. J. TI Comparing clinical outcomes in HIV-infected and uninfected older men hospitalized with community-acquired pneumonia SO HIV MEDICINE LA English DT Article DE HIV; outcomes; pneumonia ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; VETERANS AGING COHORT; BACTERIAL PNEUMONIA; PULMONARY MANIFESTATIONS; ERA; INDEX; MANAGEMENT; MORTALITY; SEVERITY AB ObjectivesOutcomes of community-acquired pneumonia (CAP) among HIV-infected older adults are unclear. MethodsAssociations between HIV infection and three CAP outcomes (30-day mortality, readmission within 30 days post-discharge, and hospital length of stay [LOS]) were examined in the Veterans Aging Cohort Study (VACS) of male Veterans, age 50 years, hospitalized for CAP from 10/1/2002 through 08/31/2010. Associations between the VACS Index and CAP outcomes were assessed in multivariable models. ResultsAmong 117557 Veterans (36922 HIV-infected and 80635 uninfected), 1203 met our eligibility criteria. The 30-day mortality rate was 5.3%, the mean LOS was 7.3 days, and 13.2% were readmitted within 30 days of discharge. In unadjusted analyses, there were no significant differences between HIV-infected and uninfected participants regarding the three CAP outcomes (P>0.2). A higher VACS Index was associated with increased 30-day mortality, readmission, and LOS in both HIV-infected and uninfected groups. Generic organ system components of the VACS Index were associated with adverse CAP outcomes; HIV-specific components were not. Among HIV-infected participants, those not on antiretroviral therapy (ART) had a higher 30-day mortality (HR 2.94 [95% CI 1.51, 5.72]; P=0.002) and a longer LOS (slope 2.69 days [95% CI 0.65, 4.73]; P=0.008), after accounting for VACS Index. Readmission was not associated with ART use (OR 1.12 [95% CI 0.62, 2.00] P=0.714). ConclusionAmong HIV-infected and uninfected older adults hospitalized for CAP, organ system components of the VACS Index were associated with adverse CAP outcomes. Among HIV-infected individuals, ART was associated with decreased 30-day mortality and LOS. C1 [Barakat, L. A.; Juthani-Mehta, M.; Quagliarello, V. J.] Yale Univ, Sch Med, Infect Dis, New Haven, CT 06510 USA. [Barakat, L. A.; Juthani-Mehta, M.; Allore, H.; Trentalange, M.; Pisani, M.; Akguen, K. M.; Justice, A. C.; Quagliarello, V. J.] Yale Univ, Sch Med, Internal Med, New Haven, CT 06510 USA. [Tate, J.; Akguen, K. M.; Duggal, M.; Justice, A. C.] VA Connecticut Healthcare Syst, Internal Med, West Haven, CT USA. [Rimland, D.] VA Med Ctr, Infect Dis, Decatur, GA USA. [Pisani, M.; Akguen, K. M.] Yale Univ, Sch Med, Pulm Dis & Crit Care, New Haven, CT 06510 USA. [Goetz, M. B.] VA Greater Los Angles Healthcare Syst, Infect Dis, Los Angeles, CA USA. [Butt, A. A.] Univ Pittsburgh, Internal Med, Pittsburgh, PA USA. [Rodriguez-Barradas, M.] Michael E Debakey VA Med Ctr, Infect Dis MS 111G, Houston, TX USA. [Crothers, K.] Univ Washington, Pulm Dis & Crit Care, Seattle, WA 98195 USA. RP Barakat, LA (reprint author), Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06510 USA. EM lydia.barakat@yale.edu OI Butt, Adeel/0000-0002-1118-1826; Justice, Amy/0000-0003-0139-5502; Allore, Heather/0000-0001-7685-8175 FU NIA NIH HHS [K23 AG028691, K23AG028691, P30 AG021342, K07 AG030093, K07AG030093, P30AG021342]; NIAAA NIH HHS [U10 AA013566, U10AA013566] NR 40 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-2662 EI 1468-1293 J9 HIV MED JI HIV Med. PD AUG PY 2015 VL 16 IS 7 BP 421 EP 430 DI 10.1111/hiv.12244 PG 10 WC Infectious Diseases SC Infectious Diseases GA CM9CF UT WOS:000358002900004 PM 25959543 ER PT J AU Hoste, E Bagshaw, S Bellomo, R Cely, C Colman, R Cruz, D Edipidis, K Forni, L Gomersall, C Govil, D Honore, PM Joannes-Boyau, O Joannidis, M Korhonen, AM Lavrentieva, A Mehta, R Palevsky, P Roessler, E Ronco, C Uchino, S Vazquez, J Vidal Andrade, E Webb, S Kellum, J AF Hoste, Eric A. J. Bagshaw, Sean M. Bellomo, Rinaldo Cely, Cynthia M. Colman, Roos Cruz, Dinna N. Edipidis, Kyriakos Forni, Lui G. Gomersall, Charles D. Govil, Deepak Honore, Patrick M. Joannes-Boyau, Olivier Joannidis, Michael Korhonen, Anna-Maija Lavrentieva, Athina Mehta, Ravindra L. Palevsky, Paul Roessler, Eric Ronco, Claudio Uchino, Shigehiko Vazquez, Jorge A. Vidal Andrade, Erick Webb, Steve Kellum, John A. TI Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study SO INTENSIVE CARE MEDICINE LA English DT Article DE Acute kidney injury; Critically ill; Renal replacement therapy; Epidemiology; Kidney function; Hospital mortality ID RENAL REPLACEMENT THERAPY; GLOMERULAR-FILTRATION; 90-DAY MORTALITY; RISK-FACTORS; FAILURE; ICU; CLASSIFICATION; DEFINITION; CREATININE; PROGNOSIS AB Current reports on acute kidney injury (AKI) in the intensive care unit (ICU) show wide variation in occurrence rate and are limited by study biases such as use of incomplete AKI definition, selected cohorts, or retrospective design. Our aim was to prospectively investigate the occurrence and outcomes of AKI in ICU patients. The Acute Kidney Injury-Epidemiologic Prospective Investigation (AKI-EPI) study was an international cross-sectional study performed in 97 centers on patients during the first week of ICU admission. We measured AKI by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and outcomes at hospital discharge. A total of 1032 ICU patients out of 1802 [57.3 %; 95 % confidence interval (CI) 55.0-59.6] had AKI. Increasing AKI severity was associated with hospital mortality when adjusted for other variables; odds ratio of stage 1 = 1.679 (95 % CI 0.890-3.169; p = 0.109), stage 2 = 2.945 (95 % CI 1.382-6.276; p = 0.005), and stage 3 = 6.884 (95 % CI 3.876-12.228; p < 0.001). Risk-adjusted rates of AKI and mortality were similar across the world. Patients developing AKI had worse kidney function at hospital discharge with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) in 47.7 % (95 % CI 43.6-51.7) versus 14.8 % (95 % CI 11.9-18.2) in those without AKI, p < 0.001. This is the first multinational cross-sectional study on the epidemiology of AKI in ICU patients using the complete KDIGO criteria. We found that AKI occurred in more than half of ICU patients. Increasing AKI severity was associated with increased mortality, and AKI patients had worse renal function at the time of hospital discharge. Adjusted risks for AKI and mortality were similar across different continents and regions. C1 [Hoste, Eric A. J.] Univ Ghent, Ghent Univ Hosp, Dept Intens Care Med, B-9000 Ghent, Belgium. [Hoste, Eric A. J.] Res Fdn Flanders, Brussels, Belgium. [Hoste, Eric A. J.; Kellum, John A.] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Clin Res Invest & Syst Modelling Acute Illnes CRI, Pittsburgh, PA USA. [Bagshaw, Sean M.] Univ Alberta, Fac Med & Dent, Div Crit Care Med, Edmonton, AB, Canada. [Bellomo, Rinaldo] Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia. [Cely, Cynthia M.] Univ Miami, Miller Sch Med, Div Pulm Crit Care & Sleep Med, Miami, FL 33136 USA. [Colman, Roos] Univ Ghent, Dept Publ Hlth, B-9000 Ghent, Belgium. [Cruz, Dinna N.] Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, San Diego, CA 92103 USA. [Edipidis, Kyriakos] Hygeia Med Ctr, Athens, Greece. [Forni, Lui G.] Univ Surrey, Fac Hlth & Med Sci, Dept Intens Care Med, Guildford GU2 7TE, Surrey, England. [Forni, Lui G.] Univ Surrey, Surrey Peri Operat Anaesthesia Crit Care Res Grp, Royal Surrey Cty Hosp NHS Fdn Trust, Guildford GU2 7TE, Surrey, England. [Gomersall, Charles D.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anaesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China. [Govil, Deepak] Medanta, Inst Crit Care & Anesthesia, Gurgaon, India. [Honore, Patrick M.] VUB Univ, Univ Ziekenhuis Brussel, Dept Intens Care, Brussels, Belgium. [Joannes-Boyau, Olivier] CHU Bordeaux, Serv Anesthesie Reanimat 2, F-33000 Bordeaux, France. [Joannidis, Michael] Med Univ Innsbruck, Dept Internal Med, Div Intens Care & Emergency Med, A-6020 Innsbruck, Austria. [Korhonen, Anna-Maija] Meilahti Univ Hosp, Cent Hosp, Dept Surg, Intens Care Unit,Div Anaesthesia & Intens Care Me, Helsinki, Finland. [Korhonen, Anna-Maija] Univ Helsinki, Dept Clin Sci, Helsinki, Finland. [Lavrentieva, Athina] Papanikolaou Gen Hosp, Burn ICU, Thessaloniki, Greece. [Mehta, Ravindra L.] Univ Calif San Diego, Dept Med, Med Ctr, San Diego, CA 92103 USA. [Palevsky, Paul] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Palevsky, Paul] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. [Palevsky, Paul; Kellum, John A.] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Ctr Crit Care Nephrol, Pittsburgh, PA 15213 USA. [Roessler, Eric] Pontificia Univ Catolica Chile, Fac Med, Dept Nephrol, Santiago, Chile. [Ronco, Claudio] San Bortolo Hosp, Int Renal Res Inst, Dept Nephrol Dialysis & Transplantat, Vicenza, Italy. [Uchino, Shigehiko] Jikei Univ, Sch Med, Dept Anesthesiol, Intens Care Unit, Tokyo, Japan. [Vazquez, Jorge A.] Clin Modelo Lanus, Dept Crit Care Med, Buenos Aires, DF, Argentina. [Vidal Andrade, Erick] Hosp Angeles Lomas, Dept Crit Care Med, Mexico City, DF, Mexico. [Webb, Steve] Univ Western Australia, Dept Crit Care Med, Perth, WA 6009, Australia. [Webb, Steve] Royal Perth Hosp, Perth, WA 6001, Australia. RP Hoste, E (reprint author), Univ Ghent, Ghent Univ Hosp, Dept Intens Care Med, De Pintelaan 185, B-9000 Ghent, Belgium. EM eric.hoste@ugent.be OI Hoste, Eric/0000-0001-9301-8055; Palevsky, Paul/0000-0002-7334-5400 FU Astute Medical; Industrial Research Fund (IOF) from Ghent University; Gambro; BBraun; Fresenius; Baxter; Alere; AM Pharma; Spectral; Grifols; Cytosorbents; Alung; Atox Bio; Bard; Kaneka; International Safety Adverse Events Consortium; Thrasos FX EH received speakers fee from Astute Medical, and an Industrial Research Fund (IOF) from Ghent University for a validation study on a biomarker for AKI. SMB has consulted for and received honoraria from Gambro-Baxter. CG has received sponsorship for an academic conference from Gambro. OJB has received grants and non-financial support from Gambro, BBraun, Fresenius, and Astute Medical. MJ has consulted for and received honoraria from Baxter, Gambro, Fresenius, CLS Behring, BBraun, AM Pharma, Sanofi, Astute. JK has received grant support and/or consulting fees from Fresenius, Gambro, Baxter, Astute Medical, Alere, AM Pharma, Spectral, Grifols, Cytosorbents, Alung, Atox Bio, Bard, Kaneka. RM has received grants from the International Safety Adverse Events Consortium and Thrasos, he has options in Astute Medical and served in the scientific advisory board for trials for Abbvie, AM Pharma, and Eli Lilly, and consulted for CSL Behring, GSK, Baxter, Sova, Astellas, and Sanofi-Aventis. PP has consulted for Complexa Inc. SW is Director and Shareholder of Aalix Healthcare Services Consulting, which has provided services related to AKI. NR 40 TC 97 Z9 98 U1 3 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD AUG PY 2015 VL 41 IS 8 BP 1411 EP 1423 DI 10.1007/s00134-015-3934-7 PG 13 WC Critical Care Medicine SC General & Internal Medicine GA CM9VI UT WOS:000358057000003 PM 26162677 ER PT J AU Belsky, J Alvey, H Bencze, A Thompson, B Stokes-Buzzelli, S AF Belsky, Justin Alvey, Heidi Bencze, Alexis Thompson, Brooke Stokes-Buzzelli, Stephanie TI Blue toe syndrome, ischemic pain treated with digital block SO INTERNAL AND EMERGENCY MEDICINE LA English DT Editorial Material ID MANAGEMENT C1 [Belsky, Justin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02138 USA. [Alvey, Heidi; Bencze, Alexis; Stokes-Buzzelli, Stephanie] Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. [Thompson, Brooke] Hurley Med Ctr, Dept Emergency Med, Flint, MI USA. RP Belsky, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02138 USA. EM jbelsky@partners.org NR 10 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1828-0447 EI 1970-9366 J9 INTERN EMERG MED JI Intern. Emerg. Med. PD AUG PY 2015 VL 10 IS 5 BP 637 EP 638 DI 10.1007/s11739-015-1190-z PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CM9RS UT WOS:000358047200017 PM 25605677 ER PT J AU Zhu, CW Cosentino, S Ornstein, K Gu, Y Andrews, H Stern, Y AF Zhu, Carolyn W. Cosentino, Stephanie Ornstein, Katherine Gu, Yian Andrews, Howard Stern, Yaakov TI Use and cost of hospitalization in dementia: longitudinal results from a community-based study SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE dementia; hospitalization; healthcare expenditures; longitudinal follow-up ID ALZHEIMERS-DISEASE; INCIDENT DEMENTIA; CARE; ASSOCIATION; DIAGNOSIS; ADMISSIONS; REASONS; ILLNESS; IMPACT; RISK AB ObjectivesThe aim of this study is to examine the relative contribution of functional impairment and cognitive deficits on risk of hospitalization and costs. MethodsA prospective cohort of Medicare beneficiaries aged 65 and older who participated in the Washington Heights-Inwood Columbia Aging Project (WHICAP) were followed approximately every 18months for over 10years (1805 never diagnosed with dementia during study period, 221 diagnosed with dementia at enrollment). Hospitalization and Medicare expenditures data (1999-2010) were obtained from Medicare claims. Multivariate analyses were conducted to examine (1) risk of all-cause hospitalizations, (2) hospitalizations from ambulatory care sensitive (ACSs) conditions, (3) hospital length of stay (LOS), and (4) Medicare expenditures. Propensity score matching methods were used to reduce observed differences between demented and non-demented groups at study enrollment. Analyses took into account repeated observations within each individual. ResultsCompared to propensity-matched individuals without dementia, individuals with dementia had significantly higher risk for all-cause hospitalization, longer LOS, and higher Medicare expenditures. Functional and cognitive deficits were significantly associated with higher risks for hospitalizations, hospital LOS, and Medicare expenditures. Functional and cognitive deficits were associated with higher risks of for some ACS but not all admissions. ConclusionsThese results allow us to differentiate the impact of functional and cognitive deficits on hospitalizations. To develop strategies to reduce hospitalizations and expenditures, better understanding of which types of hospitalizations and which disease characteristics impact these outcomes will be critical. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Zhu, Carolyn W.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Zhu, Carolyn W.] James J Peters VA Med Ctr, Bronx, NY USA. [Cosentino, Stephanie; Gu, Yian; Stern, Yaakov] Columbia Univ Med Ctr, Cognit Neurosci Div, Gertrude H Sergievsky Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Cosentino, Stephanie; Gu, Yian; Stern, Yaakov] Columbia Univ Med Ctr, Dept Neurol, New York, NY USA. [Ornstein, Katherine] Icahn Sch Med Mt Sinai, Samuel Bronfman Dept Med, Div Gen Internal Med, New York, NY 10029 USA. [Andrews, Howard] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. RP Zhu, CW (reprint author), Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. EM carolyn.zhu@mssm.edu FU National Institute on Aging [AG07370, AG037212] FX This research was supported by grants from the National Institute on Aging (AG07370, AG037212). NR 36 TC 8 Z9 8 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD AUG PY 2015 VL 30 IS 8 BP 833 EP 841 DI 10.1002/gps.4222 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA CM7OM UT WOS:000357884200006 PM 25351909 ER PT J AU Kim, YA Gosselin, R Van Cott, EM AF Kim, Y. A. Gosselin, R. Van Cott, E. M. TI The effects of dabigatran on lupus anticoagulant, diluted plasma thrombin time, and other specialized coagulation assays SO INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY LA English DT Letter ID INHIBITOR DABIGATRAN; ETEXILATE; TESTS C1 [Kim, Y. A.; Van Cott, E. M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kim, Y. A.; Van Cott, E. M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gosselin, R.] Calif State Univ Sacramento, Davis Hlth Syst, Sacramento, CA 95819 USA. RP Kim, YA (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM evancott@mgh.harvard.edu NR 8 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-5521 EI 1751-553X J9 INT J LAB HEMATOL JI Int. J. Lab. Hematol. PD AUG PY 2015 VL 37 IS 4 BP e81 EP e84 DI 10.1111/ijlh.12319 PG 4 WC Hematology SC Hematology GA CM8ME UT WOS:000357954600008 PM 25515302 ER PT J AU Zietman, A AF Zietman, Anthony TI Letters Regarding the TARGIT-A Trial: The Editor's Introduction SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter ID BREAST-CANCER C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM azietman@partners.org NR 3 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2015 VL 92 IS 5 BP 951 EP 952 DI 10.1016/j.ijrobp.2015.05.048 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CM7TY UT WOS:000357900600001 PM 26194661 ER PT J AU Wazer, DE Hepel, JT Riker, AI Harness, JK Chung, C Khan, AJ Offersen, BV Poortmans, P Taghian, A AF Wazer, David E. Hepel, Jaroslaw T. Riker, Adam I. Harness, Jay K. Chung, Caroline Khan, Atif J. Offersen, Birgitte Vrou Poortmans, Philip Taghian, Alphonse TI Letters Regarding the TARGIT-A Trial: The Editor's Introduction SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter ID INTRAOPERATIVE RADIATION-THERAPY; BREAST-CANCER; WOMEN; IRRADIATION; TAMOXIFEN; OLDER; AGE C1 [Wazer, David E.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Hepel, Jaroslaw T.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Riker, Adam I.] Advocate Christ Med Ctr, Advocate Canc Inst, Oak Lawn, IL USA. [Riker, Adam I.] Univ Illinois, Chicago, IL USA. [Harness, Jay K.] Univ Calif Irvine, St Joseph Hosp, Ctr Canc Prevent & Treatment, Orange, CA 92668 USA. [Chung, Caroline] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Khan, Atif J.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Offersen, Birgitte Vrou] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Poortmans, Philip] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Taghian, Alphonse] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Wazer, DE (reprint author), Tufts Univ, Sch Med, Boston, MA 02111 USA. RI Poortmans, P.M.P./L-4581-2015 NR 12 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2015 VL 92 IS 5 BP 952 EP 953 DI 10.1016/j.ijrobp.2015.05.032 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CM7TY UT WOS:000357900600002 PM 26194662 ER PT J AU Baldini, EH Abrams, RA Bosch, W Roberge, D Haas, RLM Catton, CN Indelicato, DJ Olsen, JR Deville, C Chen, YL Finkelstein, SE DeLaney, TF Wang, D AF Baldini, Elizabeth H. Abrams, Ross A. Bosch, Walter Roberge, David Haas, Rick L. M. Catton, Charles N. Indelicato, Daniel J. Olsen, Jeffrey R. Deville, Curtiland Chen, Yen-Lin Finkelstein, Steven E. DeLaney, Thomas F. Wang, Dian TI Retroperitoneal Sarcoma Target Volume and Organ at Risk Contour Delineation Agreement Among NRG Sarcoma Radiation Oncologists SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID SOFT-TISSUE SARCOMA; INTERMEDIATE-GRADE; PROGNOSTIC-FACTORS; RANDOMIZED-TRIAL; DOSE-ESCALATION; THERAPY; RADIOTHERAPY; CONSENSUS; CANCER; GUIDELINES AB Purpose: The purpose of this study was to evaluate the variability in target volume and organ at risk (OAR) contour delineation for retroperitoneal sarcoma (RPS) among 12 sarcoma radiation oncologists. Methods and Materials: Radiation planning computed tomography (CT) scans for 2 cases of RPS were distributed among 12 sarcoma radiation oncologists with instructions for contouring gross tumor volume (GTV), clinical target volume (CTV), high-risk CTV (HR CTV: area judged to be at high risk of resulting in positive margins after resection), and OARs: bowel bag, small bowel, colon, stomach, and duodenum. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. Results: Ten radiation oncologists contoured both RPS cases, 1 contoured only RPS1, and 1 contoured only RPS2 such that each case was contoured by 11 radiation oncologists. The first case (RPS 1) was a patient with a de-differentiated (DD) liposarcoma (LPS) with a predominant well-differentiated (WD) component, and the second case (RPS 2) was a patient with DD LPS made up almost entirely of a DD component. Contouring agreement for GTV and CTV contours was high. However, the agreement for HR CTVs was only moderate. For OARs, agreement for stomach, bowel bag, small bowel, and colon was high, but agreement for duodenum (distorted by tumor in one of these cases) was fair to moderate. Conclusions: For preoperative treatment of RPS, sarcoma radiation oncologists contoured GTV, CTV, and most OARs with a high level of agreement. HR CTV contours were more variable. Further clarification of this volume with the help of sarcoma surgical oncologists is necessary to reach consensus. More attention to delineation of the duodenum is also needed. (C) 2015 Elsevier Inc. All rights reserved. C1 [Baldini, Elizabeth H.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Abrams, Ross A.; Wang, Dian] Rush Univ, Dept Radiat Oncol, Med Ctr, Chicago, IL 60612 USA. [Bosch, Walter; Olsen, Jeffrey R.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. [Roberge, David] Ctr Hosp Univ Montreal, Dept Radiat Oncol, Montreal, PQ, Canada. [Haas, Rick L. M.] Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. [Catton, Charles N.] Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Indelicato, Daniel J.] Univ Florida, Med Ctr, Dept Radiat Oncol, Jacksonville, FL 32209 USA. [Deville, Curtiland] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Chen, Yen-Lin; DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Finkelstein, Steven E.] 21st Century Oncol, Translat Res Consortium, Scottsdale, AZ USA. RP Baldini, EH (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM ebaldini@partners.org RI Deville, Curtiland/B-2819-2013 OI Deville, Curtiland/0000-0003-4846-6486 FU National Cancer Institute grants [U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA180803, U24CA81647] FX Supported by National Cancer Institute grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA180803, and U24CA81647. NR 34 TC 4 Z9 4 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2015 VL 92 IS 5 BP 1053 EP 1059 DI 10.1016/j.ijrobp.2015.04.039 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CM7TY UT WOS:000357900600025 PM 26194680 ER PT J AU Schuemann, J Giantsoudi, D Grassberger, C Moteabbed, M Min, CH Paganetti, H AF Schuemann, Jan Giantsoudi, Drosoula Grassberger, Clemens Moteabbed, Maryam Min, Chul Hee Paganetti, Harald TI Assessing the Clinical Impact of Approximations in Analytical Dose Calculations for Proton Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID MONTE-CARLO SIMULATIONS; RANGE UNCERTAINTIES; PROSTATE-CANCER; RADIOTHERAPY; ACCURACY; DISTRIBUTIONS; FIELDS; VOLUME; TOPAS; LUNG AB Purpose: To assess the impact of approximations in current analytical dose calculation methods (ADCs) on tumor control probability (TCP) in proton therapy. Methods: Dose distributions planned with ADC were compared with delivered dose distributions as determined by Monte Carlo simulations. A total of 50 patients were investigated in this analysis with 10 patients per site for 5 treatment sites (head and neck, lung, breast, prostate, liver). Differences were evaluated using dosimetric indices based on a dose-volume histogram analysis, a gamma-index analysis, and estimations of TCP. Results: We found that ADC overestimated the target doses on average by 1% to 2% for all patients considered. The mean dose, D95, D50, and D02 (the dose value covering 95%, 50% and 2% of the target volume, respectively) were predicted within 5% of the delivered dose. The gamma-index passing rate for target volumes was above 96% for a 3%/3 mm criterion. Differences in TCP were up to 2%, 2.5%, 6%, 6.5%, and 11% for liver and breast, prostate, head and neck, and lung patients, respectively. Differences in normal tissue complication probabilities for bladder and anterior rectum of prostate patients were less than 3%. Conclusion: Our results indicate that current dose calculation algorithms lead to under-dosage of the target by as much as 5%, resulting in differences in TCP of up to 11%. To ensure full target coverage, advanced dose calculation methods like Monte Carlo simulations may be necessary in proton therapy. Monte Carlo simulations may also be required to avoid biases resulting from systematic discrepancies in calculated dose distributions for clinical trials comparing proton therapy with conventional radiation therapy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Schuemann, Jan] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Schuemann, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM jschuemann@mgh.harvard.edu OI Schuemann, Jan/0000-0002-7554-8818 FU NIH/NCI [CA U19 21239] FX This work was supported by NIH/NCI under CA U19 21239. We would like to thank the MGH Monte Carlo group for many fruitful discussions. We also thank Jonathan Jackson and Tao Song of the Enterprise Research Infrastructure and Services (ERIS) group at Partners Healthcare for their in-depth support and smooth computing cluster operations, upgrades, and fixes. NR 30 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2015 VL 92 IS 5 BP 1157 EP 1164 DI 10.1016/j.ijrobp.2015.04.006 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CM7TY UT WOS:000357900600038 PM 26025779 ER PT J AU Jones, M Chebib, I Deshpande, V Nielsen, GP AF Jones, Martin Chebib, Ivan Deshpande, Vikram Nielsen, G. Petur TI Radiation-Associated Low-Grade Extraskeletal Osteosarcoma of the Neck Following Treatment for Thyroid Cancer SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE low-grade extraskeletal osteosarcoma; radiation-associated sarcoma; thyroid ID SOFT-TISSUE SARCOMAS; CHEST-WALL; BONE AB Low-grade extraskeletal osteosarcoma is a rare tumor that may arise de novo or following radiation therapy. Because of the low-grade histology, it may be misdiagnosed as a benign lesion. We present a case of a 59-year-old man with a past history of radiotherapy for papillary carcinoma of the thyroid, presenting 16 years later with a low-grade extraskeletal osteosarcoma of the neck. The patient was treated with surgical excision and is disease free after 12 months of followup. The prognosis for patients with low-grade extraskeletal osteosarcoma is relatively good when compared with high-grade sarcomas. While there is a report of a low-grade extraskeletal osteosarcoma arising following radiotherapy for a benign condition, to the best of our knowledge this is the first reported case of a low-grade extraskeletal osteosarcoma occurring following radiotherapy for thyroid cancer, and the only case reported in the soft tissue of the head and neck region. C1 [Jones, Martin; Chebib, Ivan; Deshpande, Vikram; Nielsen, G. Petur] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Nielsen, GP (reprint author), Massachusetts Gen Hosp, Dept Pathol WRN 2, 55 Fruit St, Boston, MA 02114 USA. EM gnielsen@partners.org NR 31 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1066-8969 EI 1940-2465 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD AUG PY 2015 VL 23 IS 5 BP 384 EP 387 DI 10.1177/1066896915587757 PG 4 WC Pathology; Surgery SC Pathology; Surgery GA CM8DR UT WOS:000357927700010 PM 26009571 ER PT J AU Chodosh, J Colaiaco, BA Connor, KI Cope, DW Liu, HS Ganz, DA Richman, MJ Cherry, DL Blank, JM Carbone, RD Wolf, SM Vickrey, BG AF Chodosh, Joshua Colaiaco, Benjamin A. Connor, Karen Ilene Cope, Dennis Wesley Liu, Hangsheng Ganz, David Avram Richman, Mark Jason Cherry, Debra Lynn Blank, Joseph Moshe Carbone, Raquel del Pilar Wolf, Sheldon Mark Vickrey, Barbara Grace TI Dementia Care Management in an Underserved Community: The Comparative Effectiveness of Two Different Approaches SO JOURNAL OF AGING AND HEALTH LA English DT Article DE dementia; Alzheimer's; care management; comparative effectiveness; health care delivery ID NURSING-HOME PLACEMENT; ALZHEIMER-DISEASE; CONTROLLED-TRIAL; COLLABORATIVE CARE; CHRONIC ILLNESS; CAREGIVERS; HISPANICS; QUALITY; INTERVENTION; UTILITY AB Objectives: To compare the effectiveness and costs of telephone-only approach to in-person plus telephone for delivering an evidence-based, coordinated care management program for dementia. Methods: We randomized 151 patient-caregiver dyads from an underserved predominantly Latino community to two arms that shared a care management protocol but implemented in different formats: in-person visits at home and/or in the community plus telephone and mail, versus telephone and mail only. We compared between-arm caregiver burden and care-recipient problem behaviors (primary outcomes) and patient-caregiver dyad retention, care quality, health care utilization, and costs (secondary outcomes) at 6- and 12-months follow-up. Results: Care quality improved substantially over time in both arms. Caregiver burden, care-recipient problem behaviors, retention, and health care utilization did not differ across arms but the in-person program cost more to deliver. Discussion: Dementia care quality improved regardless of how care management was delivered; large differences in effectiveness or cost offsets were not detected. C1 [Chodosh, Joshua; Connor, Karen Ilene; Cope, Dennis Wesley; Ganz, David Avram; Richman, Mark Jason; Cherry, Debra Lynn; Blank, Joseph Moshe; Wolf, Sheldon Mark; Vickrey, Barbara Grace] Univ Calif Los Angeles, Los Angeles, CA USA. [Chodosh, Joshua; Connor, Karen Ilene; Ganz, David Avram; Carbone, Raquel del Pilar; Vickrey, Barbara Grace] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Chodosh, Joshua; Colaiaco, Benjamin A.; Liu, Hangsheng; Ganz, David Avram; Vickrey, Barbara Grace] RAND Corp, Santa Monica, CA USA. [Cope, Dennis Wesley; Richman, Mark Jason; Blank, Joseph Moshe; Wolf, Sheldon Mark] Olive View UCLA Med Ctr, Los Angeles, CA USA. [Liu, Hangsheng] RAND Corp, Boston, MA USA. [Cherry, Debra Lynn] Alzheimers Assoc, Los Angeles, CA USA. [Cherry, Debra Lynn] Univ So Calif, Los Angeles, CA USA. RP Chodosh, J (reprint author), VA Greater Los Angeles Healthcare Syst, GRECC Sepulveda COE 11G,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM JChodosh@mednet.ucla.edu OI Chodosh, Joshua/0000-0001-7784-4306 FU National Institute on Aging [RC4AG038804] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Award Number RC4AG038804 from the National Institute on Aging. NR 33 TC 3 Z9 3 U1 5 U2 13 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 AUG PY 2015 VL 27 IS 5 BP 864 EP 893 DI 10.1177/0898264315569454 PG 30 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA CM5SO UT WOS:000357749100006 PM 25656074 ER PT J AU Grabek, KR Martin, SL Hindle, AG AF Grabek, Katharine R. Martin, Sandra L. Hindle, Allyson G. TI Proteomics approaches shed new light on hibernation physiology SO JOURNAL OF COMPARATIVE PHYSIOLOGY B-BIOCHEMICAL SYSTEMIC AND ENVIRONMENTAL PHYSIOLOGY LA English DT Review DE Ground squirrel; Bear; Bat; Metabolic depression ID 13-LINED GROUND-SQUIRRELS; BROWN ADIPOSE-TISSUE; MAMMALIAN HIBERNATION; DAILY TORPOR; SKELETAL-MUSCLE; QUANTITATIVE-ANALYSIS; MOLECULAR ADAPTATIONS; METABOLIC SUPPRESSION; CIRCANNUAL RHYTHMS; CITELLUS-LATERALIS AB The broad phylogenetic distribution and rapid phenotypic transitions of mammalian hibernators imply that hibernation is accomplished by differential expression of common genes. Traditional candidate gene approaches have thus far explained little of the molecular mechanisms underlying hibernation, likely due to (1) incomplete and imprecise sampling of a complex phenotype, and (2) the forming of hypotheses about which genes might be important based on studies of model organisms incapable of such dynamic physiology. Unbiased screening approaches, such as proteomics, offer an alternative means to discover the cellular underpinnings that permit successful hibernation and may reveal previously overlooked, important pathways. Here, we review the findings that have emerged from proteomics studies of hibernation. One striking feature is the stability of the proteome, especially across the extreme physiological shifts of torpor-arousal cycles during hibernation. This has led to subsequent investigations of the role of post-translational protein modifications in altering protein activity without energetically wasteful removal and rebuilding of protein pools. Another unexpected finding is the paucity of universal proteomic adjustments across organ systems in response to the extreme metabolic fluctuations despite the universality of their physiological challenges; rather each organ appears to respond in a unique, tissue-specific manner. Additional research is needed to extend and synthesize these results before it will be possible to address the whole body physiology of hibernation. C1 [Grabek, Katharine R.; Martin, Sandra L.; Hindle, Allyson G.] Univ Colorado, Sch Med, Dept Cell & Dev Biol, Aurora, CO 80045 USA. [Grabek, Katharine R.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Hindle, Allyson G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Martin, SL (reprint author), Univ Colorado, Sch Med, Dept Cell & Dev Biol, Aurora, CO 80045 USA. EM sandy.martin@ucdenver.edu NR 113 TC 6 Z9 6 U1 13 U2 43 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0174-1578 EI 1432-136X J9 J COMP PHYSIOL B JI J. Comp. Physiol. B-Biochem. Syst. Environ. Physiol. PD AUG PY 2015 VL 185 IS 6 BP 607 EP 627 DI 10.1007/s00360-015-0905-9 PG 21 WC Physiology; Zoology SC Physiology; Zoology GA CN0FK UT WOS:000358089300002 PM 25976608 ER PT J AU Ceppa, EP McCurdy, RM Becerra, DC Kilbane, EM Zyromski, NJ Nakeeb, A Schmidt, CM Lillemoe, KD Pitt, HA House, MG AF Ceppa, Eugene P. McCurdy, Robert M. Becerra, David C. Kilbane, E. Molly Zyromski, Nicholas J. Nakeeb, Attila Schmidt, C. Max Lillemoe, Keith D. Pitt, Henry A. House, Michael G. TI Does Pancreatic Stump Closure Method Influence Distal Pancreatectomy Outcomes? SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE ACS-NSQIP; Distal pancreatectomy; Pancreatic fistula; Saline-linked radiofrequency; Stump closure ID RANDOMIZED-CONTROLLED-TRIAL; INTERNATIONAL STUDY-GROUP; FISTULA; SURGERY; RISK; METAANALYSIS; TRANSECTION; RESECTION; REMNANT; QUALITY AB Pancreatic fistula remains the primary source of morbidity following distal pancreatectomy. Previous studies have reported specific methods of parenchymal transection/stump sealing in an effort to decrease the pancreatic fistula rate with highly variable results. The aim of this study was to determine postoperative outcomes following various pancreatic stump-sealing methods. All cases of distal pancreatectomy were reviewed at a single institution between January 2008 and June 2011 and were monitored with complete 30-day outcomes through ACS-NSQIP. Pancreatic stump-sealing method was used to create three operation groups (suture, staple, or saline-linked radiofrequency). Two- and three-way statistical analyses were performed among the operation groups. Two hundred three patients underwent distal pancreatectomy. The most common diagnoses included chronic pancreatitis, adenocarcinoma, and IPMN. The suture, staple, and SLRF groups included 90 (44 %), 61 (30 %), and 52 (26 %) patients, respectively. Overall complications (range 31-38 %) and pancreatic fistula (range 25-26 %) were similar with each pancreatic closure technique. Operative technique was not associated with an increased need for postoperative interventions or hospital readmission. Postoperative outcomes after distal pancreatectomy are unaffected by the use of SLRF sealing of the pancreatic stump when compared to traditional suture or reinforced stapling techniques. C1 [Ceppa, Eugene P.; McCurdy, Robert M.; Becerra, David C.; Kilbane, E. Molly; Zyromski, Nicholas J.; Nakeeb, Attila; Schmidt, C. Max; House, Michael G.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA. [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Pitt, Henry A.] Temple Univ, Sch Med, Dept Surg, Philadelphia, PA 19122 USA. RP Ceppa, EP (reprint author), Indiana Univ Sch Med, Dept Surg, 545 Barnhill Dr,EH 541, Indianapolis, IN 46202 USA. EM eceppa@iupui.edu NR 26 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD AUG PY 2015 VL 19 IS 8 BP 1449 EP 1456 DI 10.1007/s11605-015-2825-0 PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CM9SB UT WOS:000358048200009 PM 25903852 ER PT J AU Amri, R Bordeianou, LG Sylla, P Berger, DL AF Amri, Ramzi Bordeianou, Liliana G. Sylla, Patricia Berger, David L. TI Variations in Metastasis Site by Primary Location in Colon Cancer SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Colon cancer; Metastasis site; Metastatic patterns; Outcomes; Primary disease site ID COLORECTAL-CANCER; PATTERNS AB The purpose of this paper is to determine whether sites of distant recurrence are associated with specific locations of primary disease in colon cancer. A cohort including all patients (n = 947) undergoing a segmental colonic resection for colon cancer at our center (2004-2011) comparing site-specific metastatic presentation and recurrence rates, as well as their respective multivariable American Joint Committee on Cancer (AJCC) stage-adjusted hazard ratios (mHR). Right-sided colectomies (n = 557) had a lower overall metastasis rate (24.8 % vs. 31.8 %; P = 0.017; mHR = 1.24 [95% CI: 0.96-1.60]; P = 0.011) due to significantly lower pulmonary metastasis in follow-up (2.7 % vs. 9 %; P < 0.001; mHR = 0.32 [95% CI: 0.17-0.58]; P = 0.001) and lower overall liver metastasis rate (15.6 vs. 22.1 %; P = 0.012; mHR = 0.74 [95% CI: 0.55-0.99];P = 0.050). Left colectomies (n = 127) had higher rates of liver metastasis during follow-up (9.4 % vs. 4.8 %; P = 0.029; mHR = 1.64 [95% CI: 0.86-3.15]; P = 0.134). Sigmoid resections (n = 238) had higher baseline rates of liver metastasis (17.1 % vs. 11.3 %; P = 0.015) and higher cumulative rates of lung (12.2 % vs. 5.4 %; P < 0.001; mHR = 2.26 [95 % CI: 1.41-3.63]; P = 0.001) and brain metastases (2.3 % vs. 0.6 %; P = 0.033; mHR = 4.03 [95% CI: 1.14-14.3]; P = 0.031). Other sites of metastasis, including the (retro) peritoneum, omentum, ovary, and bone, did not yield significant differences. Important variations in site-specific rates of metastatic disease exist within major resection regions of colon cancer. These variations may be important to consider when evaluating options for adjuvant treatment and surveillance after resection of the primary disease. C1 [Amri, Ramzi; Bordeianou, Liliana G.; Berger, David L.] Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Boston, MA 02114 USA. [Amri, Ramzi; Bordeianou, Liliana G.; Berger, David L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Sylla, Patricia] Mt Sinai Hosp, Dept Colon & Rectal Surg, Icahn Sch Med, New York, NY 10029 USA. RP Berger, DL (reprint author), Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, 15 Parkman St, Boston, MA 02114 USA. EM dberger@partners.org OI Amri, Ramzi/0000-0001-7416-6650 FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (Harvard University and its affiliated academic health care centers) FX This work was conducted with support from the 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 8UL1TR000170-05, and financial contributions from the Harvard University and its affiliated academic health care 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 health care centers, or the National Institutes of Health. NR 12 TC 4 Z9 5 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD AUG PY 2015 VL 19 IS 8 BP 1522 EP 1527 DI 10.1007/s11605-015-2837-9 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CM9SB UT WOS:000358048200016 PM 25933582 ER PT J AU Macht, R Sheldon, HK Fisichella, PM AF Macht, Ryan Sheldon, Holly K. Fisichella, P. Marco TI Giant Colonic Diverticulum: a Rare Diagnostic and Therapeutic Challenge of Diverticular Disease SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Editorial Material DE Giant colonic diverticulum; Diverticular disease; Diverticulectomy AB A giant colonic diverticulum is a diverticulum of the colon greater than 4 cm in diameter that can present, albeit rarely, as a complication of diverticular disease. We discuss the three different histologic subtypes that have been described and the challenges in the diagnosis and treatment. C1 [Macht, Ryan; Sheldon, Holly K.; Fisichella, P. Marco] Boston VA Healthcare Syst, Boston Med Ctr, Dept Surg, Boston, MA 02132 USA. [Macht, Ryan; Sheldon, Holly K.; Fisichella, P. Marco] Harvard Univ, Sch Med, Boston, MA 02132 USA. RP Fisichella, PM (reprint author), Boston VA Healthcare Syst, Boston Med Ctr, Dept Surg, 1400 VFW Pkwy West Roxbury, Boston, MA 02132 USA. EM Marco6370@yahoo.com NR 8 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD AUG PY 2015 VL 19 IS 8 BP 1559 EP 1560 DI 10.1007/s11605-015-2773-8 PG 2 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CM9SB UT WOS:000358048200021 PM 25681218 ER PT J AU Kaiser, AM Hogen, R Bordeianou, L Alavi, K Wise, PE Sudan, R AF Kaiser, Andreas M. Hogen, Rachel Bordeianou, Liliana Alavi, Karim Wise, Paul E. Sudan, Ranjan CA SSAT TI Clostridium Difficile Infection from a Surgical Perspective (vol 19, pg 1363, 2015) SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Correction C1 [Kaiser, Andreas M.; Hogen, Rachel] Univ So Calif, Keck Sch Med, Div Colorectal Surg, Dept Surg, Los Angeles, CA 90033 USA. [Bordeianou, Liliana] Massachusetts Gen Hosp, Dept Surg, Colorectal Surg Program, Boston, MA 02114 USA. [Alavi, Karim] Univ Massachusetts, Mem Med Ctr, Dept Surg, Worcester, MA 01605 USA. [Wise, Paul E.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Sudan, Ranjan] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Kaiser, AM (reprint author), Univ So Calif, Keck Sch Med, Div Colorectal Surg, Dept Surg, 1441 Eastlake Ave,Suite 7418, Los Angeles, CA 90033 USA. EM akaiser@usc.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD AUG PY 2015 VL 19 IS 8 BP 1563 EP 1563 DI 10.1007/s11605-015-2863-7 PG 1 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CM9SB UT WOS:000358048200023 PM 26037139 ER PT J AU Ma, JT Fox, CS Jacques, PF Speliotes, EK Hoffmann, U Smith, CE Saltzman, E McKeown, NM AF Ma, Jiantao Fox, Caroline S. Jacques, Paul F. Speliotes, Elizabeth K. Hoffmann, Udo Smith, Caren E. Saltzman, Edward McKeown, Nicola M. TI Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts SO JOURNAL OF HEPATOLOGY LA English DT Article DE Sugar-sweetened beverages; Diet soda; Alanine transaminase; Fatty liver disease ID FOOD FREQUENCY QUESTIONNAIRE; VISCERAL FAT; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; AMINOTRANSFERASE LEVELS; COMPUTED-TOMOGRAPHY; INSULIN-RESISTANCE; UNITED-STATES; PPAR-ALPHA; FRUCTOSE AB Background & Aims: Non-alcoholic fatty liver disease affects similar to 30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods: Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and P1 serving/day) of sugar-sweetened beverages or diet soda. Results: After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. Conclusion: In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Ma, Jiantao; Jacques, Paul F.; Smith, Caren E.; Saltzman, Edward; McKeown, Nicola M.] Tufts Univ, USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Speliotes, Elizabeth K.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP McKeown, NM (reprint author), Tufts Univ, Jean Mayer USDA HNRCA, 711 Washington St, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU NIH/NHLBI's Framingham Heart Study [N01-HC-25195]; Boston University School of Medicine; United States Department of Agriculture, Agricultural Research Service (USDA) [58-1950-0-014]; NIH [HL112845] FX This project has been funded by the NIH/NHLBI's Framingham Heart Study (Contract N01-HC-25195); the Boston University School of Medicine; and the United States Department of Agriculture, Agricultural Research Service (USDA Agreement No. 58-1950-0-014). C.E.S was supported by the NIH K08 award (HL112845). NR 47 TC 17 Z9 17 U1 2 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2015 VL 63 IS 2 BP 462 EP 469 DI 10.1016/j.jhep.2015.03.032 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM8YX UT WOS:000357991700024 PM 26055949 ER PT J AU Mellinger, JL Pencina, KM Massaro, JM Hoffmann, U Seshadri, S Fox, CS O'Donnell, CJ Speliotes, EK AF Mellinger, Jessica L. Pencina, Karol M. Massaro, Joseph M. Hoffmann, Udo Seshadri, Sudha Fox, Caroline S. O'Donnell, Christopher J. Speliotes, Elizabeth K. TI Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study SO JOURNAL OF HEPATOLOGY LA English DT Article DE Fatty liver; Abdominal aortic calcium; Coronary artery calcium; Cardiovascular disease ID NONALCOHOLIC FATTY LIVER; CORONARY-ARTERY CALCIUM; TYPE-2 DIABETIC-PATIENTS; COMPUTED-TOMOGRAPHY; ADIPOSE-TISSUE; INSULIN-RESISTANCE; RISK-FACTORS; EVENTS; PREDICTOR; COHORT AB Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and is associated with development of metabolic disease including atherosclerotic cardiovascular disease (CVD). Our aim is to examine the association of hepatic steatosis with prevalent clinical and subclinical CVD outcomes in a large community-based sample, the Framingham Heart Study. Methods: Hepatic steatosis was measured in 3529 participants using multidetector computed tomography scanning. Multivariable logistic regression was used to determine whether hepatic steatosis is associated with prevalent CVD adjusted for covariates. We also tested whether associations were independent of other metabolic diseases/traits. The primary clinical outcome was composite prevalent clinical CVD defined by prior non-fatal myocardial infarction, stroke, transient ischemic attack, heart failure, or peripheral arterial disease. Subclinical cardiovascular outcomes were coronary artery calcium (CAC) and abdominal artery calcium (AAC). Results: 3014 participants were included (50.5% women). There was a non-significant association of hepatic steatosis with clinical CVD (OR 1.14 [p = 0.07]). Hepatic steatosis was associated with both CAC and AAC (OR 1.20 [p < 0.001] and OR 1.16 [p < 0.001], respectively). Associations persisted for CAC even when controlling for other risk factors/metabolic diseases, but for AAC, the associations became non-significant after adjustment for visceral adipose tissue. The association between hepatic steatosis and AAC was stronger in men than in women (p sex interaction = 0.022). Conclusion: There was a significant association of hepatic steatosis with subclinical CVD outcomes independent of many metabolic diseases/traits with a trend towards association between hepatic steatosis and clinical CVD outcomes. The association with AAC was stronger in men than in women. (C) 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Mellinger, Jessica L.; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Pencina, Karol M.] Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Stat, Boston, MA 02215 USA. [Hoffmann, Udo; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Dept Radiol, Boston, MA 02115 USA. [Seshadri, Sudha] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Seshadri, Sudha; Fox, Caroline S.; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Speliotes, EK (reprint author), Univ Michigan Hlth Syst, Div Gastroenterol & Hepatol, Taubman Ctr 3912, 1500 E Med Ctr Dr,SPC 5362, Ann Arbor, MI 48109 USA. EM espeliot@med.umich.edu OI Seshadri, Sudha/0000-0001-6135-2622 FU National Institutes of Health [K23DK080145-01]; Doris Duke Medical Foundation; University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [AG08122, AG033193]; [T32DK062708] FX JLM is supported by a T32DK062708 educational grant. EKS was supported by National Institutes of Health grant K23DK080145-01, the Doris Duke Medical Foundation, and the University of Michigan Internal Medicine Department, Division of Gastroenterology, and Biological Sciences Scholars Program. SS was supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (AG08122, AG033193). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, the NHLBI or the NIH. NR 34 TC 27 Z9 27 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2015 VL 63 IS 2 BP 470 EP 476 DI 10.1016/j.jhep.2015.02.045 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM8YX UT WOS:000357991700025 PM 25776891 ER PT J AU Fridman, V Bundy, B Reilly, MM Pareyson, D Bacon, C Burns, J Day, J Feely, S Finkel, RS Grider, T Kirk, CA Herrmann, DN Laura, M Li, J Lloyd, T Sumner, CJ Muntoni, F Piscosquito, G Ramchandren, S Shy, R Siskind, CE Yum, SW Moroni, I Pagliano, E Zuchner, S Scherer, SS Shy, ME AF Fridman, V. Bundy, B. Reilly, M. M. Pareyson, D. Bacon, C. Burns, J. Day, J. Feely, S. Finkel, R. S. Grider, T. Kirk, C. A. Herrmann, D. N. Laura, M. Li, J. Lloyd, T. Sumner, C. J. Muntoni, F. Piscosquito, G. Ramchandren, S. Shy, R. Siskind, C. E. Yum, S. W. Moroni, I. Pagliano, E. Zuchner, S. Scherer, S. S. Shy, M. E. CA Inherited Neuropathies Consortium TI CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID CHARCOT-MARIE-TOOTH; GENETIC SUBTYPES; DUPLICATION; DISABILITY; MUTATIONS; 1A; RELIABILITY; POPULATION; VALIDATION; PHENOTYPES AB Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1 AIPMP22 duplication, CMT1X/G./81 mutation, CMT2A/MFN2 mutation, CMT1 BIMPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. C1 [Fridman, V.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bundy, B.; Kirk, C. A.] Univ S Florida, Epidemiol Ctr, Tampa, FL USA. [Reilly, M. M.; Laura, M.] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. [Pareyson, D.; Piscosquito, G.; Moroni, I.; Pagliano, E.] IRCCS Fdn, Carlo Besta Neurol Inst, Dept Neurol, Milan, Italy. [Bacon, C.; Feely, S.; Grider, T.; Shy, R.; Shy, M. E.] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. [Burns, J.] Univ Sydney, Dept Neurol, Sydney, NSW 2006, Australia. [Burns, J.] Childrens Hosp, Dept Neurol, Sydney, NSW, Australia. [Day, J.; Siskind, C. E.] Stanford Univ, Dept Neurol, Stanford, CA 94305 USA. [Feely, S.; Ramchandren, S.; Shy, R.; Shy, M. E.] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Finkel, R. S.] Nemours Childrens Hosp, Dept Neurol, Orlando, FL USA. [Herrmann, D. N.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Li, J.] Vanderbilt Univ, Dept Neurol, Nashville, TN 37235 USA. [Lloyd, T.; Sumner, C. J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD USA. [Muntoni, F.] UCL Inst Child Hlth, Dept Neurol, London, England. [Muntoni, F.] Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England. [Ramchandren, S.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Yum, S. W.] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. [Yum, S. W.; Scherer, S. S.] Hosp Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Zuchner, S.] Univ Miami, Ctr Human Mol Genom, Dept Neurol, Miami, FL USA. RP Fridman, V (reprint author), 165 Cambridge St, Boston, MA 02114 USA. EM vfridman@partners.org OI piscosquito, giuseppe/0000-0001-6768-8936 FU National Institutes of Neurological Diseases and Stroke (NINDS) [U54N5065712]; NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Sciences (NCATS); Muscular Dystrophy Association (MDA); Charcot Marie Tooth Association (CMTA); NINDS [R01 NS066927]; Vanderbilt Institute for Clinical and Translational Research fund [VR1687]; Department of Health's National Institute for Health Research Biomedical Research Centres FX Funding and/or programmatic support for this project has been provided by U54N5065712 from the National Institutes of Neurological Diseases and Stroke (NINDS) and the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Sciences (NCATS). The INC also receives support from the Muscular Dystrophy Association (MDA) and the Charcot Marie Tooth Association (CMTA). Additional support for this study includes the NINDS grant R01 NS066927 and Vanderbilt Institute for Clinical and Translational Research fund VR1687 to JL. Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. NR 30 TC 28 Z9 28 U1 2 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD AUG PY 2015 VL 86 IS 8 BP 873 EP 878 DI 10.1136/jnnp-2014-308826 PG 6 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA CM7ON UT WOS:000357884300009 PM 25430934 ER PT J AU Reagan, JL Sullivan, MR Winer, ES Lansigan, F Cardin, MS Castillo, JJ AF Reagan, John L. Sullivan, Matthew R. Winer, Eric S. Lansigan, Frederick Cardin, Michael S. Castillo, Jorge J. TI Potential for improved survival with intensification of daunorubicin based induction chemotherapy in acute myeloid leukemia patients who do not receive transplant: A multicenter retrospective study SO LEUKEMIA RESEARCH LA English DT Article DE Acute myeloid leukemia; Acute myeloid leukemia therapy; Chemotherapy; Leukemia ID ANTHRACYCLINE DOSE INTENSIFICATION; ACUTE MYELOGENOUS LEUKEMIA; CYTOSINE-ARABINOSIDE; ONCOLOGY-GROUP; THERAPY; STANDARD; OUTCOMES; YOUNGER; ADULTS; AGE AB Introduction: During induction daunorubicin intensification from 45 mg/m(2)/day to 90 mg/m(2)/day has shown improved response and survival rates in AML patients. We retrospectively reviewed outcomes of daunorubicin 60 mg/m(2)/day (DNR60) versus daunorubicin 90 mg/m(2)/day (DNR90) in adult AML patients. Material and methods: Newly diagnosed AML patients >= 18 years who received 7 + 3 with or without etoposide as frontline therapy from 11112006 to 51112013 were identified. Chi-square and Wilcoxon rank sum tests were used to compare characteristics. Kaplan-Meier curves were estimated for overall survival ( OS). Univariate and multivariate Cox proportional hazard regression models were developed to determine independent predictors for survival. Results: A total of 128 patients were included (DNR90 = 48 patients, DNR60 = 80 patients). The estimated 3-year OS rate in the DNR90 group was 56% (95% CI 38-70%), while in the DNR60 group was 34% (95% CI 23-44%). Multivariate analysis (MVA) in non-allotransplanted patients showed that unfavorable cytogenetics and worse performance status were associated with decreased OS while DNR intensification, etoposide use and site were associated with improved OS. In MVA of allotransplanted patients re-induction based on day-14 marrow was associated with worse OS. Conclusions: Based on our retrospective study, initial DNR based induction chemotherapy intensification improved OS in non-allotransplanted patients. Prospective studies are needed to confirm this preliminary finding. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Reagan, John L.; Winer, Eric S.] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Hematol & Oncol, Providence, RI 02903 USA. [Sullivan, Matthew R.; Lansigan, Frederick] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Div Hematol & Oncol, Lebanon, NH 03766 USA. [Cardin, Michael S.] Rhode Isl Hosp, Ctr Comprehens Canc, Div Pharm, Providence, RI USA. [Castillo, Jorge J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Reagan, JL (reprint author), Rhode Isl Hosp, George 3, Providence, RI 02903 USA. EM jreagan@lifespan.org OI Sullivan, Matthew/0000-0002-5112-7621; Castillo, Jorge/0000-0001-9490-7532 FU Leukemia & Lymphoma Society Special Fellow in Clinical Research [CDA 4298-14] FX JLR is supported by a Leukemia & Lymphoma Society Special Fellow in Clinical Research Grant Number CDA 4298-14. The authors report no other conflicts of interest. NR 21 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2015 VL 39 IS 8 BP 812 EP 817 DI 10.1016/j.leukres.2015.04.015 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA CM9FJ UT WOS:000358012500003 PM 26045177 ER PT J AU Caocci, G Voso, MT Angelucci, E Stauder, R Cottone, F Abel, G Nguyen, K Platzbecker, U Beyne-Rauzy, O Gaidano, G Invernizzi, R Molica, S Criscuolo, M Breccia, M Lubbert, M Sanpaolo, G Buccisano, F Ricco, A Palumbo, GA Niscola, P Zhang, H Fenu, S La Nasa, G Mandelli, F Efficace, F AF Caocci, G. Voso, M. T. Angelucci, E. Stauder, R. Cottone, F. Abel, G. Nguyen, K. Platzbecker, U. Beyne-Rauzy, O. Gaidano, G. Invernizzi, R. Molica, S. Criscuolo, M. Breccia, M. Luebbert, M. Sanpaolo, G. Buccisano, F. Ricco, A. Palumbo, G. A. Niscola, P. Zhang, H. Fenu, S. La Nasa, G. Mandelli, F. Efficace, F. TI Accuracy of physician assessment of treatment preferences and health status in elderly patients with higher-risk myelodysplastic syndromes SO LEUKEMIA RESEARCH LA English DT Article DE Health status; Decision making; Myelodysplastic syndromes; Cancer; Oncology; Hematology ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; SHARED DECISION-MAKING; ONCOLOGY PRACTICE; CANCER-PATIENTS; SYNDROMES MDS; CARE; COMMUNICATION; ORGANIZATION; INFORMATION AB Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Control Preference Scale. Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring anactive or collaborative role. Absence of the patient's request for prognostic information (P = 0.001) and judging the patient as having a poor health status (P = 0.036) were factors independently associated with the physicians' attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate healthstatus of patients who reported low-level health status. The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Caocci, G.; La Nasa, G.] Univ Cagliari, Dept Internal Med, Hematol Unit, Cagliari, Italy. [Voso, M. T.; Criscuolo, M.] Univ Rome Cattol S Cuore, Dept Hematol, Rome, Italy. [Angelucci, E.] A Businco Hosp, Dept Hematol, Cagliari, Italy. [Stauder, R.] Med Univ Innsbruck, Dept Internal Med Hematol & Oncol 5, A-6020 Innsbruck, Austria. [Cottone, F.] Italian Grp Adult Hematol Dis GIMEMA, Data Ctr & Hlth Outcomes Res Unit, Rome, Italy. [Abel, G.; Mandelli, F.; Efficace, F.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [Nguyen, K.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Platzbecker, U.] Univ Hosp Dresden Carl Gustav Carus, Dept Med 1, Dresden, Germany. [Beyne-Rauzy, O.] CHU Toulouse Purpan, Dept Internal Med, F-31059 Toulouse, France. [Gaidano, G.] Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy. [Invernizzi, R.] Univ Pavia IRCCS, Policlin San Matteo Fdn, Dept Internal Med, Pavia, Italy. [Molica, S.] Pugliese Ciaccio Hosp Ctr, Dept Oncol Hematol, Catanzaro, Italy. [Breccia, M.] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, I-00185 Rome, Italy. [Luebbert, M.] Univ Freiburg, Med Ctr, Freiburg, Germany. [Sanpaolo, G.] IRCCS Casa Sollievo Sofferenza, Dept Hematol, San Giovanni Rotondo, Italy. [Sanpaolo, G.] IRCCS Casa Sollievo Sofferenza, Stem Cell Transplantat Unit, San Giovanni Rotondo, Italy. [Buccisano, F.] Univ Roma Tor Vergata, Dept Hematol, Rome, Italy. [Ricco, A.] Univ Bari, Hematol Sect, Dept Emergency & Organ Transplantat, Bari, Italy. [Palumbo, G. A.] AOU Policlin V Emanuele, UO Ematol, Catania, Italy. [Niscola, P.] S Eugenio Hosp, Dept Hematol, Rome, Italy. [Zhang, H.] Liaoning Univ Tradit Chinese Med, Affiliated Hosp, Dept Hematol, Shenyang, Peoples R China. [Fenu, S.] S Giovanni Addolorata Hosp, Dept Hematol, Rome, Italy. RP Efficace, F (reprint author), GIMEMA Data Ctr, Italian Grp Adult Hematol Dis GIMEMA, Hlth Outcomes Res Unit, Via Benevento 6, I-00161 Rome, Italy. RI Cottone, Francesco/M-3465-2014; OI Cottone, Francesco/0000-0001-6240-8317; Angelucci, Emanuele/0000-0002-6512-6080; La Nasa, Giorgio/0000-0002-8247-583X; Buccisano, Francesco/0000-0003-4320-9253; Caocci, Giovanni/0000-0002-6585-5187; VOSO, Maria Teresa/0000-0002-6164-4761 FU Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL); Italian Group for Adult Hematologic Diseases (GIMEMA) FX This study was funded by the "Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL)" and by the "Italian Group for Adult Hematologic Diseases (GIMEMA)". NR 29 TC 2 Z9 2 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2015 VL 39 IS 8 BP 859 EP 865 DI 10.1016/j.leukres.2015.05.012 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA CM9FJ UT WOS:000358012500011 PM 26120100 ER PT J AU Ackerman, KE Sokoloff, NC Maffazioli, GD Clarke, HM Lee, H Misra, M AF Ackerman, Kathryn E. Sokoloff, Natalia Cano Maffazioli, Giovana De Nardo Clarke, Hannah M. Lee, Hang Misra, Madhusmita TI Fractures in Relation to Menstrual Status and Bone Parameters in Young Athletes SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article ID QUANTITATIVE COMPUTED-TOMOGRAPHY; VIVO HR-PQCT; DISTAL RADIUS; STRESS-FRACTURES; MINERAL DENSITY; RISK-FACTORS; POSTMENOPAUSAL WOMEN; ADOLESCENT GIRLS; FAILURE LOAD; MICROARCHITECTURE AB Introduction This study was aimed to compare fracture prevalence in oligoamenorrheic athletes (AA), eumenorrheic athletes (EA), and nonathletes (NA) and determine relationships with bone density, structure, and strength estimates. Methods One hundred seventy-five females (100 AA, 35 EA, and 40 NA) 14-25 yr old were studied. Lifetime fracture history was obtained through participant interviews. Areal bone mineral density (BMD) was assessed by DXA at the spine, hip, and whole body (WB). Bone structure was assessed by HRpQCT at the radius and tibia, and strength by finite element analysis. Results AA, EA, and NA did not differ in age, sexual maturity, or height. AA had lower BMI, and older menarchal age than EA and NA (P <= 0.001). Bone mineral density Z-scores were lower in AA versus EA at the total hip, femoral neck, spine, and whole body (P <= 0.001). Lifetime fracture risk was higher in AA than EA and NA (47%, 25.7%, 12.5%; P <= 0.001), largely driven by stress fractures in AA versus EA and NA (32% vs 5.9% vs 0%). In AA, those who fractured had lower lumbar and WB BMD Z-scores, volumetric BMD (vBMD) of outer trabecular region in radius and tibia, and trabecular thickness of the radius (P <= 0.05). In AA, those who had two or more stress fractures had lower lumbar and WB BMD Z-scores, total cross-sectional area, trabecular vBMD, stiffness, and failure load at radius; and lower stiffness and failure load at tibia versus those with fewer than two stress fractures (P <= 0.05). Conclusion Weight-bearing athletic activity increases BMD but may increase stress fracture risk in those with menstrual dysfunction. Bone microarchitecture and strength differences are more pronounced in AA with multiple stress fractures. This is the first study to examine fractures in relation to bone structure in adolescent female athletes. C1 [Ackerman, Kathryn E.; Sokoloff, Natalia Cano; Maffazioli, Giovana De Nardo; Clarke, Hannah M.; Misra, Madhusmita] Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kathryn E.; Sokoloff, Natalia Cano; Maffazioli, Giovana De Nardo; Clarke, Hannah M.; Lee, Hang; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [Ackerman, Kathryn E.] Boston Childrens Hosp, Dept Orthoped, Div Sports Med, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp, Dept Pediat, Pediatr Endocrine Unit, Boston, MA 02114 USA. RP Ackerman, KE (reprint author), Massachusetts Gen Hosp, 55 Fruit St,BUL 457 Neuroendocrine Unit, Boston, MA 02114 USA. EM Kathryn.ackerman@childrens.harvard.edu OI Cano Sokoloff, Natalia/0000-0002-4840-5686 FU National Institutes of Health [1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD060827-01A1, K24 HD071843] FX This work was supported by National Institutes of Health grants 1 UL1 RR025758-01, 1UL1TR001102-01, 1 R01 HD060827-01A1, and K24 HD071843. NR 56 TC 4 Z9 4 U1 5 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD AUG PY 2015 VL 47 IS 8 BP 1577 EP 1586 DI 10.1249/MSS.0000000000000574 PG 10 WC Sport Sciences SC Sport Sciences GA CM8IF UT WOS:000357942200004 PM 25397605 ER PT J AU Cortes-Briones, J Skosnik, PD Mathalon, D Cahill, J Pittman, B Williams, A Sewell, RA Ranganathan, M Roach, B Ford, J D'Souza, DC AF Cortes-Briones, Jose Skosnik, Patrick D. Mathalon, Daniel Cahill, John Pittman, Brian Williams, Ashley Sewell, R. Andrew Ranganathan, Mohini Roach, Brian Ford, Judith D'Souza, Deepak Cyril TI Delta(9)-THC Disrupts Gamma (gamma)-Band Neural Oscillations in Humans SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID LONGITUDINAL DATA-ANALYSIS; CANNABINOID CB1 RECEPTOR; BASKET CELLS; GABAERGIC INTERNEURONS; GLUTAMATERGIC NEURONS; NETWORK OSCILLATIONS; STEADY-STATE; SCHIZOPHRENIA; HIPPOCAMPUS; CHOLECYSTOKININ AB Gamma (gamma)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt gamma-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Delta-9-tetrahydrocannabinol (Delta(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Delta(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Delta(9)-THC (0.03 mg/kg) reduced intertrialcoherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Delta(9)-THC. Delta(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Delta(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt gamma-band neural oscillations. Furthermore, there is a relationship between disruption of gamma-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders. C1 [Cortes-Briones, Jose; Skosnik, Patrick D.; Cahill, John; Williams, Ashley; Sewell, R. Andrew; Ranganathan, Mohini; D'Souza, Deepak Cyril] VA Connecticut Healthcare Syst, Psychiat Serv, West Haven, CT 06516 USA. [Cortes-Briones, Jose; Skosnik, Patrick D.; Mathalon, Daniel; Cahill, John; Pittman, Brian; Sewell, R. Andrew; Ranganathan, Mohini; Ford, Judith; D'Souza, Deepak Cyril] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Skosnik, Patrick D.; Cahill, John; Pittman, Brian; Williams, Ashley; Sewell, R. Andrew; Ranganathan, Mohini; D'Souza, Deepak Cyril] Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, New Haven, CT USA. [Mathalon, Daniel; Roach, Brian; Ford, Judith] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel; Roach, Brian; Ford, Judith] San Francisco VA Med Ctr, Mental Hlth Serv Line, San Francisco, CA USA. RP D'Souza, DC (reprint author), VA Connecticut Healthcare Syst, Psychiat Serv, 950 Campbell Ave, West Haven, CT 06516 USA. EM deepak.dsouza@yale.edu RI Skosnik, Patrick/D-6466-2016 FU Yale University School of Medicine from AbbVie; Pfizer FX Jose Cortes-Briones, Patrick Skosnik, John Cahill, Ashley Williams, Brian Roach, Mohini Ranganathan, and R Andrew Sewell (deceased) declare no conflict of interest. Deepak Cyril D'Souza has in the past 3 years or currently receives research grant support administered through Yale University School of Medicine from AbbVie and Pfizer, and is a consultant for Bristol-Myers Squibb and Johnson and Johnson. Dr Mathalon is a consultant for Bristol-Myers Squibb, and Amgen. NR 79 TC 4 Z9 4 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2015 VL 40 IS 9 BP 2124 EP 2134 DI 10.1038/npp.2015.53 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CM8OY UT WOS:000357962700009 PM 25709097 ER PT J AU Foust-Wright, C Pulliam, S Batalden, R Berk, T Weinstein, M Wakamatsu, M Phillippe, M AF Foust-Wright, C. Pulliam, S. Batalden, R. Berk, T. Weinstein, M. Wakamatsu, M. Phillippe, M. TI HORMONE MODULATION OF TOLL-LIKE RECEPTOR 5 IN CULTURED HUMAN BLADDER EPITHELIAL CELLS SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Continence-Society (ICS) CY OCT 06-09, 2015 CL Montreal, CANADA SP Int Continence Soc ID MENSTRUAL-CYCLE C1 [Foust-Wright, C.; Pulliam, S.; Batalden, R.; Berk, T.; Weinstein, M.; Wakamatsu, M.; Phillippe, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2015 VL 34 SU 3 MA 467 BP S369 EP S371 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA CM2QY UT WOS:000357528000269 ER PT J AU Liu, T Wang, Z Cristofaro, V Cao, H Sullivan, MP Olumi, AF AF Liu, T. Wang, Z. Cristofaro, V Cao, H. Sullivan, M. P. Olumi, A. F. TI DIABETIC BLADDER DYSFUNCTION IS ALTERED BY OBESITY SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Continence-Society (ICS) CY OCT 06-09, 2015 CL Montreal, CANADA SP Int Continence Soc C1 [Liu, T.; Cristofaro, V; Cao, H.; Sullivan, M. P.] Harvard Univ, Sch Med, Boston VA Helathcare Syst, Cambridge, MA 02138 USA. [Wang, Z.; Olumi, A. F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2015 VL 34 SU 3 MA 50 BP S86 EP S87 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CM2QY UT WOS:000357528000051 ER PT J AU Su, N Choi, H Yang, J Azadzoi, K AF Su, N. Choi, H. Yang, J. Azadzoi, K. TI CHRONIC ISCHEMIA ALTERS THE BLADDER PROTEOMIC PROFILES AND ACTIVATES DEGENERATIVE PATHWAYS AND SURVIVAL SIGNALING SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Continence-Society (ICS) CY OCT 06-09, 2015 CL Montreal, CANADA SP Int Continence Soc C1 [Su, N.; Choi, H.; Yang, J.; Azadzoi, K.] VA Boston Healthcare Syst, Boston, MA USA. [Su, N.; Choi, H.; Yang, J.; Azadzoi, K.] Boston Univ, Sch Med, Boston, MA 02215 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2015 VL 34 SU 3 MA 464 BP S366 EP S367 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CM2QY UT WOS:000357528000266 ER PT J AU Zhao, Z Yang, J Li, Y Azadzoi, K AF Zhao, Z. Yang, J. Li, Y. Azadzoi, K. TI ISCHEMIA SURVIVAL SIGNALING VIA PI3-K/AKT PATHWAY MEDIATES OVERACTIVE BLADDER PROGRESSION TO UNDERACTIV BLADDER SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT 45th Annual Meeting of the International-Continence-Society (ICS) CY OCT 06-09, 2015 CL Montreal, CANADA SP Int Continence Soc C1 [Zhao, Z.; Yang, J.; Li, Y.; Azadzoi, K.] VA Boston Healthcare Syst, Boston, MA USA. [Zhao, Z.; Yang, J.; Li, Y.; Azadzoi, K.] Boston Univ Med Sch, Boston, MA USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2015 VL 34 SU 3 MA 465 BP S367 EP S368 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CM2QY UT WOS:000357528000267 ER PT J AU Lai, PS Hang, JQ Valeri, L Zhang, FY Zheng, BY Mehta, AJ Shi, J Su, L Brown, D Eisen, EA Christiani, DC AF Lai, Peggy S. Hang, Jing-qing Valeri, Linda Zhang, Feng-ying Zheng, Bu-Yong Mehta, Amar J. Shi, Jing Su, Li Brown, Dan Eisen, Ellen A. Christiani, David C. TI Endotoxin and gender modify lung function recovery after occupational organic dust exposure: a 30-year study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID COTTON TEXTILE WORKERS; OBSTRUCTIVE PULMONARY-DISEASE; RESPIRATORY HEALTH; PREDICTORS; MORTALITY; CESSATION; SHANGHAI; CHILDREN; INDUSTRY; MODELS AB Objectives The purpose of this study is to determine the trajectory of lung function change after exposure cessation to occupational organic dust exposure, and to identify factors that modify improvement. Methods The Shanghai Textile Worker Study is a longitudinal study of 447 cotton workers exposed to endotoxin-containing dust and 472 silk workers exposed to non-endotoxin-containing dust. Spirometry was performed at 5-year intervals. Air sampling was performed to estimate individual cumulative exposures. The effect of work cessation on forced expiratory volume in 1 s (FEV1) was modelled using generalised additive mixed effects models to identify the trajectory of FEV1 recovery. Linear mixed effects models incorporating interaction terms were used to identify modifiers of FEV1 recovery. Loss to follow-up was accounted for with inverse probability of censoring weights. Results 74.2% of the original cohort still alive participated in 2011. Generalised additive mixed models identified a non-linear improvement in FEV1 for all workers after exposure cessation, with no plateau noted 25 years after retirement. Linear mixed effects models incorporating interaction terms identified prior endotoxin exposure (p=0.01) and male gender (p=0.002) as risk factors for impaired FEV1 improvement after exposure cessation. After adjusting for gender, smoking delayed the onset of FEV1 gain but did not affect the overall magnitude of change. Conclusions Lung function improvement after cessation of exposure to organic dust is sustained. Endotoxin exposure and male gender are risk factors for less FEV1 improvement. C1 [Lai, Peggy S.; Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lai, Peggy S.; Valeri, Linda; Mehta, Amar J.; Su, Li; Eisen, Ellen A.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lai, Peggy S.; Christiani, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Hang, Jing-qing; Zhang, Feng-ying; Zheng, Bu-Yong] Shanghai Putuo Dist Peoples Hosp, Shanghai, Peoples R China. [Shi, Jing] China Inst Ind Relat, Beijing, Peoples R China. [Brown, Dan; Eisen, Ellen A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Lai, PS (reprint author), Massachusetts Gen Hosp, Pulm Crit Care Unit, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM pslai@hsph.harvard.edu FU National Institute of Occupational Safety and Health [NIOSH OH002421]; National Institute of Health [NIH-NIEHS K23ES023700, F32ES020082, ES00002] FX Funding was obtained from the National Institute of Occupational Safety and Health (NIOSH OH002421) and the National Institute of Health (NIH-NIEHS K23ES023700, F32ES020082 and ES00002). The study sponsors had no role in the study design, gathering, analysis and interpretation of data, or in writing of the manuscript. NR 40 TC 3 Z9 3 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 2015 VL 72 IS 8 BP 546 EP 552 DI 10.1136/oemed-2014-102579 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM9IB UT WOS:000358020600003 PM 25666844 ER PT J AU Buchy, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Heinssen, R Bearden, CE Mathalon, D Addington, J AF Buchy, L. Cadenhead, K. S. Cannon, T. D. Cornblatt, B. A. McGlashan, T. H. Perkins, D. O. Seidman, L. J. Tsuang, M. T. Walker, E. F. Woods, S. W. Heinssen, R. Bearden, C. E. Mathalon, D. Addington, J. TI Substance use in individuals at clinical high risk of psychosis SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Alcohol; cannabis; prodrome; substance use; tobacco ID ULTRA-HIGH-RISK; CANNABIS USE; 1ST-EPISODE PSYCHOSIS; ADULT PSYCHOSIS; SYMPTOMS; PEOPLE; IMPACT; DISORDERS; ONSET; ADOLESCENTS AB Background. A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. Method. At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. Results. CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. Conclusions. In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone. C1 [Buchy, L.; Addington, J.] Univ Calgary, Dept Psychiat, Calgary, AB T2N 4Z6, Canada. [Cadenhead, K. S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, T. D.; Tsuang, M. T.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Cornblatt, B. A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [McGlashan, T. H.; Woods, S. W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, D. O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, L. J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, L. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, E. F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, E. F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Heinssen, R.] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. [Bearden, C. E.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Bearden, C. E.] Univ Calif Los Angeles, Dept Biobehav Sci & Psychol, Los Angeles, CA USA. [Mathalon, D.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health (NIMH) [U01MH081984, U01 MH081928, P50 MH080272, SCDMH82101008006, R01 MH60720, U01 MH082022, K24 MH76191, U01MH081902, P50 MH066286, U01MH082004, U01MH081988, U01MH08022, UO1 MH081857-05] FX This study was supported by the National Institute of Mental Health (NIMH) [grant U01MH081984 to J.A.; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to L.J.S.; grants R01 MH60720, U01 MH082022 and K24 MH76191 to K.S.C.; grant U01MH081902 to T.D.C.; P50 MH066286 (Prodromal Core) to C.E.B.; grant U01MH082004 to D.O.P.; grant U01MH081988 to E.F.W.; grant U01MH08022 to S.W.W.; and UO1 MH081857-05 grant to B.A.C.]. The NIMH 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 38 TC 6 Z9 6 U1 7 U2 14 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 AUG PY 2015 VL 45 IS 11 BP 2275 EP 2284 DI 10.1017/S0033291715000227 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CM5PC UT WOS:000357739400004 PM 25727300 ER PT J AU Dillon, DG Wiecki, T Pechtel, P Webb, C Goer, F Murray, L Trivedi, M Fava, M McGrath, PJ Weissman, M Parsey, R Kurian, B Adams, P Carmody, T Weyandt, S Shores-Wilson, K Toups, M McInnis, M Oquendo, MA Cusin, C Deldin, P Bruder, G Pizzagalli, DA AF Dillon, D. G. Wiecki, T. Pechtel, P. Webb, C. Goer, F. Murray, L. Trivedi, M. Fava, M. McGrath, P. J. Weissman, M. Parsey, R. Kurian, B. Adams, P. Carmody, T. Weyandt, S. Shores-Wilson, K. Toups, M. McInnis, M. Oquendo, M. A. Cusin, C. Deldin, P. Bruder, G. Pizzagalli, D. A. TI A computational analysis of flanker interference in depression SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Cognitive control; computational modelling; depression; executive function; flanker ID HAMILTON PLEASURE SCALE; BASAL GANGLIA; NEUROCOMPUTATIONAL ACCOUNT; COGNITIVE DEFICITS; EXECUTIVE FUNCTION; MAJOR DEPRESSION; DIFFUSION-MODELS; DECISION-MAKING; RATING-SCALE; STROOP TASK AB Background. Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. Method. One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). Results. Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). Conclusions. Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression. C1 [Dillon, D. G.; Pechtel, P.; Webb, C.; Goer, F.; Murray, L.; Pizzagalli, D. A.] Harvard Univ, McLean Hosp, Sch Med, Ctr Depress Anxiety & Stress Res, Belmont, MA 02478 USA. [Wiecki, T.] Brown Univ, Dept Cognit Linguist & Psychol Sci, Providence, RI 02912 USA. [Trivedi, M.; Kurian, B.; Carmody, T.; Weyandt, S.; Shores-Wilson, K.; Toups, M.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Fava, M.; Cusin, C.] Massachusetts Gen Hosp, Clin Res Program, Boston, MA 02114 USA. [McGrath, P. J.; Weissman, M.; Adams, P.; Oquendo, M. A.; Bruder, G.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [McGrath, P. J.; Weissman, M.; Adams, P.; Oquendo, M. A.; Bruder, G.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Parsey, R.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. [Toups, M.; Deldin, P.] Univ Michigan Hlth Syst, Dept Psychiat, Ann Arbor, MI USA. RP Pizzagalli, DA (reprint author), McLean Hosp, Ctr Depress Anxiety & Stress Res, 115 Mill St, Belmont, MA 02478 USA. EM dap@mclean.harvard.edu RI Parsey, Ramin/J-8254-2014; OI Dillon, Daniel/0000-0002-1977-700X FU National Institute of Mental Health of the National Institutes of Health [U01MH092221, U01MH092250]; EMBARC National Coordinating Center at UT Southwestern Medical Center; Data Center at Columbia University; Data Center at Stony Brook University; NIMH [R00MH094438] FX The EMBARC study was supported by the National Institute of Mental Health of the National Institutes of Health under award numbers U01MH092221 (M. H. Trivedi,) and U01MH092250 (P. J. McGrath, R. V. Parsey, M. M. Weissman). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Valeant Pharmaceuticals donated the Wellbutrin XL used in the study. This work was supported by the EMBARC National Coordinating Center at UT Southwestern Medical Center (M. H. Trivedi, M.D., Coordinating PI), and the Data Center at Columbia and Stony Brook Universities. Dr Dillon was supported by NIMH grant R00MH094438. NR 57 TC 2 Z9 2 U1 2 U2 8 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 AUG PY 2015 VL 45 IS 11 BP 2333 EP 2344 DI 10.1017/S0033291715000276 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA CM5PC UT WOS:000357739400009 PM 25727375 ER PT J AU Venkat, A Hasegawa, K Basior, JM Crandall, C Healy, M Inboriboon, PC Sullivan, AF Camargo, CA AF Venkat, Arvind Hasegawa, Kohei Basior, Jeanne M. Crandall, Cameron Healy, Megan Inboriboon, P. Charles Sullivan, Ashley F. Camargo, Carlos A., Jr. TI Race/ethnicity and asthma management among adults presenting to the emergency department SO RESPIROLOGY LA English DT Article DE adults; asthma exacerbation; emergency department; quality of care; race; ethnicity ID AMERICAN AB We investigated whether racial/ethnic disparities exist in asthma management among 1785 adults requiring emergency department (ED) treatment. In this multicentre study, non-Hispanic blacks with increased chronic asthma severity were only as likely (P>0.05) as non-Hispanic whites or Hispanics to utilize controller medications or see asthma specialists before ED presentation and to be prescribed recommended inhaled corticosteroids at ED discharge. Improved ED education on evidence-based chronic disease management is needed to address continuing race/ethnicity-based asthma disparities. C1 [Venkat, Arvind] Allegheny Hlth Network, Dept Emergency Med, Pittsburgh, PA USA. [Healy, Megan] Temple Univ Hosp & Med Sch, Dept Emergency Med, Philadelphia, PA 19140 USA. [Hasegawa, Kohei; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Basior, Jeanne M.] SUNY Buffalo, Dept Emergency Med, Buffalo Gen Med Ctr, Buffalo, NY 14260 USA. [Crandall, Cameron] Univ New Mexico, Hlth Sci Ctr, Dept Emergency Med, Albuquerque, NM 87131 USA. [Inboriboon, P. Charles] Truman Med Ctr Hosp, Dept Emergency Med, Kansas City, MO USA. RP Venkat, A (reprint author), Allegheny Gen Hosp, Dept Emergency Med, 320 East North Ave, Pittsburgh, PA 15212 USA. EM avenkat@wpahs.org FU Novartis Pharmaceuticals Corporation FX We thank the MARC-36 study hospitals and research personnel for their ongoing dedication to asthma research (see Supplementary Table S2). The study is funded by a grant from Novartis Pharmaceuticals Corporation to Massachusetts General Hospital (PI: CAC). The sponsor had no role in the conduct of the study, nor in the collection, management or analysis of the data. NR 8 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD AUG PY 2015 VL 20 IS 6 BP 994 EP 997 DI 10.1111/resp.12572 PG 4 WC Respiratory System SC Respiratory System GA CM7MY UT WOS:000357879100022 PM 26081521 ER PT J AU Yu, T Sinha, M Stockmann, C Hillard, MA Spigarelli, MG Russell, SJ Sherwin, CMT AF Yu, T. Sinha, M. Stockmann, C. Hillard, M. A. Spigarelli, M. G. Russell, S. J. Sherwin, C. M. T. TI POPULATION PHARMACOKINETICS OF SUBCUTANEOUS AND INTRADERMAL GLUCAGON IN PATIENTS WITH TYPE 1 DIABETES SO CLINICAL THERAPEUTICS LA English DT Meeting Abstract CT 12th Congress of the European-Association-for-Clinical-Pharmacology-and-Therapeutics CY JUN 27-30, 2015 CL Madrid, SPAIN SP European Assoc Clin Pharmacol & Therapeut C1 [Yu, T.; Stockmann, C.; Spigarelli, M. G.; Sherwin, C. M. T.] Univ Utah, Salt Lake City, UT USA. [Sinha, M.; Hillard, M. A.; Russell, S. J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 EI 1879-114X J9 CLIN THER JI Clin. Ther. PD AUG PY 2015 VL 37 IS 8 SU S BP E15 EP E15 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DY2VW UT WOS:000384951200043 ER PT J AU Taplin, ME Balk, SP AF Taplin, Mary-Ellen Balk, Steven P. TI Has the Time Arrived for Biomarker-Directed Therapy in Castration-Resistant Prostate Cancer? SO JAMA ONCOLOGY LA English DT Editorial Material ID RECEPTOR SPLICE VARIANTS; ANDROGEN RECEPTOR C1 [Taplin, Mary-Ellen] Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA USA. [Balk, Steven P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA USA. [Balk, Steven P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Canc, Boston, MA USA. RP Taplin, ME (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM mary_taplin@dfci.harvard.edu NR 11 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 577 EP 579 DI 10.1001/jamaoncol.2015.1457 PG 3 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100005 PM 26181796 ER PT J AU Mack, JW Chen, LH Cannavale, K Sattayapiwat, O Cooper, RM Chao, CR AF Mack, Jennifer W. Chen, Lie H. Cannavale, Kimberley Sattayapiwat, Olivia Cooper, Robert M. Chao, Chun R. TI End-of-Life Care Intensity Among Adolescent and Young Adult Patients With Cancer in Kaiser Permanente Southern California SO JAMA ONCOLOGY LA English DT Article ID ONCOLOGIST ALLIANCE; PALLIATIVE CARE; QUALITY; AGGRESSIVENESS; PREFERENCES; DISCUSSIONS; PROGNOSIS AB IMPORTANCE Cancer is the leading disease-related cause of death among adolescents and young adults (AYAs), but little is known about the care that AYA patients with cancer receive at the end of life (EOL). OBJECTIVE To evaluate the intensity of EOL care among AYA patients with cancer. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of Kaiser Permanente Southern California (KSPC) cancer registry data and electronic health records for 663 AYA patients with either stage I to III cancer and evidence of cancer recurrence or stage IV cancer at diagnosis. All patients were treated within KSPC, an integrated health care delivery system, and died between 2001 and 2010 before age 40 years (age range at time of death, 15-39 years). MAIN OUTCOMES AND MEASURES (1) Chemotherapy use in the last 14 days of life; (2) intensive care unit (ICU) care in the last 30 days of life; (3) more than 1 emergency department (ED) visit in the last 30 days of life; (4) hospitalization in the last 30 days of life; and (5) a composite measure of medically intensive EOL care including any of the aforementioned measures. RESULTS Eleven percent of patients (72 of 663) received chemotherapy within 14 days of death. In the last 30 days of life, 22% of patients (144 of 663) were admitted to the ICU; 22% (147 of 663) had more than 1 ED visit; and 62%(413 of 663) were hospitalized. Overall, 68% of patients (449 of 663) received at least 1 medically intensive EOL care measure. CONCLUSIONS AND RELEVANCE Most AYA patients received at least 1 form of medically intensive EOL care. These findings suggest the need to better understand EOL care preferences and decision making in this young population. C1 [Mack, Jennifer W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Mack, Jennifer W.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Div Populat Sci, Boston, MA 02115 USA. [Chen, Lie H.; Chao, Chun R.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Cannavale, Kimberley; Sattayapiwat, Olivia] Kaiser Permanente Southern Calif, Pasadena, CA 91101 USA. [Cooper, Robert M.] Kaiser Permanente Southern Calif, Dept Pediat Oncol, Pasadena, CA 91101 USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_mack@dfci.harvard.edu FU Cancer Research Network/National Cancer Institute (CRN/NCI) [U24CA171524] FX This study was funded by grant U24CA171524 from the Cancer Research Network/National Cancer Institute (CRN/NCI). NR 27 TC 4 Z9 4 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 592 EP 600 DI 10.1001/jamaoncol.2015.1953 PG 9 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100008 PM 26181778 ER PT J AU Narang, AK Wright, AA Nicholas, LH AF Narang, Amol K. Wright, Alexi A. Nicholas, Lauren H. TI Trends in Advance Care Planning in Patients With Cancer Results From a National Longitudinal Survey SO JAMA ONCOLOGY LA English DT Article ID END-OF-LIFE; SURROGATE DECISION-MAKING; MEDICARE BENEFICIARIES; PALLIATIVE CARE; NEAR-DEATH; BEREAVED CAREGIVERS; REGIONAL-VARIATION; OVARIAN-CANCER; MENTAL-HEALTH; OLDER-ADULTS AB IMPORTANCE Advance care planning (ACP) may prevent end-of-life (EOL) care that is nonbeneficial and discordant with patient wishes. Despite long-standing recognition of the merits of ACP in oncology, it is unclear whether participation in ACP by patients with cancer has increased over time. OBJECTIVES To characterize trends in durable power of attorney (DPOA) assignment, living will creation, and participation in discussions of EOL care preferences and to explore associations between ACP subtypes and EOL treatment intensity as reflected in EOL care decisions and terminal hospitalizations. DESIGN, SETTING, AND PARTICIPANTS We analyzed prospectively collected survey data from 1985 next-of-kin surrogates of Health and Retirement Study (HRS) participants with cancer who died between 2000 and 2012, including data from in-depth "exit" interviews conducted with the surrogates after the participant's death. The HRS is a nationally representative, biennial, longitudinal panel study of US residents older than 50 years. Trends in ACP subtypes were tested, and multivariable logistic regression models examined for associations between ACP subtypes and measures of treatment intensity. MAIN OUTCOMES AND MEASURES Trends in the surrogate-reported frequency of DPOA assignment, living will creation, and participation in discussions of EOL care preferences; associations between ACP subtypes and both surrogate-reported EOL care decisions and terminal hospitalizations. RESULTS From 2000 to 2012, there was an increase in DPOA assignment (52% to 74%, P = .03), without significant change in use of living wills (49% to 40%, P = .63) or EOL discussions (68% to 60%, P = .62). Surrogate reports that patients received "all care possible" at EOL increased during the period (7% to 58%, P = .004), and rates of terminal hospitalizations were unchanged (29% to 27%, P = .70). Limiting or withholding treatment was associated with living wills (adjusted odds ratio [AOR], 2.51; 95% CI, 1.53-4.11; P < .001) and EOL discussions (AOR, 1.93; 95% CI, 1.53-3.14; P = .002) but not with DPOA assignment. CONCLUSIONS AND RELEVANCE Use of DPOA increased significantly between 2000 and 2012 but was not associated with EOL care decisions. Importantly, there was no growth in key ACP domains such as discussions of care preferences. Efforts that bolster communication of EOL care preferences and also incorporate surrogate decision makers are critically needed to ensure receipt of goal-concordant care. C1 [Narang, Amol K.] Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, 401 N Broadway,Ste 1440, Baltimore, MD 21231 USA. [Wright, Alexi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wright, Alexi A.] Harvard Med Sch, Boston, MA USA. [Nicholas, Lauren H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Nicholas, Lauren H.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. RP Narang, AK (reprint author), Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, 401 N Broadway,Ste 1440, Baltimore, MD 21231 USA. EM anarang2@jhmi.edu FU National Cancer Institute [K07CA166210]; National Institute on Aging [K01AG041763] FX Dr Wright is supported by career development award K07CA166210 from the National Cancer Institute. Dr Nicholas is supported by career development award K01AG041763 from the National Institute on Aging. NR 53 TC 14 Z9 14 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 601 EP 608 DI 10.1001/jamaoncol.2015.1976 PG 8 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100009 PM 26181909 ER PT J AU Mima, K Sukawa, Y Nishihara, R Qian, ZR Yamauchi, M Inamura, K Kim, SA Masuda, A Nowak, JA Nosho, K Kostic, AD Giannakis, M Watanabe, H Bullman, S Milner, DA Harris, CC Giovannucci, E Garraway, LA Freeman, GJ Dranoff, G Chan, AT Garrett, WS Huttenhower, C Fuchs, CS Ogino, S AF Mima, Kosuke Sukawa, Yasutaka Nishihara, Reiko Qian, Zhi Rong Yamauchi, Mai Inamura, Kentaro Kim, Sun A. Masuda, Atsuhiro Nowak, Jonathan A. Nosho, Katsuhiko Kostic, Aleksandar D. Giannakis, Marios Watanabe, Hideo Bullman, Susan Milner, Danny A. Harris, Curtis C. Giovannucci, Edward Garraway, Levi A. Freeman, Gordon J. Dranoff, Glenn Chan, Andrew T. Garrett, Wendy S. Huttenhower, Curtis Fuchs, Charles S. Ogino, Shuji TI Fusobacterium nucleatum and T Cells in Colorectal Carcinoma SO JAMA ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MICROSATELLITE INSTABILITY; COLON-CANCER; IMMUNE MICROENVIRONMENT; MOLECULAR-FEATURES; PATIENT SURVIVAL; PIK3CA MUTATION; HUMAN GUT; MICROBIOTA; TUMORS AB IMPORTANCE Evidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity. OBJECTIVE To test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided a level to.013 for multiple hypothesis testing. MAIN OUTCOMES AND MEASURES Densities of CD3(+), CD8(+), CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])(+), and FOXP3(+) T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis. RESULTS F nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3(+) T cells (for a unit increase in quartile categories of CD3(+) T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend =.006). The amount of F nucleatum was not significantly associated with the density of CD8(+), CD45RO(+), or FOXP3(+) T cells (P for trend =.24,.88, and.014, respectively). CONCLUSIONS AND RELEVANCE The amount of tissue F nucleatum is inversely associated with CD3(+) T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis. C1 [Mima, Kosuke; Sukawa, Yasutaka; Qian, Zhi Rong; Yamauchi, Mai; Inamura, Kentaro; Kim, Sun A.; Masuda, Atsuhiro; Giannakis, Marios; Watanabe, Hideo; Bullman, Susan; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn; Garrett, Wendy S.; Fuchs, Charles S.; Ogino, Shuji] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. [Nishihara, Reiko; Giovannucci, Edward] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko; Giovannucci, Edward; Ogino, Shuji] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Inamura, Kentaro; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Nowak, Jonathan A.; Milner, Danny A.; Ogino, Shuji] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Nosho, Katsuhiko] Sapporo Med Univ, Sch Med, Dept Gastroenterol Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan. [Kostic, Aleksandar D.; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kostic, Aleksandar D.; Garrett, Wendy S.; Huttenhower, Curtis] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. [Milner, Danny A.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Freeman, Gordon J.; Dranoff, Glenn] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Chan, Andrew T.; Fuchs, Charles S.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Ogino, S (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health (NIH) [P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, K07 CA190673, R01 CA137178, P50 CA127003, R01 CA151993]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Uehara Memorial Foundation; Asan Medical Center FX This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. NR 49 TC 39 Z9 39 U1 6 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 653 EP 661 DI 10.1001/jamaoncol.2015.1377 PG 9 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100020 PM 26181352 ER PT J AU Shankar, GM Francis, JM Rinne, ML Ramkissoon, SH Huang, FW Venteicher, AS Akama-Garren, EH Kang, YJ Lelic, N Kim, JC Brown, LE Charbonneau, SK Golby, AJ Pedamallu, CS Hoang, MP Sullivan, RJ Cherniack, AD Garraway, LA Stemmer-Rachamimov, A Reardon, DA Wen, PY Brastianos, PK Curry, WT Barker, FG Hahn, WC Nahed, BV Ligon, KL Louis, DN Cahill, DP Meyerson, M AF Shankar, Ganesh M. Francis, Joshua M. Rinne, Mikael L. Ramkissoon, Shakti H. Huang, Franklin W. Venteicher, Andrew S. Akama-Garren, Elliot H. Kang, Yun Jee Lelic, Nina Kim, James C. Brown, Loreal E. Charbonneau, Sarah K. Golby, Alexandra J. Pedamallu, Chandra Sekhar Hoang, Mai P. Sullivan, Ryan J. Cherniack, Andrew D. Garraway, Levi A. Stemmer-Rachamimov, Anat Reardon, David A. Wen, Patrick Y. Brastianos, Priscilla K. Curry, William T. Barker, Fred G., II Hahn, William C. Nahed, Brian V. Ligon, Keith L. Louis, David N. Cahill, Daniel P. Meyerson, Matthew TI Rapid Intraoperative Molecular Characterization of Glioma SO JAMA ONCOLOGY LA English DT Article ID TERT PROMOTER MUTATIONS; CLINICAL-TRIAL; RESECTION; SURGERY; BIOPSY; IDH1 AB IMPORTANCE Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%-99%) and 100% specificity (95% CI, 95%-100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations. C1 [Shankar, Ganesh M.; Venteicher, Andrew S.; Lelic, Nina; Curry, William T.; Barker, Fred G., II; Nahed, Brian V.; Cahill, Daniel P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Shankar, Ganesh M.; Francis, Joshua M.; Rinne, Mikael L.; Huang, Franklin W.; Pedamallu, Chandra Sekhar; Cherniack, Andrew D.; Garraway, Levi A.; Hahn, William C.; Meyerson, Matthew] Broad Inst, Canc Program, Cambridge, MA USA. [Francis, Joshua M.; Ramkissoon, Shakti H.; Huang, Franklin W.; Kang, Yun Jee; Brown, Loreal E.; Charbonneau, Sarah K.; Pedamallu, Chandra Sekhar; Garraway, Levi A.; Hahn, William C.; Ligon, Keith L.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rinne, Mikael L.; Golby, Alexandra J.; Reardon, David A.; Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Rinne, Mikael L.; Wen, Patrick Y.] Brigham & Womens Hosp, Div Neurol, Boston, MA 02115 USA. [Ramkissoon, Shakti H.; Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Ramkissoon, Shakti H.; Ligon, Keith L.; Meyerson, Matthew] Harvard Med Sch, Dept Pathol, Boston, MA USA. [Venteicher, Andrew S.; Kim, James C.; Hoang, Mai P.; Stemmer-Rachamimov, Anat; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Akama-Garren, Elliot H.] MIT, Dept Biol, Cambridge, MA USA. [Golby, Alexandra J.] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Sullivan, Ryan J.; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Ligon, Keith L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. RP Meyerson, M (reprint author), Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. EM Matthew_Meyerson@dfci.harvard.edu OI Cahill, Daniel/0000-0003-2552-6546 FU National Institutes of Health (NIH) National Institutes of Neurologic Disorders and Stroke [R25NSO65743]; American Brain Tumor Association Basic Research Fellowship - Humor to Fight the Tumor Event Committee; National Cancer Institute (NCI) K12 Training Fellowship; Claudia Adams Barr Program in Basic Cancer Research; Burroughs Wellcome Career Award; NIH-NCI Specialized Programs of Research Excellence (SPORE) grant [P5OCA165962] FX Dr Shankar is supported by grant R25NSO65743 from the National Institutes of Health (NIH) National Institutes of Neurologic Disorders and Stroke, the American Brain Tumor Association Basic Research Fellowship supported by the Humor to Fight the Tumor Event Committee. Dr Rinne is supported by a National Cancer Institute (NCI) K12 Training Fellowship and the Claudia Adams Barr Program in Basic Cancer Research. Dr Cahill is supported by the Burroughs Wellcome Career Award and the NIH-NCI Specialized Programs of Research Excellence (SPORE) grant P5OCA165962. NR 15 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD AUG PY 2015 VL 1 IS 5 BP 662 EP 667 DI 10.1001/jamaoncol.2015.0917 PG 6 WC Oncology SC Oncology GA DW5HA UT WOS:000383673100021 PM 26181761 ER PT J AU Drapkin, M Epstein, EE McCrady, B Eddie, D AF Drapkin, Michelle Epstein, Elizabeth E. McCrady, Barbara Eddie, David TI Sudden gains among women receiving treatment for alcohol use disorders SO ADDICTION RESEARCH & THEORY LA English DT Article DE Alcohol; mechanisms of change; sudden gains; treatment ID COGNITIVE-BEHAVIORAL THERAPY; TIMELINE FOLLOWBACK; CRITICAL SESSIONS; DEPRESSION; PSYCHOTHERAPY; DRINKING; INTERVENTIONS; COMPLEXITY; DRINKERS; RELAPSE AB Understanding the timing and types of change during treatment for mental health disorders is an important step toward elucidating possible mechanisms of behaviour change in response to therapeutic interventions, yet these issues have not been adequately addressed in the alcohol dependence treatment literature. The current study applied sudden gains (SGs) methodology, an approach originally developed in depression treatment studies, to a sample of women receiving treatment for alcohol use disorders. SGs are drastic improvements in symptoms that occur between two psychotherapy sessions and are hypothesised to be the result of what occurred in the first of those two sessions. SGs can happen at any time during the course of treatment, can happen more than once, and are individualised, as opposed to aggregated for a sample. For the current study, SGs were examined across three variables: percent drinking days (PDD), urge frequency (UF), and urge intensity (UI) in a sample of 102 women receiving either individual or couple cognitive-behavioural therapy for alcohol use disorders. Results indicated the presence of SGs; one-third of the sample experienced at least one SG in either alcohol use or urges to drink; the most common SGs were in frequency of urges to drink. SGs in urge frequency during treatment predicted better post-treatment drinking outcome. C1 [Drapkin, Michelle] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Drapkin, Michelle] Vet Affairs Med Ctr, Mental Hlth Serv, Philadelphia, PA USA. [Epstein, Elizabeth E.; Eddie, David] Rutgers State Univ, Ctr Alcohol Studies, Piscataway, NJ USA. [McCrady, Barbara] Univ New Mexico, Ctr Alcoholism Substance Abuse & Addict, Albuquerque, NM 87131 USA. RP Drapkin, M (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. EM michelledrapkinmet@gmail.com FU NIAAA [R37 AA07070, T32 AA07569] FX This research was supported by NIAAA Grants R37 AA07070 and T32 AA07569. Parts of these findings were presented at the 2006 and 2007 Annual Meetings of the Research Society on Alcoholism as well as at the 13th world congress of the International Society for Biomedical Research on Alcoholism, Sydney, Australia. NR 42 TC 0 Z9 0 U1 3 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1606-6359 EI 1476-7392 J9 ADDICT RES THEORY JI Addict. Res. Theory PD AUG PY 2015 VL 23 IS 4 BP 273 EP 279 DI 10.3109/16066359.2014.981809 PG 7 WC Substance Abuse; Social Issues SC Substance Abuse; Social Issues GA CL8OY UT WOS:000357235200003 ER PT J AU Nedjat-Haiem, FR Carrion, IV AF Nedjat-Haiem, Frances R. Carrion, Iraida V. TI Assessing Challenges in End-of-Life Conversations With Patients Utilizing a Public Safety-Net Health Care System SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE safety-net health care; Latinos; Hispanics; providers; barriers; end-of-life communication; qualitative ID PALLIATIVE CARE; LATINO PATIENTS; PHYSICIANS; RISK AB Multiple factors influence end-of-life (EOL) care discussions that occur in health care systems, within organizations, among individuals working within these systems and in patients and family/friend support networks. This study examined barriers to EOL care discussions as experienced by health care providers working in a public safety-net health care system where the majority of their patients were low-income and immigrant Latinos seeking medical treatment. Qualitative data were collected in South Central Los Angeles through semistructured interviews with 46 health care providers from different disciplines in medicine, nursing, social work, and chaplaincy. The themes indicated communication barriers in the public sector health care setting and sociocultural patient- and family-level factors. All providers made valuable contributions to clarify the complexity of the problems. Universal strategies are needed to improve communication. C1 [Nedjat-Haiem, Frances R.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Nedjat-Haiem, Frances R.] Univ So Calif, Sch Social Work, Los Angeles, CA 90089 USA. [Carrion, Iraida V.] Univ S Florida, Sch Social Work, Tampa, FL USA. RP Nedjat-Haiem, FR (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, HSR&D Ctr Excellence, Off Acad Affiliat, VA Associated Hlth Postdoctoral Fellowship Progra, 11301 Wilshire Blvd,Code 111-G, Los Angeles, CA 90073 USA. EM nedjatha@gmail.com OI Carrion, Iraida/0000-0003-4076-6644 FU American Cancer Society [DSW-06-220-01-SW]; US Department of Veterans Affairs, Hartford/VA Social Work Scholars Program FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the American Cancer Society Doctoral Training Grants in Oncology Social Work DSW-06-220-01-SW (F. R. Nedjat-Haiem, PI), and US Department of Veterans Affairs, Hartford/VA Social Work Scholars Program. NR 33 TC 2 Z9 2 U1 2 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD AUG PY 2015 VL 32 IS 5 BP 528 EP 536 DI 10.1177/1049909114530550 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CM5QZ UT WOS:000357745000008 PM 24752233 ER PT J AU Sanz, MA Montesinos, P Kim, HT Ruiz-Arguelles, GJ Undurraga, MS Uriarte, MR Martinez, L Jacomo, RH Gutierrez-Aguirre, H Melo, RAM Bittencourt, R Pasquini, R Pagnano, K Fagundes, EM Vellenga, E Holowiecka, A Gonzalez-Huerta, AJ Fernandez, P De la Serna, J Brunet, S De Lisa, E Gonzalez-Campos, J Ribera, JM Krsnik, I Ganser, A Berliner, N Ribeiro, RC Lo-Coco, F Lowenberg, B Rego, EM AF Sanz, Miguel A. Montesinos, Pau Kim, Haesook T. Ruiz-Argueelles, Guillermo J. Undurraga, Maria S. Uriarte, Maria R. Martinez, Lem Jacomo, Rafael H. Gutierrez-Aguirre, Homero Melo, Raul A. M. Bittencourt, Rosane Pasquini, Ricardo Pagnano, Katia Fagundes, Evandro M. Vellenga, Edo Holowiecka, Alexandra Gonzalez-Huerta, Ana J. Fernandez, Pascual De la Serna, Javier Brunet, Salut De Lisa, Elena Gonzalez-Campos, Jose Ribera, Jose M. Krsnik, Isabel Ganser, Arnold Berliner, Nancy Ribeiro, Raul C. Lo-Coco, Francesco Lowenberg, Bob Rego, Eduardo M. CA IC-APL Grp PETHEMA Grp HOVON Grp TI All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies SO ANNALS OF HEMATOLOGY LA English DT Article DE Acute promyelocytic leukaemia; Risk-adapted therapy; All-trans retinoic acid; Anthracyclines; Cytarabine; Prognostic factors; Matched-pair analysis ID AGENT ARSENIC TRIOXIDE; RESPONSE CRITERIA; THERAPY; ANTHRACYCLINE; CONSOLIDATION; OUTCOMES AB Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at as #NCT00408278 [ClinicalTrials.gov]. C1 [Sanz, Miguel A.; Montesinos, Pau] Univ Hosp La Fe, Dept Hematol, Valencia 46026, Spain. [Sanz, Miguel A.; Montesinos, Pau] Univ Valencia, Dept Med, Valencia, Spain. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ruiz-Argueelles, Guillermo J.] Clin Ruiz Puebla, Puebla, Mexico. [Undurraga, Maria S.] Hosp Salvador, Dept Hematol, Santiago, Chile. [Uriarte, Maria R.; Martinez, Lem] Asociac Espanola Primera Socorros Mutuos, Montevideo, Uruguay. [Jacomo, Rafael H.; Rego, Eduardo M.] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Internal Med, Hematol Oncol Div, BR-14049 Ribeirao Preto, Brazil. [Jacomo, Rafael H.; Rego, Eduardo M.] Univ Sao Paulo, Ctr Cell Based Therapy, BR-14049 Ribeirao Preto, Brazil. [Gutierrez-Aguirre, Homero] Hosp Univ Dr Jose E Gonzalez, Div Hematol, Monterrey, Mexico. [Melo, Raul A. M.] Fundacao HEMOPE, Recife, PE, Brazil. [Bittencourt, Rosane] Univ Fed Rio Grande do Sul, Div Hematol, Porto Alegre, RS, Brazil. [Pasquini, Ricardo] Univ Fed Parana, Div Hematol, BR-80060000 Curitiba, Parana, Brazil. [Pagnano, Katia] Univ Campinas UNICAMP, Hematol & Hemotherapy Ctr, Campinas, SP, Brazil. [Fagundes, Evandro M.] Univ Fed Minas Gerais, Div Hematol, Belo Horizonte, MG, Brazil. [Vellenga, Edo] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, NL-9713 AV Groningen, Netherlands. [Holowiecka, Alexandra] Silesian Med Univ, Dept Hematol, Katowice, Poland. [Gonzalez-Huerta, Ana J.] Univ Oviedo, Hosp Cent Asturias, E-33080 Oviedo, Spain. [Fernandez, Pascual] Hosp Gen Univ Alicante, Dept Hematol, Alicante, Spain. [De la Serna, Javier] Hosp 12 Octubre, Dept Hematol, E-28041 Madrid, Spain. [Brunet, Salut] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [De Lisa, Elena] Hosp Maciel, Dept Hematol, Montevideo, Uruguay. [Gonzalez-Campos, Jose] Hosp Virgen del Rocio, Dept Hematol, Seville, Spain. [Ribera, Jose M.] Hosp Badalona Germans Trias & Pujol, Dept Hematol, Badalona, Spain. [Krsnik, Isabel] Hosp Puerta de Hierro, Dept Hematol, Madrid, Spain. [Ganser, Arnold] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany. [Berliner, Nancy] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Ribeiro, Raul C.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Lo-Coco, Francesco] Univ Roma Tor Vergata, Dept Biopathol, Rome, Italy. [Lo-Coco, Francesco] Santa Lucia Fdn, Rome, Italy. [Lowenberg, Bob] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. RP Sanz, MA (reprint author), Univ Hosp La Fe, Dept Hematol, Avinguda Fernando Abril Martorell 106, Valencia 46026, Spain. EM msanz@uv.es RI IBIS, ONCOHEMATOLOGI/P-3457-2015; Rego, Eduardo/A-1058-2012; OI Rego, Eduardo/0000-0003-1567-4086; DE LA SERNA, JAVIER/0000-0003-3904-1101; BERGUA BURGUES, JUAN MIGUEL/0000-0001-8229-1208 FU Instituto de Salud Carlos III [RD12/0036/014]; European Regional Development Fund [RD12/0036/014]; American Society of Hematology; Fondazione Umberto Veronesi; Roche South Arabia; Fundacao de Apoio a Pesquisa do Estado de Sao Paulo [1998/14247-6]; Fundacion Mexicana para la Salud; St. Jude Children's Research Hospital; Cephalon Europe FX The authors thank all participating institutions and clinicians in the PETHEMA/HOVON and IC-APL studies. This work was supported in part by Cooperative Research Thematic Network Grant RD12/0036/014 (Instituto de Salud Carlos III and European Regional Development Fund). The authors are thankful for the support of the American Society of Hematology, Fondazione Umberto Veronesi, Roche South Arabia, Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (Grant No. 1998/14247-6), Fundacion Mexicana para la Salud, St. Jude Children's Research Hospital and Cephalon Europe. NR 19 TC 2 Z9 3 U1 0 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 EI 1432-0584 J9 ANN HEMATOL JI Ann. Hematol. PD AUG PY 2015 VL 94 IS 8 BP 1347 EP 1356 DI 10.1007/s00277-015-2393-0 PG 10 WC Hematology SC Hematology GA CL9EU UT WOS:000357279200011 PM 25975975 ER PT J AU Jank, BJ Xiong, LJ Moser, PT Guyette, JP Ren, X Cetrulo, CL Leonard, DA Fernandez, L Fagan, SP Ott, HC AF Jank, Bernhard J. Xiong, Linjie Moser, Philipp T. Guyette, Jacques P. Ren, Xi Cetrulo, Curtis L. Leonard, David A. Fernandez, Leopoldo Fagan, Shawn P. Ott, Harald C. TI Engineered composite tissue as a bioartificial limb graft SO BIOMATERIALS LA English DT Article DE Bioprosthesis; Mechanical properties; Muscle; Bone graft ID EXPERIMENTAL ORTHOTOPIC TRANSPLANTATION; HAND TRANSPLANTATION; NERVE GRAFTS; IN-VIVO; REGENERATION; RECONSTRUCTION; DECELLULARIZATION; IMMUNOGENICITY; AMPUTATION; RECOVERY AB The loss of an extremity is a disastrous injury with tremendous impact on a patient's life. Current mechanical prostheses are technically highly sophisticated, but only partially replace physiologic function and aesthetic appearance. As a biologic alternative, approximately 70 patients have undergone allogeneic hand transplantation to date worldwide. While outcomes are favorable, risks and side effects of transplantation and long-term immunosuppression pose a significant ethical dilemma. An autologous, bio-artificial graft based on native extracellular matrix and patient derived cells could be produced on demand and would not require immunosuppression after transplantation. To create such a graft, we decellularized rat and primate forearms by detergent perfusion and yielded acellular scaffolds with preserved composite architecture. We then repopulated muscle and vasculature with cells of appropriate phenotypes, and matured the composite tissue in a perfusion bioreactor under electrical stimulation in vitro. After confirmation of composite tissue formation, we transplanted the resulting bio-composite grafts to confirm perfusion in vivo. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ott, Harald C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Jank, Bernhard J.; Xiong, Linjie; Moser, Philipp T.; Guyette, Jacques P.; Ren, Xi; Fernandez, Leopoldo] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Jank, Bernhard J.; Moser, Philipp T.; Guyette, Jacques P.; Ren, Xi; Cetrulo, Curtis L.; Leonard, David A.; Ott, Harald C.] Harvard Univ, Sch Med, Boston, MA USA. [Cetrulo, Curtis L.; Leonard, David A.] Massachusetts Gen Hosp, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Fagan, Shawn P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Burn Surg, Cambridge, MA 02138 USA. RP Ott, HC (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 4700, Boston, MA 02114 USA. EM hott@partners.org OI Ren, Xi/0000-0003-3187-1311; Jank, Bernhard/0000-0003-1420-5034 FU NIH HHS [DP2 OD008749] NR 39 TC 13 Z9 13 U1 3 U2 47 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 AUG PY 2015 VL 61 BP 246 EP 256 DI 10.1016/j.biomaterials.2015.04.051 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CL8MX UT WOS:000357229900023 PM 26004237 ER PT J AU Tsurumi, A Que, YA Yan, SC Tompkins, RG Rahme, LG Ryan, CM AF Tsurumi, Amy Que, Yok-Ai Yan, Shuangchun Tompkins, Ronald G. Rahme, Laurence G. Ryan, Colleen M. TI Do standard burn mortality formulae work on a population of severely burned children and adults? SO BURNS LA English DT Article DE Burn; Trauma; Mortality; Severity score; Ryan Score; Baux index ID RISK-FACTORS; BAUX SCORE; PREDICTING SURVIVAL; SEVERITY INDEX; INJURY; OUTCOMES; DEATH; PROBABILITY; PATIENT; SYSTEMS AB Accurate prediction of mortality following burns is useful as an audit tool, and for providing treatment plan and resource allocation criteria. Common burn formulae (Ryan Score, Abbreviated Burn Severity Index (ABSI), classic and revised Baux) have not been compared with the standard Acute Physiology and Chronic Health Evaluation II (APACHEII) or revalidated in a severely (>= 20% total burn surface area) burned population. Furthermore, the revised Baux (R-Baux) has been externally validated thoroughly only once and the pediatric Baux (P-Baux) has yet to be. Using 522 severely burned patients, we show that burn formulae (ABSI, Baux, revised Baux) outperform APACHEII among adults (AUROC increase p < 0.001 adults; p > 0.5 children). The Ryan Score performs well especially among the most at-risk populations (estimated mortality [90% CI] original versus current study: 33% [26-41%] versus 30.18% [24.25-36.86%] for Ryan Score 2; 87% [78-93%] versus 66.48% [51.31-78.87%] for Ryan Score 3). The R-Baux shows accurate discrimination (AUROC 0.908 [0.869-0.947]) and is well-calibrated. However, the ABSI and P-Baux, although showing high measures of discrimination (AUROC 0.826 [0.737-0.916] and 0.848 [0.758-0.938]) in children), exceedingly overestimates mortality, indicating poor calibration. We highlight challenges in designing and employing scores that are applicable to a wide range of populations. (C) 2015 Elsevier Ltd and ISBI. All rights reserved. C1 [Tsurumi, Amy; Yan, Shuangchun; Tompkins, Ronald G.; Rahme, Laurence G.; Ryan, Colleen M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tsurumi, Amy; Yan, Shuangchun; Rahme, Laurence G.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Tsurumi, Amy; Yan, Shuangchun; Rahme, Laurence G.; Ryan, Colleen M.] Shriners Hosp Children, Boston, MA USA. [Que, Yok-Ai] Univ Lausanne Hosp, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. RP Ryan, CM (reprint author), Massachusetts Gen Hosp, Bigelow 1302,55 Fruit St, Boston, MA 02114 USA. EM tsurumi@research.mgh.harvard.edu; Yok-Ai.Que@chuv.ch; yansc@research.mgh.harvard.edu; rtompkins@mgh.harvard.edu; rahme@molbio.mgh.harvard.edu; CRYAN@mgh.harvard.edu OI Ryan, Colleen/0000-0002-6455-936X FU US Army Medical Research Acquisition Act of US Department of Defense; Congressionally Directed Medical Research Programs (CDMRP); Defense Medical Research and Development Program (DMRDP) Basic Research Award [W81XWH-10-DMRDP-BRA]; Shriners Hospitals Research Fellowship [84293]; National Institute of General Medical Sciences [5U54GM062119] FX This work was supported by the US Army Medical Research Acquisition Act of US Department of Defense, Congressionally Directed Medical Research Programs (CDMRP), Defense Medical Research and Development Program (DMRDP) Basic Research Award, W81XWH-10-DMRDP-BRA to LGR. AT was supported by the Shriners Hospitals Research Fellowship #84293. The investigators acknowledge the contribution of the Inflammation and the Host Response to Injury Large-Scale Collaborative Project Award 5U54GM062119 from the National Institute of General Medical Sciences. NR 34 TC 0 Z9 0 U1 0 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 AUG PY 2015 VL 41 IS 5 BP 935 EP 945 DI 10.1016/j.burns.2015.03.017 PG 11 WC Critical Care Medicine; Dermatology; Surgery SC General & Internal Medicine; Dermatology; Surgery GA CM0EB UT WOS:000357350100005 PM 25922299 ER PT J AU Olszewski, AJ Winer, ES Castillo, JJ AF Olszewski, Adam J. Winer, Eric S. Castillo, Jorge J. TI Validation of clinical prognostic indices for diffuse large B-cell lymphoma in the National Cancer Data Base SO CANCER CAUSES & CONTROL LA English DT Article DE Diffuse large B-cell lymphoma; Non-Hodgkin lymphoma; Prognosis; Epidemiology; Outcomes research; Survival analysis; Model validation ID RITUXIMAB ERA; NCCN-IPI; SURVIVAL MODELS; R-CHOP; EPIDEMIOLOGY; SURVEILLANCE; CHEMOTHERAPY; OLDER AB Accurate risk stratification is necessary for epidemiologic and outcomes research in diffuse large B-cell lymphoma (DLBCL). We evaluated performance characteristics of the clinically derived International Prognostic Index (IPI) and revised IPI (R-IPI) with a regression model-based score using the National Cancer Data Base. We studied DLBCL patients diagnosed in 2004-2011, divided into derivation and validation cohorts. The model-based score was calculated from a Cox model incorporating variables routinely recorded by cancer registries. Calibration and discrimination of the indices with regard to overall survival were evaluated in the validation cohort. The IPI was recorded in 19,511 of 119,942 patients, of whom 79 % received chemotherapy. Both clinical indices provided good survival discrimination (5-year estimate range 33-74 % for the IPI, and 41-87 % for the R-IPI), but explained only 16 % of variation in survival. Survival predictions among chemotherapy-treated patients were similar to estimates from published clinical cohorts. The model-based score had significantly better discrimination characteristics (5-year survival estimate range 22-87 %) and explained 23 % of variation in survival. We validated the IPI and R-IPI as recorded by cancer registries to provide robust risk stratification in the general population with DLBCL, but a prognostic model using raw registry data provides superior performance. Explicit recording of prognostic factors is preferable to abstracting coarsened clinical indices for the purpose of population-based epidemiologic research. Considering low variation of survival explained by the standard clinical variables, incorporating molecular markers into registry data is necessary to improve risk stratification. C1 [Olszewski, Adam J.; Winer, Eric S.] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Olszewski, Adam J.] Mem Hosp Rhode Isl, Div Hematol Oncol, Pawtucket, RI 02860 USA. [Winer, Eric S.] Rhode Isl Hosp, Div Hematol Oncol, Providence, RI USA. [Castillo, Jorge J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. RP Olszewski, AJ (reprint author), Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. EM adam_olszewski@brown.edu OI Olszewski, Adam/0000-0002-6472-6658; Castillo, Jorge/0000-0001-9490-7532 FU authors' academic departments FX The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator. The study was funded by the authors' academic departments. NR 40 TC 2 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2015 VL 26 IS 8 BP 1163 EP 1172 DI 10.1007/s10552-015-0610-8 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM4LX UT WOS:000357657200011 PM 26054914 ER PT J AU Boeke, CE Tamimi, RM Berkey, CS Colditz, GA Giovannucci, E Malspeis, S Willett, WC Frazier, AL AF Boeke, Caroline E. Tamimi, Rulla M. Berkey, Catherine S. Colditz, Graham A. Giovannucci, Edward Malspeis, Susan Willett, Walter C. Frazier, A. Lindsay TI Adolescent dietary vitamin D and sun exposure in relation to benign breast disease SO CANCER CAUSES & CONTROL LA English DT Article DE Vitamin D; Sun; Cancer; Adolescent health; Diet; Breast ID FOOD FREQUENCY QUESTIONNAIRE; D DEFICIENCY; LIFE-STYLE; CANCER; RISK; WOMEN; PREVENTION; CHILDREN; MODELS AB Vitamin D may reduce cell proliferation and tumor growth in breast tissue, and exposure may be most important during adolescence when breast tissue is developing. In the Nurses' Health Study II, higher recalled adolescent vitamin D intake was associated with a lower risk of benign breast disease (BBD). Our study aimed to assess adolescent vitamin D exposure in relation to BBD in young women. Vitamin D was assessed in 6,593 adolescent girls (9-15 years of age at baseline) in the prospective Growing Up Today Study cohort using the mean energy-adjusted intakes from food frequency questionnaires in 1996, 1997, and 1998. In 1999, 5,286 girls reported skin color, sunscreen use, tanning bed use, and number of sunburns in the past year, and we used state of residence to assess low versus high ultraviolet index. Biopsy-confirmed BBD was reported on questionnaires in 2005, 2007, and 2010 (n = 122). Dietary vitamin D, tanning behaviors, and other sun exposure variables were not significantly associated with BBD in logistic regression models adjusted for age, family history of breast cancer or BBD, age at menarche, nulliparity, alcohol intake, body mass index, and physical activity. The relative risk for the top (> 467 IU/day) versus bottom (< 243 IU/day) quartile of vitamin D intake was 0.76 (95 % CI 0.47, 1.23). Sun exposure was not significantly associated with BBD in this prospective cohort. However, a suggestive inverse association between dietary vitamin D and BBD was observed that merits further study. C1 [Boeke, Caroline E.; Tamimi, Rulla M.; Giovannucci, Edward; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Boeke, Caroline E.; Tamimi, Rulla M.; Berkey, Catherine S.; Giovannucci, Edward; Malspeis, Susan; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Tamimi, Rulla M.; Berkey, Catherine S.; Giovannucci, Edward; Willett, Walter C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Giovannucci, Edward; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. RP Boeke, CE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM caroline.boeke@mail.harvard.edu FU NIH [R01 DK084001, UM1 CA176726, R01 CA 050385]; Breast Cancer Research Foundation; American Institute for Cancer Research; [T32 CA 09001] FX We would like to thank the female participants of the Growing Up Today Study, their mothers from the Nurses' Health Study II, and our colleagues working on both cohort studies. We would also like to acknowledge the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School. This work was funded by NIH grants R01 DK084001, UM1 CA176726, and R01 CA 050385, as well as the Breast Cancer Research Foundation. Caroline Boeke was funded by T32 CA 09001. Lindsay Frazier was supported by an award from the American Institute for Cancer Research. NR 22 TC 1 Z9 1 U1 1 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2015 VL 26 IS 8 BP 1181 EP 1187 DI 10.1007/s10552-015-0612-6 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CM4LX UT WOS:000357657200013 PM 26084210 ER PT J AU King, LY Canasto-Chibuque, C Johnson, KB Yip, S Chen, XT Kojima, K Deshmukh, M Venkatesh, A Tan, PS Sun, XC Villanueva, A Sangiovanni, A Nair, V Mahajan, M Kobayashi, M Kumada, H Iavarone, M Colombo, M Fiel, MI Friedman, SL Llovet, JM Chung, RT Hoshida, Y AF King, Lindsay Y. Canasto-Chibuque, Claudia Johnson, Kara B. Yip, Shun Chen, Xintong Kojima, Kensuke Deshmukh, Manjeet Venkatesh, Anu Tan, Poh Seng Sun, Xiaochen Villanueva, Augusto Sangiovanni, Angelo Nair, Venugopalan Mahajan, Milind Kobayashi, Masahiro Kumada, Hiromitsu Iavarone, Massimo Colombo, Massimo Fiel, Maria Isabel Friedman, Scott L. Llovet, Josep M. Chung, Raymond T. Hoshida, Yujin TI A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration SO GUT LA English DT Article ID HEPATOCELLULAR-CARCINOMA; VIRUS-INFECTION; GENE-EXPRESSION; UNITED-STATES; FIBROSIS; CHALLENGES; MORTALITY; DISEASE; BURDEN; SURVEILLANCE AB Objective The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. Design We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). Results In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). Conclusions A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. C1 [King, Lindsay Y.; Johnson, Kara B.; Chung, Raymond T.] Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Dept Med,Liver Ctr & Gastrointestinal Div, Boston, MA 02115 USA. [Canasto-Chibuque, Claudia; Yip, Shun; Chen, Xintong; Kojima, Kensuke; Deshmukh, Manjeet; Venkatesh, Anu; Tan, Poh Seng; Sun, Xiaochen; Friedman, Scott L.; Llovet, Josep M.; Hoshida, Yujin] Icahn Sch Med Mt Sinai, Hess Ctr Sci & Med, Dept Med, Div Liver Dis,Tisch Canc Inst,Liver Canc Program, New York, NY 10029 USA. [Tan, Poh Seng] Natl Univ Hlth Syst, Univ Med Cluster, Div Gastroenterol & Hepatol, Singapore, Singapore. [Villanueva, Augusto] Kings Coll London, Inst Liver Sci, London, England. [Sangiovanni, Angelo; Iavarone, Massimo; Colombo, Massimo] Univ Milan, M&A Migliavacca Ctr Liver Dis, Milan, Italy. [Sangiovanni, Angelo; Iavarone, Massimo; Colombo, Massimo] Univ Milan, Div Gastroenterol 1, Fdn IRCCS Granda Osped Maggiore Policlin, Milan, Italy. [Nair, Venugopalan] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Mahajan, Milind] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Kobayashi, Masahiro; Kumada, Hiromitsu] Toranomon Gen Hosp, Dept Hepatol, Tokyo, Japan. [Fiel, Maria Isabel] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Llovet, Josep M.] Hosp Clin Barcelona, Inst Invest Biomed August & Sunyer Ctr Invest Red, Barcelona Clin Liver Canc Grp, HCC Translat Res Lab, Barcelona, Catalonia, Spain. [Llovet, Josep M.] ICREA, Barcelona, Catalonia, Spain. RP Hoshida, Y (reprint author), Icahn Sch Med Mt Sinai, Hess Ctr Sci & Med, Dept Med, Div Liver Dis,Tisch Canc Inst,Liver Canc Program, 1470 Madison Ave,Box 1123, New York, NY 10029 USA. EM yujin.hoshida@mssm.edu RI Llovet, Josep M /D-4340-2014; Yip, Shun/K-8074-2016 OI Llovet, Josep M /0000-0003-0547-2667; Yip, Shun/0000-0003-4027-2927 FU National Institute of Health [DK099558, DA033541, DK098079, DK078772, DK56621, AA020709, DK076986, DK007191]; European Commission; Samuel Waxman Cancer Research Foundation; Spanish National Health Institute [SAF-2010-16055]; Asociacion Espanola para el Estudio del Cancer (AECC) FX This research was supported by the National Institute of Health (DK099558 to YH; DA033541, DK098079, DK078772 to RTC; DK56621 and AA020709 to SLF; DK076986 to JML; DK007191 to LYK and KBJ); the European Commission Framework Programme 7 (Heptromic, proposal number 259744 to YH, JML); the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2010-16055) and the Asociacion Espanola para el Estudio del Cancer (AECC) to JML. NR 46 TC 7 Z9 7 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD AUG PY 2015 VL 64 IS 8 BP 1296 EP 1302 DI 10.1136/gutjnl-2014-307862 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM4ZZ UT WOS:000357697000017 PM 25143343 ER PT J AU Zhang, W Du, JY Yu, Q Jin, JO AF Zhang, Wei Du, Jiang-Yuan Yu, Qing Jin, Jun-O TI Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen SO INFECTION AND IMMUNITY LA English DT Article ID BASAL HOMEOSTATIC PROLIFERATION; TISSUE-INDUCER CELLS; CD8(+) T-CELLS; LYMPHOID-TISSUE; BACTERIAL PATHOGENS; DENDRITIC CELLS; TH1 RESPONSE; IN-VIVO; MEMORY; IL-7 AB Interleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacterium Citrobacter rodentium. C. rodentium infection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response to C. rodentium was dependent on gamma interferon (IFN-gamma)-producing NK1.1(+) cells and IL-12. Treatment with anti-IL-7R alpha antibody during C. rodentium infection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity against C. rodentium during the first 6 days after infection. An impaired bacterial clearance upon IL-7R alpha blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover, C. rodentium-induced expansion and activation of intestinal CD4(+) lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7R alpha blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response to C. rodentium infection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium. C1 [Zhang, Wei; Du, Jiang-Yuan; Jin, Jun-O] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai Med Coll, Shanghai 200433, Peoples R China. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai Med Coll, Shanghai 200433, Peoples R China. EM Junojin1@gmail.com FU National Natural Science Foundation of China [81450110090] FX This study was supported by the Research Fund for International Young Scientists from the National Natural Science Foundation of China (81450110090). NR 44 TC 2 Z9 2 U1 0 U2 4 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 AUG PY 2015 VL 83 IS 8 BP 3213 EP 3223 DI 10.1128/IAI.00320-15 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CM3XI UT WOS:000357618300021 PM 26034215 ER PT J AU Cheng, JT Ravicz, M Guignard, J Furlong, C Rosowski, JJ AF Cheng, Jeffrey Tao Ravicz, Michael Guignard, Jeremie Furlong, Cosme Rosowski, John J. TI The Effect of Ear Canal Orientation on Tympanic Membrane Motion and the Sound Field Near the Tympanic Membrane SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE ear canal orientation; tympanic membrane motion; umbo displacement; sound pressure distribution; middle ear; stroboscopic holography ID HUMAN TEMPORAL BONES; PRESSURE DISTRIBUTION; WAVE MODEL; SURFACE; KHZ AB The contribution of human ear canal orientation to tympanic membrane (TM) surface motion and sound pressure distribution near the TM surface is investigated by using an artificial ear canal (aEC) similar in dimensions to the natural human ear canal. The aEC replaced the bony ear canal of cadaveric human temporal bones. The radial orientation of the aEC relative to the manubrium of the TM was varied. Tones of 0.2 to 18.4 kHz delivered through the aEC induced surface motions of the TM that were quantified using stroboscopic holography; the distribution of sound in the plane of the tympanic ring P (TR) was measured with a probe tube microphone. The results suggest that the ear canal orientation has no substantial effect on TM surface motions, but P (TR) at frequencies above 10 kHz is influenced by the ear canal orientation. The complex TM surface motion patterns observed at frequencies above a few kilohertz are not correlated with simpler variations in P (TR) distribution at the same frequencies, suggesting that the complex sound-induced TM motions are more related to the TM mechanical properties, shape, and boundary conditions rather than to spatial variations in the acoustic stimulus. C1 [Cheng, Jeffrey Tao; Ravicz, Michael; Guignard, Jeremie; Furlong, Cosme; Rosowski, John J.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Eaton Peabody Lab,Dept Otol & Laryngol, Boston, MA 02114 USA. [Furlong, Cosme] Worcester Polytech Inst, Ctr Holog Studies & Laser MicromechaTron, Dept Mech Engn, Worcester, MA 01609 USA. [Rosowski, John J.] MIT Harvard Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. RP Cheng, JT (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Eaton Peabody Lab,Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Tao_Cheng@meei.harvard.edu FU NRSA from NIDCD [1F32DC009949-01, 1R03DC011617-01, R01-DC008642]; Swiss National Science Foundation (SNSF) FX The authors thank Diane Jones at the Eaton-Peabody Laboratory (EPL) of the Massachusetts Eye and Ear Infirmary (MEEI) for help in acquiring temporal bone specimens. Ivo Dobrev and Morteza Khaleghi from the Center for Holographic Studies and Laser Micro-mechaTronics (CHSLT) at the Worcester Polytechnic Institute (WPI) have provided technical assistances in the use of the Holographic Interferometry system. Nima Maftoon and Melissa McKinnon from MEEI for commenting on the manuscript. This work was supported by NRSA 1F32DC009949-01, 1R03DC011617-01, and R01-DC008642 from NIDCD and a donation from L. Mittal. JG was funded by the Swiss National Science Foundation (SNSF). NR 27 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD AUG PY 2015 VL 16 IS 4 BP 413 EP 432 DI 10.1007/s10162-015-0516-x PG 20 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA CL9JF UT WOS:000357293500001 PM 25910607 ER PT J AU Abramovitch, A Abramowitz, JS Mittelman, A Stark, A Ramsey, K Geller, DA AF Abramovitch, Amitai Abramowitz, Jonathan S. Mittelman, Andrew Stark, Abigail Ramsey, Kesley Geller, Daniel A. TI Research Review: Neuropsychological test performance in pediatric obsessive-compulsive disorder - a meta-analysis SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Review DE Obsessive-compulsive disorder; pediatric; neuropsychology; meta-analysis; executive function; developmental; cognitive functions ID MAJOR DEPRESSIVE DISORDER; EXECUTIVE FUNCTION; MOTOR INHIBITION; CHILDREN; ADOLESCENTS; TRICHOTILLOMANIA; DEFICITS; OCD AB BackgroundResearch into the neuropsychology of pediatric obsessive-compulsive disorder (OCD) reveals inconsistent results, limiting the ability to draw conclusions about possible neurocognitive deficits in youth with OCD. The aim of this study was to conduct a meta-analysis of the available literature. MethodsWe identified 36 studies, of which 11 studies met inclusion criteria. Results were categorized into nine functional subdomains: planning, response inhibition/interference control, set shifting/cognitive flexibility, verbal memory, nonverbal memory, processing speed, working memory, visuospatial functions, and attention. For each domain, weighted pooled Hedges' g effect size was calculated using random model analyses. ResultsSmall effect sizes were found across all subdomains, none of which were found to be statistically significant. DiscussionResults indicate that youth with OCD do not exhibit noteworthy neuropsychological deficits. This is in line with recent suggestions that OCD may not be characterized by clinically meaningful neuropsychological impairments. However, the small number of available controlled studies highlights the urgent need for more neuropsychological research in this population, as well as for further exploration of the neurodevelopmental hypothesis in pediatric OCD. Finally, the relatively low persistence rates of OCD into adulthood should be taken under consideration, especially in the context of the putative neuropsychological performance differences between adult and pediatric OCD populations. C1 [Abramovitch, Amitai; Geller, Daniel A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Abramovitch, Amitai; Mittelman, Andrew; Stark, Abigail; Ramsey, Kesley; Geller, Daniel A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Abramovitch, Amitai] Texas State Univ, Dept Psychol, San Marcos, TX USA. [Abramowitz, Jonathan S.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Abramovitch, Amitai] Texas State Univ, Dept Psychol, Undergrad Acad Ctr, San Marcos, TX 78666 USA. RP Abramovitch, A (reprint author), Massachusetts Gen Hosp, OCD & Related Disorders Program, Dept Psychiat, 185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM aabramovitch@mgh.harvard.edu OI Abramovitch, Amitai/0000-0001-9640-0970 NR 58 TC 2 Z9 2 U1 8 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD AUG PY 2015 VL 56 IS 8 BP 837 EP 847 DI 10.1111/jcpp.12414 PG 11 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA CM1WZ UT WOS:000357472500002 PM 25866081 ER PT J AU Spelman, T Morris, MD Zang, G Rice, T Page, K Maher, L Lloyd, A Grebely, J Dore, GJ Kim, AY Shoukry, NH Hellard, M Bruneau, J AF Spelman, T. Morris, M. D. Zang, G. Rice, T. Page, K. Maher, L. Lloyd, A. Grebely, J. Dore, G. J. Kim, A. Y. Shoukry, N. H. Hellard, M. Bruneau, J. CA Int Collaborative Incident HIV Hep TI A longitudinal study of hepatitis C virus testing and infection status notification on behaviour change in people who inject drugs SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID OPIATE SUBSTITUTION THERAPY; ALCOHOL-CONSUMPTION; RISK BEHAVIOR; LIVER-DISEASE; GLOBAL BURDEN; USERS; EPIDEMIOLOGY; EQUIPMENT; IMPACT; HIV AB Background Hepatitis C virus (HCV) testing and counselling have the potential to impact individual behaviour and transmission dynamics at the population level. Evidence of the impact of an HCV-positive status notification on injection risk reduction is limited. The objective of our study was to (1) assess drug and alcohol use and injection risk behaviours following notification; (2) to compare behaviour change in people who inject drugs (PWID) who received a positive test result and those who remained negative; and (3) to assess the effect of age on risk behaviour. Methods Data from the International Collaboration of Incident HIV and HCV Infection in Injecting Cohorts (InC3 Study) were analysed. Participants who were initially HCV seronegative were followed prospectively with periodic HCV blood testing and post-test disclosure and interview-administered questionnaires assessing drug use and injection behaviours. Multivariable generalised estimating equations were used to assess behavioural changes over time. Results Notification of an HCV-positive test was independently associated with a small increase in alcohol use relative to notification of a negative test. No significant differences in postnotification injection drug use, receptive sharing of ancillary injecting equipment and syringe borrowing postnotification were observed between diagnosis groups. Younger PWID receiving a positive HCV test notification demonstrated a significant increase in subsequent alcohol use compared with younger HCV negative. Conclusions The proportion of PWID reporting alcohol use increased among those receiving an HCV-positive notification, increased the frequency of alcohol use postnotification, while no reduction in injection drug use behaviours was observed between notification groups. These findings underscore the need to develop novel communication strategies during post-test notification to improve their impact on subsequent alcohol use and risk behaviours. C1 [Spelman, T.; Hellard, M.] Burnet Inst, Ctr Populat Hlth, Melbourne, Vic, Australia. [Morris, M. D.; Rice, T.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Zang, G.; Shoukry, N. H.; Bruneau, J.] Univ Montreal, CRCHUM, Montreal, PQ H2X 0A9, Canada. [Page, K.] Univ New Mexico, Hlth Sci Ctr, Dept Epidemiol Biostat & Prevent Med, Albuquerque, NM 87131 USA. [Maher, L.; Grebely, J.; Dore, G. J.] UNSW Australia, Kirby Inst, Sydney, NSW, Australia. [Lloyd, A.] UNSW Australia, Sydney, NSW, Australia. [Kim, A. Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kim, A. Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Bruneau, J (reprint author), Univ Montreal, CRCHUM, 850 Rue St Denis,S02-810, Montreal, PQ H2X 0A9, Canada. EM julie.bruneau@umontreal.ca OI Page, Kimberly/0000-0002-7120-1673; Mirzazadeh, Ali/0000-0002-0478-3220 FU National Institute of Health (NIH) National Institute on Drug Abuse (NIDA) [R01-DA32056-01A1]; NIH/NIDA [R01 DA016017, K01 DA037802, RO1 DA 15999-01]; CIHR [MOP-103138, MOP-210232]; National Health and Medical Research Council (NHMRC) Senior Research Fellowship (Elizabeth Blackburn Fellowship-Public Health); NHMRC Career Development Fellowship; NHMRC Practitioner Research Fellowships; Australian Government Department of Health; University of New South Wales (The UNSW Hepatitis C Vaccine Initiative); National Health and Medical Research Council [630483] FX InC3 includes public funding from the National Institute of Health (NIH) National Institute on Drug Abuse (NIDA) grant number R01-DA32056-01A1. MDM is funded in part by NIH/NIDA grant number R01 DA016017 and K01 DA037802. Other research support includes MOP-103138, MOP-210232 (CIHR, JB). LM is supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (Elizabeth Blackburn Fellowship-Public Health). JG is supported by an NHMRC Career Development Fellowship. GJD and AL are supported by NHMRC Practitioner Research Fellowships. The Kirby Institute is affiliated with the Faculty of Medicine, UNSW and received funding from the Australian Government Department of Health. ATAHC was funded by NIH/NIDA grant number RO1 DA 15999-01. HITS-c was initially funded by the University of New South Wales (The UNSW Hepatitis C Vaccine Initiative) and subsequently by the National Health and Medical Research Council (Grant #630483, Hepatitis C Vaccine Preparedness Study). NR 50 TC 2 Z9 2 U1 3 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD AUG PY 2015 VL 69 IS 8 BP 745 EP 752 DI 10.1136/jech-2014-205224 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CM5ID UT WOS:000357720500006 PM 25814695 ER PT J AU Lee, RJ AF Lee, Richard J. TI Molecular Determinants of Metastasis in Renal Cell Cancer: Tracking Down the Real Killer SO JOURNAL OF UROLOGY LA English DT Editorial Material ID CARCINOMA; OSTEOPONTIN; EVOLUTION C1 [Lee, Richard J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Lee, Richard J.] Harvard Univ, Sch Med, Boston, MA USA. RP Lee, RJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 12 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2015 VL 194 IS 2 BP 278 EP 279 DI 10.1016/j.juro.2015.05.032 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CM5QA UT WOS:000357742000001 PM 25986511 ER PT J AU Dinh, KT Mahal, BA Ziehr, DR Muralidhar, V Chen, YW Viswanathan, VB Nezolosky, MD Beard, CJ Choueiri, TK Martin, NE Orio, PF Sweeney, CJ Trinh, QD Nguyen, PL AF Dinh, Kathryn T. Mahal, Brandon A. Ziehr, David R. Muralidhar, Vinayak Chen, Yu-Wei Viswanathan, Vidya B. Nezolosky, Michelle D. Beard, Clair J. Choueiri, Toni K. Martin, Neil E. Orio, Peter F. Sweeney, Christopher J. Trinh, Quoc D. Nguyen, Paul L. TI Incidence and Predictors of Upgrading and Up Staging among 10,000 Contemporary Patients with Low Risk Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE neoplasm grading; neoplasm staging; prostatic neoplasms; SEER program; watchful waiting ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; TARGETED BIOPSY; GLEASON SCORE; NEEDLE-BIOPSY; DIAGNOSIS; OUTCOMES; MEN; PSA AB Purpose: We determined the incidence of pathological upgrading and up staging for contemporary, clinically low risk patients, and identified predictors of having occult, advanced disease to inform the selection of patients for active surveillance. Materials and Methods: We studied 10,273 patients in the SEER database diagnosed with clinically low risk disease (cT1c/T2a, prostate specific antigen less than 10 ng/ml, Gleason 3+3=6) in 2010 to 2011 and treated with prostatectomy. The primary outcome was the incidence of upgrading to pathological Gleason score 7-10 or up staging to pathological T3-T4/N1 disease. Multivariable logistic regression of cases with complete biopsy data (5,581) identified significant predictors of upgrading or up staging, which were then used to create a risk stratification table. Results: At prostatectomy 44% of cases were upgraded and 9.7% were up staged. Multivariable analysis of 5,581 patients showed age, prostate specific antigen and percent positive cores (all p <0.001) but not race were associated with occult, advanced disease. With these variables dichotomized at the median, age older than 60 years (AOR 1.39), prostate specific antigen greater than 5.0 ng/ml (AOR 1.28) and more than 25% positive cores (AOR 1.76) were significantly associated with upgrading (all p <0.001). Similarly, age older than 60 years (AOR 1.42), prostate specific antigen greater than 5.0 ng/ml (AOR 1.44) and more than 25% positive cores (AOR 2.26) were associated with up staging (all p <0.001). Overall 60% of 5,581 low risk cases with prostate specific antigen 7.5 to 9.9 ng/ml and more than 25% positive cores were upgraded. This study is limited by possible bias introduced by only using patients selected for prostatectomy. Conclusions: Nearly half of clinically low risk patients harbor Gleason 7 or greater, or pT3 or greater disease, and should be risk stratified by prostate specific antigen and percent positive cores for consideration of further testing before deciding on active surveillance. C1 [Dinh, Kathryn T.; Mahal, Brandon A.; Ziehr, David R.; Muralidhar, Vinayak] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Yu-Wei] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Viswanathan, Vidya B.; Nezolosky, Michelle D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Viswanathan, Vidya B.; Nezolosky, Michelle D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Beard, Clair J.; Martin, Neil E.; Orio, Peter F.; Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Beard, Clair J.; Choueiri, Toni K.; Martin, Neil E.; Orio, Peter F.; Sweeney, Christopher J.; Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Choueiri, Toni K.; Sweeney, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Trinh, Quoc D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Fitz's Cancer Warriors; Prostate Cancer Foundation FX Supported by Fitz's Cancer Warriors, David and Cynthia Chapin, the Prostate Cancer Foundation, Hugh Simons in honor of Frank and Anne Simons, Scott Forbes and Gina Ventre, and a grant from an anonymous family foundation. NR 30 TC 24 Z9 24 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2015 VL 194 IS 2 BP 343 EP 349 DI 10.1016/j.juro.2015.02.015 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CM5QA UT WOS:000357742000023 PM 25681290 ER PT J AU Pho, MT Jensen, DM Meltzer, DO Kim, AY Linas, BP AF Pho, M. T. Jensen, D. M. Meltzer, D. O. Kim, A. Y. Linas, B. P. TI Clinical impact of treatment timing for chronic hepatitis Cinfection: a decision model SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE decision analysis; HCV; interferon sparing; treatment timing ID C VIRUS-INFECTION; QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; SINGLE HEALTH-STATES; COST-EFFECTIVENESS; FIBROSIS PROGRESSION; NATURAL-HISTORY; UNITED-STATES; SOFOSBUVIR; THERAPY AB Recent advances in the treatment of hepatitis C virus (HCV) infection have led to the availability of both highly efficacious interferon-containing and interferon-sparing regimens. However, the use of such therapies faces restrictions due to high costs. For patients who are medically eligible to receive interferon, the choice between the two will likely be impacted by preferences surrounding interferon, severity of disease, coverage policies and out-of-pocket costs. We developed a decision model to quantify the trade-offs between immediate, interferon-containing therapy and delayed, interferon-free therapy for patients with chronic, genotype 1 HCV infection. We projected the quality-adjusted life expectancy stratified by the presence or absence of cirrhosis for four strategies: (i) no treatment; (ii) immediate, one-time treatment with an interferon-containing regimen; (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1year; and (iv) delayed therapy with interferon-free therapy in 1year. When compared to one-time immediate treatment with the interferon-containing regimen, delayed treatment with the interferon-free regimen in 1year resulted in longer life expectancy, with a 0.2 quality-adjusted life year (QALY) increase in noncirrhotic patients, and a 1.1 QALY increase in patients with cirrhosis. This superiority in health benefits was lost when wait time for interferon-free therapy was greater than 3-3.2years. In this modelling analysis, interferon-free therapy resulted in superior health benefits compared to immediate therapy with interferon until wait time exceeded 3-3.2years. Such data can inform decision-making regarding treatment initiation for HCV as healthcare financing evolves. C1 [Pho, M. T.; Meltzer, D. O.] Univ Chicago, Sect Hosp Med, Dept Med, Chicago, IL 60637 USA. [Pho, M. T.] Univ Chicago, Sect Infect Dis & Global Hlth, Dept Med, Chicago, IL 60637 USA. [Jensen, D. M.] Univ Chicago Med, Sect Gastroenterol Hepatol & Nutr, Ctr Liver Dis, Chicago, IL 60637 USA. [Kim, A. Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Linas, B. P.] Boston Med Ctr, Infect Dis Sect, Dept Med, Boston, MA USA. [Linas, B. P.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Pho, MT (reprint author), Univ Chicago Med, Sect Infect Dis & Global Hlth, 5841 S Maryland Ave,MC 5065, Chicago, IL 60637 USA. EM mpho@bsd.uchicago.edu RI Meltzer, David/C-2926-2009 OI Meltzer, David/0000-0003-2790-7393 FU Agency for Healthcare Research and Quality [K99HS022433]; National Institute of Drug Abuse [R01DA031059] FX This analysis was funded in part by the Agency for Healthcare Research and Quality (K99HS022433 to M.T.P.) and the National Institute of Drug Abuse (R01DA031059 to B.P.L.). The funders did not have any role in the study design, the collection, analysis and interpretation of data, drafting of the manuscript or decision to submit for publication. NR 38 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1352-0504 EI 1365-2893 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD AUG PY 2015 VL 22 IS 8 BP 630 EP 638 DI 10.1111/jvh.12412 PG 9 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA CM0VE UT WOS:000357396100002 PM 26135026 ER PT J AU Bodhankar, S Chen, YX Lapato, A Vandenbark, AA Murphy, SJ Saugstad, JA Offner, H AF Bodhankar, Sheetal Chen, Yingxin Lapato, Andrew Vandenbark, Arthur A. Murphy, Stephanie J. Saugstad, Julie A. Offner, Halina TI Regulatory CD8(+)CD122(+) T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells SO METABOLIC BRAIN DISEASE LA English DT Article DE MCAO; IL-10-secreting B-cells; IL-10(+)CD8(+)CD122(+) regulatory T-cells; Inflammatory cells ID FOCAL CEREBRAL-ISCHEMIA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFARCT SIZE; INFLAMMATORY RESPONSES; RAT-BRAIN; IL-10; INTERLEUKIN-10; NEUROINFLAMMATION; PERMANENT; PROTECTS AB Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10(+) B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10(+) B-cells can exert therapeutic and immunoregulatory effects when injected 24 h after MCAO induction in B-cell-sufficient male WT mice. The results demonstrated that IL-10(+) B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8(+)CD122(+) Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10(+) B-cells in treating MCAO in male WT mice at a time point well beyond the similar to 4 h tPA treatment window, leading to the generation of a dominant IL-10(+)CD8(+)CD122(+) Treg population associated with spleen preservation and reduced CNS inflammation. C1 [Bodhankar, Sheetal; Lapato, Andrew; Vandenbark, Arthur A.; Offner, Halina] VA Med Ctr, Neuroimmunol Res, Portland, OR USA. [Bodhankar, Sheetal; Lapato, Andrew; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Chen, Yingxin; Murphy, Stephanie J.; Saugstad, Julie A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97201 USA. [Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, Neuroimmunol Res, R&D 31, Portland, OR 97239 USA. RP Offner, H (reprint author), Portland VA Med Ctr, Neuroimmunol Res, R&D 31, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu OI Lapato, Andrew/0000-0002-4931-7370 FU NIH/NINDS [1RO1 NS075887]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX The authors wish to thank Gail Kent for the submission of the manuscript. This work was supported by NIH/NINDS 1RO1 NS075887. This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 39 TC 4 Z9 4 U1 2 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 EI 1573-7365 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD AUG PY 2015 VL 30 IS 4 BP 911 EP 924 DI 10.1007/s11011-014-9639-8 PG 14 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA CM1VT UT WOS:000357469300007 PM 25537181 ER PT J AU Shunmugavel, A Khan, M Hughes, FM Purves, JT Singh, A Singh, I AF Shunmugavel, Anandakumar Khan, Mushfiquddin Hughes, Francis M. Purves, J. Todd Singh, Avtar Singh, Inderjit TI y S-Nitrosoglutathione protects the spinal bladder: Novel therapeutic approach to post-spinal cord injury bladder remodeling SO NEUROUROLOGY AND URODYNAMICS LA English DT Article DE bladder dysfunction; GSNO; ICAM-1; inflammation; iNOS; spinal cord injury ID EXTERNAL URETHRAL SPHINCTER; TRAUMATIC BRAIN-INJURY; NITRIC-OXIDE SYNTHASE; RAT URINARY-BLADDER; NEUROGENIC BLADDER; OXIDATIVE INJURY; EXPRESSION; INFLAMMATION; MECHANISMS; CELLS AB AimsBladder and renal dysfunction are secondary events of the inflammatory processes induced by spinal cord injury (SCI). S-Nitrosoglutathione (GSNO), an endogenous nitrosylating agent is pleiotropic and has anti-inflammatory property. Hence, GSNO ameliorates inflammatory sequelae observed in bladder and renal tissues after SCI. Thus, we postulate that GSNO will improve the recovery of micturition dysfunction by quenching the bladder tissue inflammation associated with SCI. MethodsContusion-based mild SCI was induced in female Sprague-Dawley rats. Sham operated rats served as the controls. SCI rats were gavaged daily with GSNO (50 mu g/kg) or vehicle. Bladder function was assessed by urodynamics at 2 and 14 days following SCI. Urine protein concentration and osmolality were measured. Bladder and kidney tissues were analyzed by histology and immunofluorescence for a variety of endpoints related to inflammation. ResultsTwo days after SCI, urodynamics demonstrated a hyperreflexive bladder with overflow and no clear micturition events. By Day 14, vehicle animals regained a semblance of a voiding cycle but with no definite intercontraction intervals. GSNO-treated SCI-rats showed nearly normal cystometrograms. Vehicle-treated SCI rats had increased bladder wet weight, proteinuria, and urine osmolality at Day 14, which was reversed by GSNO treatment. In addition, the SCI-induced increase in immune cell infiltration, collagen deposition, iNOS, and ICAM-1 expression and apoptosis were attenuated by GSNO. ConclusionsThese results indicate that oral administration of GSNO hastens the recovery of bladder function after mild contusion-induced SCI through dampening the inflammation sequelae. These findings also suggest that GSNO-mediated redox modulation may be a novel therapeutic target for the treatment of mild SCI-induced renal and bladder dysfunction. Neurourol. Urodynam. 34:519-526, 2015. (c) 2014 Wiley Periodicals, Inc. C1 [Shunmugavel, Anandakumar; Khan, Mushfiquddin; Singh, Inderjit] Med Univ S Carolina, Charles P Darby Childrens Res Inst, Dept Pediat, Charleston, SC 29425 USA. [Hughes, Francis M.; Purves, J. Todd] Med Univ S Carolina, Charles P Darby Childrens Res Inst, Dept Urol, Charleston, SC 29425 USA. [Purves, J. Todd] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Pathol & Lab Med Serv, Charleston, SC 29425 USA. [Singh, Avtar] Med Univ S Carolina, Pathol & Lab Med Serv, Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29425 USA. RP Singh, I (reprint author), Med Univ S Carolina, Darby Childrens Res Inst, 173 Ashley Ave, Charleston, SC 29425 USA. EM saklaks@gmail.com FU NIH [NS-72511]; Extramural Research Facilities Program of the National Center for Research Resources [CO6 RR0015455]; Spinal Research Foundation VA; Heather Perkins Trew Foundation FX Grant sponsor: NIH; Grant number: NS-72511; Grant sponsor: Extramural Research Facilities Program of the National Center for Research Resources; Grant number: CO6 RR0015455; Grant sponsor: The Spinal Research Foundation VA; Grant sponsor: Heather Perkins Trew Foundation NR 45 TC 1 Z9 1 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2015 VL 34 IS 6 BP 519 EP 526 DI 10.1002/nau.22619 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CM3UF UT WOS:000357609500005 PM 24853799 ER PT J AU Anderson, KS Gerber, JE D'Souza, G Pai, SI Cheng, JN Alam, R Kesiraju, S Chowell, D Gross, ND Haddad, R Gillison, ML Posner, M AF Anderson, Karen S. Gerber, Jennifer E. D'Souza, Gypsyamber Pai, Sara I. Cheng, Julia N. Alam, Rizwan Kesiraju, Sailaja Chowell, Diego Gross, Neil D. Haddad, Robert Gillison, Maura L. Posner, Marshall TI Biologic predictors of serologic responses to HPV in oropharyngeal cancer: The HOTSPOT study SO ORAL ONCOLOGY LA English DT Article DE Antibodies; Serology; Biomarker; HPV; Oropharyngeal cancer ID HUMAN-PAPILLOMAVIRUS; NECK-CANCER; UNITED-STATES; TONSILLAR CANCER; HEAD; ANTIBODIES; INFECTION; SURVIVAL; RISK; CARCINOMA AB Objectives: We hypothesized that viral and host factors impact the serologic responses to HPV early antigens in HPV-positive oropharyngeal cancer (HPVOPC). Materials and methods: We conducted a multicenter study to measure HPV16-specific IgG among patients with HPVOPC, their long-term sexual partners, and healthy volunteers. Risk factor surveys and rinse and gargle specimens were collected. Peripheral blood samples at diagnosis were evaluated for IgG Abs to HPV16 antigens using a programmable ELISA assay. Predictors for HPV16 serologic responses were evaluated using univariate and multivariable linear regression. Results: 116 patients with HPVOPC, 43 partners, and 81 healthy volunteers were enrolled and had baseline sera for analysis. Cases were primarily male (90%), with a median age of 56 years. Abs to E1, E2, E6 or E7 antigens were detected more often in HPVOPC compared with volunteers or partner sera (p < 0.0001). HPV16 Abs to at least one early protein (E1, E2, E4, E5, E6, or E7) were detected in the sera of 90.6% of cases, 0% of partners and 7.4% of healthy volunteers. Gender, race, sexual behavior, and viral integration were not associated with antibody response. Younger age and higher oral HPV16 copy number were associated with higher HPV16 E6 and NE2 antibody levels. Conclusions: HPV16 seroreactivity is commonly detected among patients with HPVOPC at diagnosis, but not among partners or healthy volunteers. Seroreactivity among cases are correlated with viral load and stage and not with other demographic or behavioral factors. Positive HPV16 serology was strongly associated with HPV 16 oropharyngeal cancer. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Anderson, Karen S.; Cheng, Julia N.; Alam, Rizwan; Kesiraju, Sailaja; Chowell, Diego] Arizona State Univ, Biodesign Inst, Ctr Personalized Diagnost, Tempe, AZ 85287 USA. [Gerber, Jennifer E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Pai, Sara I.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Gross, Neil D.] Univ Texas MD Anderson Canc Ctr, Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Haddad, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Posner, Marshall] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Chowell, Diego] Arizona State Univ, Simon A Levin Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. RP Anderson, KS (reprint author), Arizona State Univ, Biodesign Inst, POB 876401, Tempe, AZ 85287 USA. EM Dr.Karen@asu.edu FU Early Detection Research Network (EDRN) [U01CA117374]; Arizona State University; Johns Hopkins Richard Gelb Cancer Prevention Award FX This study was supported by a research grant from the Early Detection Research Network (EDRN) U01CA117374 (K.S.A.), Arizona State University institutional funds (K.S.A.), and the Johns Hopkins Richard Gelb Cancer Prevention Award (G.D.). The authors also thank Alicia Wentz for her data analysis support. NR 37 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD AUG PY 2015 VL 51 IS 8 BP 751 EP 758 DI 10.1016/j.oraloncology.2015.05.007 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA CM4VZ UT WOS:000357684700006 PM 26094591 ER PT J AU Ahmed, Z Samuels, PJ Mai, CL Rodriguez, S Iftikhar, AR Yaster, M AF Ahmed, Zulfiqar Samuels, Paul J. Mai, Christine L. Rodriguez, Samuel Iftikhar, Ahmed Raza Yaster, Myron TI The development of pediatric anesthesiology and critical care medicine at the Cincinnati Children's Hospital: an interview with Dr. Theodore Striker SO PEDIATRIC ANESTHESIA LA English DT Article DE Theodore Striker; pediatric anesthesiology; pediatric intensive care; pediatric critical care medicine ID PARENTS AB Dr. Theodore W. Ted' Striker (1936-), Professor of Anesthesiology and Pediatrics at the University of Cincinnati, has played a pioneering role in the development of pediatric anesthesiology in the United States. As a model educator, clinician, and administrator, he shaped the careers of hundreds of physicians-in-training and imbued them with his core values of honesty, integrity, and responsibility. C1 [Ahmed, Zulfiqar] Anesthesia Associates Ann Arbor, Ann Arbor, MI USA. [Ahmed, Zulfiqar] Wayne State Univ, Detroit, MI USA. [Samuels, Paul J.] Univ Cincinnati, Dept Anesthesia, Cincinnati, OH USA. [Mai, Christine L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Mai, Christine L.] Massachusetts Eye & Ear Infirm, Dept Anesthesia, Boston, MA 02114 USA. [Rodriguez, Samuel] Stanford Univ, Dept Anesthesia, Palo Alto, CA 94304 USA. [Iftikhar, Ahmed Raza] Agha Khan Univ, Karachi, Pakistan. [Yaster, Myron] Johns Hopkins Univ, Dept Anesthesiol, Baltimore, MD USA. [Yaster, Myron] Johns Hopkins Univ, Dept Crit Care Med, Baltimore, MD USA. [Yaster, Myron] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Yaster, Myron] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD USA. RP Mai, CL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care Med & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM cmai1@partners.org NR 5 TC 1 Z9 1 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 EI 1460-9592 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD AUG PY 2015 VL 25 IS 8 BP 764 EP 769 DI 10.1111/pan.12677 PG 6 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA CM5LY UT WOS:000357730600002 PM 25989362 ER PT J AU Schuetz, C Markmann, JF AF Schuetz, Christian Markmann, James F. TI Immunogenicity of beta-cells for autologous transplantation in type 1 diabetes SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Pancreatic beta cells; Islet transplantation; Induced pluripotent stem cells; Immune tolerance; Immunogenicity; Type 1 diabetes mellitus ID PLURIPOTENT STEM-CELLS; REGULATORY T-CELLS; ISLET TRANSPLANTATION; NONHUMAN-PRIMATES; GLYCEMIC CONTROL; MAINTENANCE IMMUNOSUPPRESSION; COSTIMULATION BLOCKADE; CHRONIC-PANCREATITIS; TOLERANCE INDUCTION; SELF-TOLERANCE AB The success of clinical islet transplantation calls for a broader application of this curative treatment for type 1 diabetes mellitus. The toxicity of immunosuppression, limited organ donor supply and high procedural costs are deterrents to expand this therapy to patients with uncomplicated diabetes. The use of pancreatic beta-cell like cells derived from the patient's own induced pluripotent cells (iPSC) holds potential to overcome these barriers. In this review, we discuss the practicality of this regenerative medicine approach and existing evidence regarding the true immunogenicity of iPSC derived cells. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Schuetz, Christian; Markmann, James F.] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Islet Transplantat Lab, Boston, MA 02114 USA. RP Schuetz, C (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Islet Transplantat Lab, 55 Fruit St,Thier 825, Boston, MA 02114 USA. EM chriscgn@gmail.com RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 NR 118 TC 4 Z9 4 U1 1 U2 15 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 AUG PY 2015 VL 98 SI SI BP 60 EP 68 DI 10.1016/j.phrs.2015.03.003 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CL8KV UT WOS:000357224500010 PM 25801943 ER PT J AU Ramos-Casals, M Brito-Zeron, P Kostov, B Siso-Almirall, A Bosch, X Buss, D Trilla, A Stone, JH Khamashta, MA Shoenfeld, Y AF Ramos-Casals, Manuel Brito-Zeron, Pilar Kostov, Belchin Siso-Almirall, Antoni Bosch, Xavier Buss, David Trilla, Antoni Stone, John H. Khamashta, Munther A. Shoenfeld, Yehuda TI Google-driven search for big data in autoimmune geoepidemiology: Analysis of 394,827 patients with systemic autoimmune diseases SO AUTOIMMUNITY REVIEWS LA English DT Review DE Geoepidemiology; Big data; Google; Systemic lupus erythematosus; Sjogren syndrome; Vasculitis; Systemic sclerosis ID GIANT-CELL ARTERITIS; PRIMARY SJOGRENS-SYNDROME; POPULATION-BASED COHORT; PRIMARY IMMUNODEFICIENCY DISEASES; ANCA-ASSOCIATED VASCULITIS; LUPUS-ERYTHEMATOSUS; BEHCETS-DISEASE; KAWASAKI-DISEASE; WEGENERS-GRANULOMATOSIS; POLYMYALGIA-RHEUMATICA AB Systemic autoimmune diseases (SADs) are a significant cause of morbidity and mortality worldwide, although their epidemiological profile varies significantly country by country. We explored the potential of the Google search engine to collect and merge large series (>1000 patients) of SADs reported in the Pubmed library, with the aim of obtaining a high-definition geoepidemiological picture of each disease. We collected data from 394,827 patients with SADs. Analysis showed a predominance of medical vs. administrative databases (74% vs. 26%), public health system vs. health insurance resources (88% vs. 12%) and patient-based vs. population-based designs (82% vs. 18%). The most unbalanced gender ratio was found in primary Sjogren syndrome (pSS), with nearly 10 females affected per 1 male, followed by systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and antiphospholipid syndrome (APS) (ratio of nearly 5:1). Each disease predominantly affects a specific age group: children (Kawasaki disease, primary immunodeficiencies and Schonlein-Henoch disease), young people (SLE Behcet disease and sarcoidosis), middle-aged people (SSc, vasculitis and pSS) and the elderly (amyloidosis, polymyalgia rheumatica, and giant cell arteritis). We found significant differences in the geographical distribution of studies for each disease, and a higher frequency of the three SADs with available data (SLE, inflammatory myopathies and Kawasaki disease) in African-American patients. Using a "big data" approach enabled hitherto unseen connections in SADs to emerge. (C) 2015 Elsevier B.V. All rights reserved. C1 [Ramos-Casals, Manuel; Brito-Zeron, Pilar; Buss, David] Hosp Clin Barcelona, IDIBAPS, Josep Font Lab Autoimmune Dis, Dept Autoimmune Dis,ICMiD,CELLEX, E-08036 Barcelona, Spain. [Kostov, Belchin; Siso-Almirall, Antoni] IDIBAPS, Primary Care Res Grp, Primary Care Ctr Les Corts, CAPSE, Barcelona, Spain. [Bosch, Xavier] Hosp Clin Barcelona, ICMiD, Dept Internal Med, E-08036 Barcelona, Spain. [Trilla, Antoni] Univ Barcelona, Hosp Clin, Prevent Med & Epidemiol Unit, Barcelona Ctr Int Hlth Res, Barcelona, Catalonia, Spain. [Stone, John H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Khamashta, Munther A.] Kings Coll Univ, St Thomas Hosp, Rayne Inst, Lupus Res Unit, London, England. [Shoenfeld, Yehuda] Chaim Sheba Med Ctr, Zabludowicz Ctr Autoimmune Dis, IL-52621 Tel Hashomer, Israel. [Shoenfeld, Yehuda] Tel Aviv Univ, Sackler Fac Med, Laura Schwarz Kipp Chair Res Autoimmune Dis, IL-69978 Tel Aviv, Israel. RP Ramos-Casals, M (reprint author), Hosp Clin Barcelona, Serv Malalties Autoimmunes, C Villarroel 170, E-08036 Barcelona, Spain. EM mramos@clinic.ub.es OI Siso Almirall, Antoni/0000-0001-9832-2689 FU Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain FX Supported by the Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain. NR 98 TC 13 Z9 13 U1 8 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD AUG PY 2015 VL 14 IS 8 BP 670 EP 679 DI 10.1016/j.autrev.2015.03.008 PG 10 WC Immunology SC Immunology GA CL8SE UT WOS:000357243600004 PM 25842074 ER PT J AU Ring, D AF Ring, David TI CORR Insights(A (R)): Higher Preoperative Patient Activation Associated With Better Patient-reported Outcomes After Total Joint Arthroplasty SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material ID TOTAL KNEE REPLACEMENT; ILLNESS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2015 VL 473 IS 8 BP 2698 EP 2699 DI 10.1007/s11999-015-4274-1 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CL9CG UT WOS:000357271500037 PM 25809875 ER PT J AU Suter, MJ Kashiwagi, M Gallagher, KA Nadkarni, SK Asanani, N Tanaka, A Conditt, GB Tellez, A Milewski, K Kaluza, GL Granada, JF Bouma, BE Tearney, GJ AF Suter, Melissa J. Kashiwagi, Manabu Gallagher, Kevin A. Nadkarni, Seemantini K. Asanani, Nayan Tanaka, Atsushi Conditt, Gerard B. Tellez, Armando Milewski, Krzysztof Kaluza, Greg L. Granada, Juan F. Bouma, Brett E. Tearney, Guillermo J. TI Optimizing flushing parameters in intracoronary optical coherence tomography: an in vivo swine study SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Optical coherence tomography; Intracoronary imaging; Optical frequency domain imaging; Refractive index; Viscosity; Flushing ID SIROLIMUS-ELUTING STENT; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; IMPLANTATION; MICROSCOPY; HISTOLOGY; DISEASE; CULPRIT AB Intracoronary optical frequency domain imaging (OFDI), requires the displacement of blood for clear visualization of the artery wall. Radiographic contrast agents are highly effective at displacing blood however, may increase the risk of contrast-induced nephropathy. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. The aim of this work was to determine the optimal flushing parameters necessary to reliably perform intracoronary OFDI while reducing the volume of administered radiographic contrast, and assess the influence of flushing media choice on vessel wall measurements. 144 OFDI pullbacks were acquired together with synchronized EKG and intracoronary pressure wire recordings in three swine. OFDI images were graded on diagnostic quality and quantitative comparisons of flushing efficiency and intracoronary cross-sectional area with and without precise refractive index calibration were performed. Flushing media with higher viscosities resulted in rapid and efficient blood displacement. Media with lower viscosities resulted in increased blood-media transition zones, reducing the pullback length of diagnostic quality images obtained. Flushing efficiency was found to increase with increases in flow rate and duration. Calculations of lumen area using different flushing media were significantly different, varying up to 23 % (p < 0.0001). This error was eliminated with careful refractive index calibration. Flushing media viscosity, flow rate, and flush duration influence the efficiency of blood displacement necessary for obtaining diagnostic quality OFDI images. For patients with sensitivity to contrast, to reduce the risk of contrast induced nephrotoxicity we recommend that intracoronary OFDI be conducted with flushing solutions containing little or no radiographic contrast. In addition, our findings show that careful refractive index compensation should be performed, taking into account the specific contrast agent used, in order to obtain accurate intravascular OFDI measurements. C1 [Suter, Melissa J.; Kashiwagi, Manabu; Gallagher, Kevin A.; Nadkarni, Seemantini K.; Asanani, Nayan; Tanaka, Atsushi; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Suter, Melissa J.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Nadkarni, Seemantini K.; Bouma, Brett E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tearney, Guillermo J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Suter, Melissa J.; Nadkarni, Seemantini K.; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA USA. [Bouma, Brett E.; Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Conditt, Gerard B.; Tellez, Armando; Milewski, Krzysztof; Kaluza, Greg L.; Granada, Juan F.] Cardiovasc Res Fdn, Skirball Ctr Cardiovasc Res, Orangeburg, NY USA. RP Suter, MJ (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM msuter@mgh.harvard.edu; gtearney@mgh.harvard.edu FU Merck; National Institutes of Health [R00CA134920, R01HL076398, R01HL093717] FX The work presented in this manuscript was supported by a gift from Merck, and from the National Institutes of Health (Grant Numbers R00CA134920, R01HL076398, R01HL093717). NR 34 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD AUG PY 2015 VL 31 IS 6 BP 1097 EP 1106 DI 10.1007/s10554-015-0668-0 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CL7BS UT WOS:000357125600001 PM 25922149 ER PT J AU Adams, SA Choi, SK Khang, L Campbell, DA Friedman, DB Eberth, JM Glasgow, RE Tucker-Seeley, R Xirasagar, S Yip, MP Young, VM Hebert, JR AF Adams, Swann Arp Choi, Seul Ki Khang, Leepao Campbell, Dayna A. Friedman, Daniela B. Eberth, Jan M. Glasgow, Russell E. Tucker-Seeley, Reginald Xirasagar, Sudha Yip, Mei Po Young, Vicki M. Hebert, James R. TI Decreased Cancer Mortality-to-Incidence Ratios with Increased Accessibility of Federally Qualified Health Centers SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Cancer; Community health centers; Medically underserved areas; African Americans; Health care disparity ID HOUSEHOLD TRAVEL SURVEY; CERVICAL-CANCER; PROSTATE-CANCER; DISPARITIES; CARE; STATISTICS; TRENDS; STATES AB Federally qualified health centers (FQHCs) offer primary and preventive healthcare, including cancer screening, for the nation's most vulnerable population. The purpose of this study was to explore the relationship between access to FQHCs and cancer mortality-to-incidence ratios (MIRs). One-way analysis of variance was conducted to compare the mean MIRs for breast, cervical, prostate, and colorectal cancers for each U.S. county for 2006-2010 by access to FQHCs (direct access, in-county FQHC; indirect access, adjacent-county FQHC; no access, no FQHC either in the county or in adjacent counties). ArcMap 10.1 software was used to map cancer MIRs and FQHC access levels. The mean MIRs for breast, cervical, and prostate cancer differed significantly across FQHC access levels (p < 0.05). In urban and healthcare professional shortage areas, mean MIRs decreased as FQHC access increased. A trend of lower breast and prostate cancer MIRs in direct access to FQHCs was found for all racial groups, but this trend was significant for whites only. States with a large proportion of rural and medically underserved areas had high mean MIRs, with correspondingly more direct FQHC access. Expanding FQHCs to more underserved areas and concentrations of disparity populations may have an important role in reducing cancer morbidity and mortality, as well as racial-ethnic disparities, in the United States. C1 [Adams, Swann Arp; Choi, Seul Ki; Friedman, Daniela B.; Eberth, Jan M.; Xirasagar, Sudha; Hebert, James R.] Univ S Carolina, Arnold Sch Publ Hlth, Canc Prevent & Control Program, Columbia, SC 29208 USA. [Adams, Swann Arp; Eberth, Jan M.; Hebert, James R.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Adams, Swann Arp] Univ S Carolina, Coll Nursing, Columbia, SC 29208 USA. [Choi, Seul Ki; Friedman, Daniela B.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. [Khang, Leepao] Calif State Univ Fresno, Dept Publ Hlth, Fresno, CA 93740 USA. [Campbell, Dayna A.; Young, Vicki M.] South Carolina Primary Hlth Care Assoc, Columbia, SC 29203 USA. [Glasgow, Russell E.] Univ Colorado Denver, Sch Med, Denver, CO 80045 USA. [Glasgow, Russell E.] Univ Colorado Denver, Colorado Hlth Outcomes Res Program, Denver, CO 80045 USA. [Tucker-Seeley, Reginald] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Tucker-Seeley, Reginald] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02215 USA. [Xirasagar, Sudha] Univ S Carolina, Arnold Sch Publ Hlth, Dept Hlth Serv Policy & Management, Columbia, SC 29208 USA. [Yip, Mei Po] Univ Washington, Div Gen Internal Med, Seattle, WA 98104 USA. RP Adams, SA (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Canc Prevent & Control Program, 915 Greene St, Columbia, SC 29208 USA. EM swann.adams@sc.edu; choi27@email.sc.edu; lkhang@csufresno.edu; daynac@scphca.org; dbfriedman@sc.edu; jmeberth@mailbox.sc.edu; Russell.glasgow@ucdenver.edu; retucker@hsph.harvard.edu; sxirasag@mailbox.sc.edu; yipm@u.washington.edu; vickiy@scphca.org; jhebert@sc.edu RI Eberth, Jan/A-1335-2014 OI Eberth, Jan/0000-0001-9500-4212 FU Centers for Disease Control and Prevention (Prevention Research Centers) [U48/DP001936]; National Cancer Institute; Cancer Training Branch of the NCI [K05 CA136975]; National Cancer Institute, Center to Reduce Cancer Health Disparities (Community Networks Program) [U54 CA153461-01]; NCI [K01 CA169041]; National Cancer Institute [R01 CA 124397] FX This publication was supported by Cooperative Agreement Number U48/DP001936 from the Centers for Disease Control and Prevention (Prevention Research Centers) and the National Cancer Institute (PIs: Dr. Hebert, Dr. Friedman). This work also was partially supported by: an Established Investigator Award in Cancer Prevention and Control from the Cancer Training Branch of the NCI to Dr. Hebert (K05 CA136975), U54 CA153461-01 from the National Cancer Institute, Center to Reduce Cancer Health Disparities (Community Networks Program) to the South Carolina Cancer Disparities Community Network-II (SCCDCN-II), and an NCI K01 Career Development Grant to Dr. Tucker-Seeley (K01 CA169041). Dr. Yip was partially supported by the National Cancer Institute (R01 CA 124397; PI: S-P Tu). NR 26 TC 4 Z9 4 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD AUG PY 2015 VL 40 IS 4 BP 633 EP 641 DI 10.1007/s10900-014-9978-8 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CM0BI UT WOS:000357342800004 PM 25634545 ER PT J AU Probst, MA Kanzaria, HK Gbedemah, M Richardson, LD Sun, BC AF Probst, Marc A. Kanzaria, Hemal K. Gbedemah, Misato Richardson, Lynne D. Sun, Benjamin C. TI National trends in resource utilization associated with ED visits for syncope SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID US EMERGENCY-DEPARTMENTS; RISK STRATIFICATION; MANAGEMENT; OUTCOMES AB Background: Over the last 20 years, numerous research articles and clinical guidelines aimed at optimizing resource utilization for emergency department (ED) patients presenting with syncope have been published. Hypothesis: We hypothesized that there would be temporal trends in syncope-related ED visits and associated trends in imaging, hospital admissions, and diagnostic frequencies. Methods: The ED component of National Hospital Ambulatory Medical Care Survey was analyzed from 2001 through 2010, comprising more than 358000 visits (representing an estimated 1.18 billion visits nationally). We selected ED visits with a reason for visit of syncope or fainting and calculated nationally representative weighted estimates for prevalence of such visits and associated rates of advanced imaging utilization and admission. For admitted patients from 2005 to 2010, the most frequent hospital discharge diagnoses were tabulated. Results: During the study period, there were more than 3500 actual ED visits (representing 11.9 million visits nationally) related to syncope, representing roughly 1% of all ED visits. Admission rates for syncope patients ranged from 27% to 35% and showed no significant downward trend (P = .1). Advanced imaging rates increased from about 21% to 45% and showed a significant upward trend (P < .001). For admitted patients, the most common hospital discharge diagnosis was the symptomatic diagnosis of "syncope and collapse" (36.4%). Conclusions: Despite substantial efforts by medical researchers and professional societies, resource utilization associated with ED visits for syncope appears to have actually increased. There have been no apparent improvements in diagnostic yield for admissions. Novel strategies may be needed to change practice patterns for such patients. (C) 2015 Elsevier Inc. All rights reserved. C1 [Probst, Marc A.; Gbedemah, Misato; Richardson, Lynne D.] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. [Kanzaria, Hemal K.] UCLA, Robert Wood Johnson Fdn Clin Scholar, Dept Emergency Med, Los Angeles, CA USA. [Kanzaria, Hemal K.] Univ Calif Los Angeles, Sch Med, Ctr Emergency Med, US Dept Vet Affairs, Los Angeles, CA 90095 USA. [Sun, Benjamin C.] Oregon Hlth & Sci Univ, CDW EM, Dept Emergency Med, Portland, OR 97239 USA. RP Probst, MA (reprint author), Icahn Sch Med Mt Sinai, Dept Emergency Med, 3 East 101st St,Second Floor,Room 209, New York, NY 10029 USA. EM mprobst@gmail.com; hemal.kanzaria@gmail.com; misato.gbedemah@mountsinai.org; lynne.richardson@mountsinai.org; sunb@ohsu.edu FU NHLBI NIH HHS [K12 HL109005, 5K12 HL109005-03, R01 HL111033] NR 13 TC 2 Z9 2 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2015 VL 33 IS 8 BP 998 EP 1001 DI 10.1016/j.ajem.2015.04.030 PG 4 WC Emergency Medicine SC Emergency Medicine GA CL0BR UT WOS:000356604000002 PM 25943042 ER PT J AU Liu, SW Obermeyer, Z Chang, YC Shankar, KN AF Liu, Shan W. Obermeyer, Ziad Chang, Yuchiao Shankar, Kalpana N. TI Frequency of ED revisits and death among older adults after a fall SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; EMERGENCY-DEPARTMENT; RISK-FACTORS; AFTER-DISCHARGE; INJURY SEVERITY; RECURRENT FALLS; PREDICTORS; PREVENTION; MORTALITY; PATTERNS AB Introduction: Falls among older adults (aged >= 65 years) are the leading cause of both injury deaths and emergency department (ED) visits for trauma. We examine the characteristics and prevalence of older adult ED fallers as well as the recurrent ED visit and mortality rate. Methods: This was a retrospective analysis of a cohort of elderly fall patients who presented to the ED between 2005 and 2011 of 2 urban, level 1 trauma, teaching hospitals with approximately 80000 to 95000 annual visits. We examined the frequency of ED revisits and death at 3 days, 7 days, 30 days, and 1 year controlling for certain covariates. Results: Our cohort included 21340 patients. The average age was 78.6 years. An increasing proportion of patients revisited the ED over the course of 1 year, ranging from 2% of patients at 3 days to 25% at 1 year. Death rates increased from 1.2% at 3 days to 15% at 1 year. A total of 10728 patients (50.2%) returned to the ED at some point during our 7-year study period, and 36% of patients had an ED revisit or death within 1 year. In multivariate logistic regression, male sex and comorbidities were associated with ED revisits and death. Conclusion: More than one-third of older adult ED fall patients had an ED revisit or died within 1 year. Falls are one of the geriatric syndromes that contribute to frequent ED revisits and death rates. Future research should determine whether falls increase the risk of such outcomes and how to prevent future fall and death. (C) 2015 Elsevier Inc. All rights reserved. C1 [Liu, Shan W.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Obermeyer, Ziad] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Shankar, Kalpana N.] Boston Univ, Med Ctr, Dept Emergency Med, Boston, MA USA. RP Liu, SW (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 3rd Floor,55 Fruit St, Boston, MA 02114 USA. EM sliu1@partners.org FU NIH HHS [DP5 OD012161] NR 25 TC 8 Z9 8 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2015 VL 33 IS 8 BP 1012 EP 1018 DI 10.1016/j.ajem.2015.04.023 PG 7 WC Emergency Medicine SC Emergency Medicine GA CL0BR UT WOS:000356604000005 PM 25983268 ER PT J AU Prabhakar, AM Misono, AS Harvey, HB Yun, BJ Saini, S Oklu, R AF Prabhakar, Anand M. Misono, Alexander S. Harvey, H. Benjamin Yun, Brian J. Saini, Sanjay Oklu, Rahmi TI Imaging utilization from the ED: no difference between observation and admitted patients SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID DEPARTMENT OBSERVATION UNITS; TRANSIENT ISCHEMIC ATTACK; EMERGENCY-DEPARTMENT; CHEST-PAIN AB Objectives: This study aims to determine the use of diagnostic imaging in emergency department (ED) observation units, particularly relative to inpatients admitted from the ED. Study Design: Retrospective, descriptive analysis. Methods: Our database of ED patients was retrospectively reviewed to identify patients managed in the observation unit or admitted to inpatient services. In February 2014, we randomly selected 105 ED observation patients and 108 patients admitted to inpatient services from the ED. Electronic medical records were reviewed to assess diagnosis as well as type and quantity of imaging tests obtained. Results: Eighty (76%) ED observation patients underwent imaging tests (radiographs, 39%; computed tomography, 25%; magnetic resonance imaging (MRI), 24%; ultrasound, 8%; other, 4%); 85 inpatients (79%) underwent imaging tests while in the ED (radiographs, 52%; computed tomography, 30%; MRI, 8%; ultrasound, 9%; other, 1%). There was no significant difference in overall imaging use between ED observation patients and inpatients, but ED observation patients were more likely to undergo MRI (P = .0243). The most common presenting diagnoses to the ED observation unit were neurologic complaints (25%), abdominal pain (17%), and cardiac symptoms (16%). Conclusion: There is no difference in the overall use of imaging in patients transferred to the ED observation unit vs those directly admitted from the ED. However, because ED observation unit patients tend to be accountable for a higher proportion of their health care bill, the impact of imaging in these patients is likely substantive. (C) 2015 Elsevier Inc. All rights reserved. C1 [Prabhakar, Anand M.] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Div Cardiovasc Imaging & Emergency Imaging,Med Sc, Boston, MA 02114 USA. [Misono, Alexander S.; Harvey, H. Benjamin; Saini, Sanjay] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Yun, Brian J.] Harvard Univ, Dept Emergency Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Oklu, Rahmi] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Div Vasc Imaging & Intervent,Med Sch, Boston, MA 02114 USA. RP Prabhakar, AM (reprint author), Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM aprabhakar@partners.org OI Yun, Brian/0000-0002-3842-420X NR 19 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2015 VL 33 IS 8 BP 1076 EP 1079 DI 10.1016/j.ajem.2015.04.025 PG 4 WC Emergency Medicine SC Emergency Medicine GA CL0BR UT WOS:000356604000017 PM 25957145 ER PT J AU Galea, E Morrison, W Hudry, E Arbel-Ornath, M Bacskai, BJ Gomez-Isla, T Stanley, HE Hyman, BT AF Galea, E. Morrison, W. Hudry, E. Arbel-Ornath, M. Bacskai, B. J. Gomez-Isla, T. Stanley, H. E. Hyman, B. T. TI A statistical physics-based spatial analysis in APP/PS1 mice reveals that astrocytes do not migrate to amyloid-beta plaques SO GLIA LA English DT Meeting Abstract CT 12th European Meeting on Glial Cell Function in Health and Disease CY JUL 15-18, 2015 CL Bilbao, SPAIN C1 [Galea, E.] Univ Autonoma Barcelona, Inst Neurociencies, Bellaterra, Spain. [Morrison, W.; Stanley, H. E.] Boston Univ, Ctr Polymer Studies, Boston, MA 02215 USA. [Hudry, E.; Arbel-Ornath, M.; Bacskai, B. J.; Gomez-Isla, T.; Hyman, B. T.] Massachusetts Gen Hosp, MIND, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD AUG PY 2015 VL 63 SU 1 MA T12-18B BP E369 EP E369 PG 1 WC Neurosciences SC Neurosciences & Neurology GA CK7CA UT WOS:000356386700621 ER PT J AU Stewart, LK Peitz, GW Nordenholz, KE Courtney, DM Kabrhel, C Jones, AE Rondina, MT Diercks, DB Klinger, JR Kline, JA AF Stewart, Lauren K. Peitz, Geoffrey W. Nordenholz, Kristen E. Courtney, D. Mark Kabrhel, Christopher Jones, Alan E. Rondina, Matthew T. Diercks, Deborah B. Klinger, James R. Kline, Jeffrey A. TI Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Pulmonary embolism; Submassive; Fibrinolysis; Quality of life ID QUALITY-OF-LIFE; RISK AB Acute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), P < 0.001, with R-2 = 0.303. Obesity had the largest effect on PCS (beta = -8.6, P < 0.001), with tenecteplase second (beta = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (-0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions. C1 [Stewart, Lauren K.; Peitz, Geoffrey W.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Nordenholz, Kristen E.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO USA. [Courtney, D. Mark] Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Chicago, IL 60611 USA. [Kabrhel, Christopher] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Jones, Alan E.] Univ Mississippi, Med Ctr, Dept Emergency Med, Jackson, MS 39216 USA. [Rondina, Matthew T.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Diercks, Deborah B.] Univ Texas SW Med Ctr Dallas, Dept Emergency Med, Dallas, TX 75390 USA. [Klinger, James R.] Brown Univ, Alpert Med Sch, Dept Internal Med, Providence, RI 02912 USA. [Kline, Jeffrey A.] Indiana Univ Sch Med, Dept Emergency Med & Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. RP Kline, JA (reprint author), Indiana Univ Sch Med, Dept Emergency Med & Cellular & Integrat Physiol, 720 Eskenazi Ave, Indianapolis, IN 46202 USA. EM laustewa@iupui.edu; gpeitz@iupui.edu; Kristen.Nordenholz@ucdenver.edu; d-courtney@northwestern.edu; ckabrhel@partners.org; aejones@umc.edu; Matthew.Rondina@hsc.utah.edu; deborah.diercks@utsouthwestern.edu; JKlinger@Lifespan.org; jefkline@iu.edu OI Kabrhel, Christopher/0000-0002-8699-7176 FU NHLBI NIH HHS [R01 HL126547, U54 HL112311, K23 HL092161]; NIA NIH HHS [R01 AG048022, R03 AG040631] NR 14 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD AUG PY 2015 VL 40 IS 2 BP 161 EP 166 DI 10.1007/s11239-014-1155-5 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CL0BT UT WOS:000356604200005 PM 25433511 ER PT J AU Vaduganathan, M Zemer-Wassercug, N Rechavia, E Lerman-Shivek, H Perl, L Leshem-Lev, D Orvin, K Kornowski, R Lev, EI AF Vaduganathan, Muthiah Zemer-Wassercug, Noa Rechavia, Eldad Lerman-Shivek, Hila Perl, Leor Leshem-Lev, Dorit Orvin, Katia Kornowski, Ran Lev, Eli I. TI Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-ST elevation acute coronary syndromes SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Antiplatelet; Percutaneous coronary intervention; Platelet function; Ticagrelor ID OUTCOMES PLATO TRIAL; MYOCARDIAL-INFARCTION; CLOPIDOGREL; INHIBITION; REACTIVITY; PRASUGREL; INTERVENTION; HETEROGENEITY; THROMBOSIS; ASPIRIN AB Antiplatelet responses to clopidogrel and prasugrel are highly variable and subject to significant rates of high on-treatment platelet reactivity (HTPR) after percutaneous coronary intervention (PCI). The proportion of circulating young reticulated platelets (RPs) inversely correlates with responsiveness to both agents. We aimed to determine the relationship between RPs and on-treatment platelet reactivity in ticagrelor-treated patients. Patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) treated with PCI and ticagrelor were tested for platelet reactivity using the VerifyNow P2Y12 assay and multiplate aggregometry. RPs levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2-4 and 30 days post-PCI. Fifty three patients were included (mean age 62.6 +/- A 9.8 years, 18.9 % women, 35.8 % diabetes), of which 41 patients (77 %) completed follow-up. Variability in response to ticagrelor was very low according to both assays with no identified cases of HTPR at either time-point. In addition, there were no differences in platelet reactivity, as analyzed by the VerifyNow P2Y12 assay, or in the proportion of RPs between the two time points (p > 0.5). With the multiplate assay, platelet reactivity increased between the two time-points (8.6 +/- A 6.0 vs. 15.5 +/- A 11 AU*min; p = 0.0007). There was no significant correlation between RPs and platelet reactivity at both time-points and using both assays (p > 0.5). There were no cases of HTPR up to 30-days post-PCI in patients with NSTE-ACS treated with ticagrelor. In this cohort, no correlation between % RPs and platelet reactivity was observed. Attenuation of RP-induced platelet reactivity as a novel mechanism for ticagrelor's benefit requires further investigation. C1 [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Zemer-Wassercug, Noa; Rechavia, Eldad; Lerman-Shivek, Hila; Perl, Leor; Orvin, Katia; Kornowski, Ran; Lev, Eli I.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Zemer-Wassercug, Noa; Rechavia, Eldad; Lerman-Shivek, Hila; Perl, Leor; Orvin, Katia; Kornowski, Ran; Lev, Eli I.] Tel Aviv Univ, Sackler Fac Med, Petah Tiqwa, Israel. [Lerman-Shivek, Hila] Hebrew Univ Jerusalem, Sch Pharm, Dept Clin Pharm, IL-91120 Jerusalem, Israel. [Leshem-Lev, Dorit] Rabin Med Ctr, Felsenstein Med Res Inst, Petah Tiqwa, Israel. RP Vaduganathan, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, 55 Fruit St,GRB 740, Boston, MA 02114 USA. EM muthu@md.northwestern.edu NR 32 TC 6 Z9 7 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD AUG PY 2015 VL 40 IS 2 BP 211 EP 217 DI 10.1007/s11239-015-1178-6 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CL0BT UT WOS:000356604200013 PM 25631351 ER PT J AU Parikh, NS Howard, SC Chantada, G Israels, T Khattab, M Alcasabas, P Lam, CG Faulkner, L Park, JR London, WB Matthay, KK AF Parikh, Nehal S. Howard, Scott C. Chantada, Guillermo Israels, Trijn Khattab, Mohammed Alcasabas, Patricia Lam, Catherine G. Faulkner, Lawrence Park, Julie R. London, Wendy B. Matthay, Katherine K. TI SIOP-PODC adapted risk stratification and treatment guidelines: Recommendations for neuroblastoma in low- and middle-income settings SO PEDIATRIC BLOOD & CANCER LA English DT Article DE diagnosis; low income countries; MYCN; Neuroblastoma; resource limited countries; treatment ID CHILDRENS-ONCOLOGY-GROUP; STAGE 4 NEUROBLASTOMA; STEM-CELL TRANSPLANTATION; OF-PEDIATRIC-ONCOLOGY; INRG TASK-FORCE; INDUCTION CHEMOTHERAPY; RANDOMIZED-TRIAL; 13-CIS-RETINOIC ACID; PHASE-II; REFRACTORY NEUROBLASTOMA AB Neuroblastoma is the most common extracranial solid tumor in childhood in high-income countries (HIC), where consistent treatment approaches based on clinical and tumor biological risk stratification have steadily improved outcomes. However, in low- and middle- income countries (LMIC), suboptimal diagnosis, risk stratification, and treatment may occur due to limited resources and unavailable infrastructure. The clinical practice guidelines outlined in this manuscript are based on current published evidence and expert opinions. Standard risk stratification and treatment explicitly adapted to graduated resource settings can improve outcomes for children with neuroblastoma by reducing preventable toxic death and relapse. Pediatr Blood Cancer 2015;62:1305-1316. (c) 2015 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc. C1 [Parikh, Nehal S.] Connecticut Childrens Med Ctr, Div Hematol Oncol, Dept Pediat, Hartford, CT 06106 USA. [Howard, Scott C.] Univ Memphis, Memphis, TN 38152 USA. [Chantada, Guillermo] Hosp JP Garrahan, Dept Hematooncol, Buenos Aires, DF, Argentina. [Israels, Trijn] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Khattab, Mohammed] Childrens Hosp Rabat, Dept Paediat, Rabat, Morocco. [Alcasabas, Patricia] Univ Philippines, Philippine Gen Hosp, Manila, Philippines. [Lam, Catherine G.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Lam, Catherine G.] St Jude Childrens Res Hosp, Int Outreach Program, Memphis, TN 38105 USA. [Faulkner, Lawrence] Cure2Children Fdn, Florence, Italy. [Park, Julie R.] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA USA. [Park, Julie R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [London, Wendy B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [London, Wendy B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Matthay, Katherine K.] UCSF Sch Med, Dept Pediat, San Francisco, CA USA. [Matthay, Katherine K.] UCSF Benioff Childrens Hosp, San Francisco, CA USA. RP Parikh, NS (reprint author), Connecticut Childrens Med Ctr, Hematol Oncol, 282 Washington St,5A, Hartford, CT 06106 USA. EM nparikh@connecticutchildrens.org RI Lam, Catherine/K-6328-2014 OI Lam, Catherine/0000-0003-1363-5331 FU Mildred V. Strouss chair; Dougherty Foundation; Campini Foundation; Conner fund; American Lebanese Syrian Associated Charities (ALSAC); Fondazione Umberto Veronesi FX Katherine K. Matthay was supported by Mildred V. Strouss chair, Dougherty Foundation, Campini Foundation, Conner fund; Catherine G. Lam was supported by American Lebanese Syrian Associated Charities (ALSAC), and Lawrence Faulkner was supported by Fondazione Umberto Veronesi. NR 91 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2015 VL 62 IS 8 BP 1305 EP 1316 DI 10.1002/pbc.25501 PG 12 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CL3RD UT WOS:000356867200003 PM 25810263 ER PT J AU Suarez, A Pina, M Nichols-Vinueza, DX Lopera, J Rengifo, L Mesa, M Cardenas, M Morrissey, L Veintemilla, G Vizcaino, M Del Toro, L Vicuna, V Fernandez, J Neuberg, D Stevenson, K Gutierrez, A AF Suarez, Amaranto Pina, Martha Nichols-Vinueza, Diana X. Lopera, John Rengifo, Lyda Mesa, Mauricio Cardenas, Marcela Morrissey, Lisa Veintemilla, Galo Vizcaino, Martha Del Toro, Ligia Vicuna, Victor Fernandez, Jorge Neuberg, Donna Stevenson, Kristen Gutierrez, Alejandro TI A strategy to improve treatment-related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ALL; outcomes research; pediatric hematology; oncology ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; PEDIATRIC ONCOLOGY; HOSPITAL MORTALITY; NURSING-CARE; PROGRAM; ADOLESCENTS; NICARAGUA; STANDARDS; INDONESIA AB BackgroundTreatment-related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world. ProcedureA collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper-middle income country, and Dana-Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced-intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact. ResultsThe Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995-2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P=0.005), abandonment (32% to 9%; P<0.001), and event-free survival with abandonment considered an event (47% to 65% at 2 years; P=0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy 4 weeks delayed predicted markedly inferior disease-free survival (P=0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high-income countries. ConclusionsImplementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395-1402. (c) 2015 Wiley Periodicals, Inc. C1 [Suarez, Amaranto; Pina, Martha; Lopera, John; Rengifo, Lyda; Mesa, Mauricio; Cardenas, Marcela; Vizcaino, Martha; Del Toro, Ligia; Vicuna, Victor] Inst Nacl Cancerol, Dept Pediat, Bogota, Colombia. [Veintemilla, Galo] Inst Nacl Cancerol, Dept Surg, Bogota, Colombia. [Nichols-Vinueza, Diana X.; Morrissey, Lisa; Gutierrez, Alejandro] Harvard Univ, Sch Med, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA USA. [Fernandez, Jorge; Gutierrez, Alejandro] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Neuberg, Donna; Stevenson, Kristen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Gutierrez, A (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM alejandro.gutierrez@childrens.harvard.edu FU World Child Cancer (London, UK); US National Cancer Institute; US Department of Defense; William Lawrence & Blanche Hughes Foundation; Boston Children's Hospital FX This work was supported by World Child Cancer (London, UK) and institutional resources of the INC. We thank the OPNICER foundation, Stella Moreno and Patricia Salcedo for help reducing abandonment of therapy, Patricia Salcedo and Carlos Diaz Villalobos for data management, and Lilliana Lopera and Susan Naughton for translation. We thank Raul Ribeiro, Scott Howard, Pedro De Alarcon, Carlos Rodriguez-Galindo and Paola Friedrich-Medina for assistance with implementation of the twinning program. We also thank Sara Day for advice on nursing assessment and education, Patricia Robinson for assistance with initial nursing site assessment, and Brian Delaney for consultation on training and clinical problems in psychosocial care. A.G. is a Research Fellow of the Gabrielle's Angel Foundation for Cancer Research, a Clinical Investigator of the Damon Runyon Cancer Research Foundation, and receives research support from the US National Cancer Institute, US Department of Defense, William Lawrence & Blanche Hughes Foundation, and Boston Children's Hospital. NR 28 TC 3 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2015 VL 62 IS 8 BP 1395 EP 1402 DI 10.1002/pbc.25510 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CL3RD UT WOS:000356867200014 PM 25808195 ER PT J AU Kassam, A Skiadaresis, J Alexander, S Wolfe, J AF Kassam, Alisha Skiadaresis, Julia Alexander, Sarah Wolfe, Joanne TI Differences in end-of-life communication for children with advanced cancer who were referred to a palliative care team SO PEDIATRIC BLOOD & CANCER LA English DT Article DE end of life; pediatric oncology; supportive care ID RANDOMIZED CONTROLLED-TRIAL; AMERICAN SOCIETY; IMPACT; CONSULTATION; MALIGNANCIES; PERSPECTIVES; ONCOLOGISTS; INTEGRATION; PREDICTORS; PROGNOSIS AB BackgroundThere is a general consensus that involving a specialized palliative care team in the care of children with advanced cancer can help optimize end-of-life communication; however, how this compares to standard oncology care is still unknown. We aimed to determine whether there was an association between specialist palliative care involvement and improved end-of-life communication for children with advanced cancer and their families. ProcedureWe administered questionnaires to 75 bereaved parents (response rate 54%). Outcome measures were presence or absence of 11 elements related to end-of-life communication. ResultsParents were significantly more likely to receive five communication elements if their child was referred to a palliative care team. These elements are: discussion of death and dying with parents by the healthcare team (P<0.01); discussion of death and dying with child by the healthcare team when appropriate (P<0.01); providing parents with guidance on how to talk to their child about death and dying when appropriate (P<0.01); preparing parents for medical aspects surrounding death (P=0.02) and sibling support (P=0.02). Children were less likely to be referred to a palliative care team if they had a hematologic malignancy. ConclusionsChildren who receive standard oncology care are at higher risk of not receiving critical communication elements at end of life. Strategies to optimize end-of-life communication for children who are not referred to a palliative care team are needed. Pediatr Blood Cancer 2015;62:1409-1413. (c) 2015 Wiley Periodicals, Inc. C1 [Kassam, Alisha; Alexander, Sarah] Hosp Sick Children, Dept Pediat, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Skiadaresis, Julia] Univ Toronto, Toronto, ON, Canada. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA 02215 USA. [Wolfe, Joanne] Harvard Univ, Sch Med, Boston, MA USA. RP Wolfe, J (reprint author), Boston Childrens Hosp, Pediat Palliat Care, DA2-012,450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu FU Pediatric Oncology Group of Ontario FX Grant sponsor: Pediatric Oncology Group of Ontario NR 24 TC 9 Z9 9 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2015 VL 62 IS 8 BP 1409 EP 1413 DI 10.1002/pbc.25530 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CL3RD UT WOS:000356867200016 PM 25882665 ER PT J AU Simon, NM Walton, ZE Bui, E Prescott, J Hoge, E Keshaviah, A Schwarz, N Dryman, T Ojserkis, RA Kovachy, B Mischoulon, D Worthington, J DeVivo, I Fava, M Wong, KK AF Simon, Naomi M. Walton, Zandra E. Bui, Eric Prescott, Jennifer Hoge, Elizabeth Keshaviah, Aparna Schwarz, Noah Dryman, Taylor Ojserkis, Rebecca A. Kovachy, Benjamin Mischoulon, David Worthington, John DeVivo, Immaculata Fava, Maurizio Wong, Kwok-Kin TI Telomere length and telomerase in a well-characterized sample of individuals with major depressive disorder compared to controls SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Major depressive disorder; Telomere length; Telomerase ID MOOD DISORDERS; MORTALITY RISK; STRESS; HEALTH; SYMPTOMS; PATHOPHYSIOLOGY; METAANALYSIS; POPULATION; DISEASE; ANXIETY AB Background: Leukocyte telomere length (LTL) is a marker of cellular turnover and oxidative stress. Studies suggest major depressive disorder (MDD) is associated with oxidative stress, but examinations of MDD and LTL have yielded mixed results, likely because of differences in measurement methods and unmeasured confounding. This study examined LTL and telomerase activity in 166 individuals with MDD compared to 166 age- and gender-matched matched controls free of any psychiatric disorder, using well-validated assays and clinical assessment methods, and controlling for a range of potential confounders. Methods: Subjects aged 18 to 70 were evaluated by trained raters and provided blood for LTL and telomerase activity measurement. LTL was assayed using Southern blot and replicated with qPCR, and telonnerase activity was assayed with a repeat amplification protocol using a commercial kit. Results: There was no significant difference in telomere length for individuals with MDD [mean (SD) = 9.1 (3.0) kbp] compared to controls [mean(SD) = 8.9(2.5) kbp] measured by Southern blot (p = 0.65) or by confirmatory qPCR (p = 0.91) assays. Controlling for potential confounders did not alter the results. Telomerase activity did not differ by MDD diagnosis overall (p = 0.40), but the effect of MDD was significantly modified by gender (t(299) = 2.67, p = 0.0079) even after controlling for potential confounders, with telomerase activity significantly greater only in males with MDD versus controls. Conclusion: Our well-characterized, well-powered examination of concurrently assessed telomere length and telomerase activity in individuals with clinically significant, chronic MDD and matched controls failed to provide strong evidence of an association of MOD with shorter LTL, while telomerase activity was lower in men with MDD. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Simon, Naomi M.; Bui, Eric; Hoge, Elizabeth; Keshaviah, Aparna; Schwarz, Noah; Dryman, Taylor; Ojserkis, Rebecca A.; Kovachy, Benjamin; Mischoulon, David; Worthington, John; Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Simon, Naomi M.; Bui, Eric; Hoge, Elizabeth; Mischoulon, David; Worthington, John; DeVivo, Immaculata; Fava, Maurizio; Wong, Kwok-Kin] Harvard Univ, Sch Med, Boston, MA USA. [DeVivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [DeVivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Prescott, Jennifer; DeVivo, Immaculata] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Walton, Zandra E.; Prescott, Jennifer; Wong, Kwok-Kin] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, One Bowdoin Sq,6th Floor,Suite 650, Boston, MA 02114 USA. EM nsimon@mgh.harvard.edu RI Bui, Eric/J-8347-2015; Hoge, Elizabeth/H-5879-2012 OI Bui, Eric/0000-0002-1413-6473; Hoge, Elizabeth/0000-0002-5513-2292 FU National Institute of Mental Health [5 R01MH077700-05] FX The study was funded by a grant from the National Institute of Mental Health (5 R01MH077700-05). NR 58 TC 12 Z9 12 U1 1 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD AUG PY 2015 VL 58 BP 9 EP 22 DI 10.1016/j.psyneuen.2015.04.004 PG 14 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA CL1XR UT WOS:000356738700002 PM 25932992 ER PT J AU Chan, A Cameron, MC Garden, B Boers-Doets, CB Schindler, K Epstein, JB Choi, J Beamer, L Roeland, E Russi, EG Bensadoun, RJ Teo, YL Chan, RJ Shih, V Bryce, J Raber-Durlacher, J Gerber, PA Freytes, CO Rapoport, B LeBoeuf, N Sibaud, V Lacouture, ME AF Chan, Alexandre Cameron, Michael C. Garden, Benjamin Boers-Doets, Christine B. Schindler, Katja Epstein, Joel B. Choi, Jennifer Beamer, Laura Roeland, Eric Russi, Elvio G. Bensadoun, Rene-Jean Teo, Yi Ling Chan, Raymond J. Shih, Vivianne Bryce, Jane Raber-Durlacher, Judith Gerber, Peter Arne Freytes, Cesar O. Rapoport, Bernardo LeBoeuf, Nicole Sibaud, Vincent Lacouture, Mario E. TI A systematic review of patient-reported outcome instruments of dermatologic adverse events associated with targeted cancer therapies SO SUPPORTIVE CARE IN CANCER LA English DT Review DE Targeted cancer therapy; Dermatologic adverse events; Patient-reported outcomes; Health-related quality of life ID QUALITY-OF-LIFE; METASTATIC COLORECTAL-CANCER; FACTOR RECEPTOR INHIBITORS; HAND-FOOT SYNDROME; INDEX DLQI; CONTROLLED-TRIAL; SKIN DISEASES; QUESTIONNAIRE; IMPACT; FACT-EGFRI-18 AB Dermatologic adverse events (dAEs) in cancer treatment are frequent with the use of targeted therapies. These dAEs have been shown to have significant impact on health-related quality of life (HRQoL). While standardized assessment tools have been developed for physicians to assess severity of dAEs, there is a discord between objective and subjective measures. The identification of patient-reported outcome (PRO) instruments useful in the context of targeted cancer therapies is therefore important in both the clinical and research settings for the overall evaluation of dAEs and their impact on HRQoL. A comprehensive, systematic literature search of published articles was conducted by two independent reviewers in order to identify PRO instruments previously utilized in patient populations with dAEs from targeted cancer therapies. The identified PRO instruments were studied to determine which HRQoL issues relevant to dAEs were addressed, as well as the process of development and validation of these instruments. Thirteen articles identifying six PRO instruments met the inclusion criteria. Four instruments were general dermatology (Skindex-16A (c), Skindex-29A (c), Dermatology Life Quality Index (DLQI), and DIELH-24) and two were symptom-specific (functional assessment of cancer therapy-epidermal growth factor receptor inhibitor-18 (FACT-EGFRI-18) and hand-foot syndrome 14 (HFS-14)). While there are several PRO instruments that have been tested in the context of targeted cancer therapy, additional work is needed to develop new instruments and to further validate the instruments identified in this study in patients receiving targeted therapies. C1 [Chan, Alexandre; Teo, Yi Ling] Natl Univ Singapore, Fac Sci, Dept Pharm, Singapore 117548, Singapore. [Cameron, Michael C.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Garden, Benjamin; Schindler, Katja; Lacouture, Mario E.] Mem Sloan Kettering Canc Ctr, Dept Dermatol, New York, NY 10021 USA. [Boers-Doets, Christine B.] IMPAQTT, Wormer, Netherlands. [Boers-Doets, Christine B.] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. [Schindler, Katja] Med Univ Vienna, Dept Dermatol, Vienna, Austria. [Epstein, Joel B.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Choi, Jennifer] Yale Univ, Sch Med, New Haven, CT USA. [Beamer, Laura] Univ Illinois, Sch Nursing & Hlth Studies, De Kalb, IL USA. [Roeland, Eric] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Russi, Elvio G.] AO S Croce Carle Teaching Hosp, Dept Radiat Oncol, Cuneo, Italy. [Bensadoun, Rene-Jean] Ctr Haute Energie, Nice, France. [Chan, Raymond J.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Shih, Vivianne] Natl Canc Ctr Singapore, Singapore, Singapore. [Bryce, Jane] Natl Canc Inst, Naples, Italy. [Raber-Durlacher, Judith] Univ Amsterdam, Acad Med Ctr, Dept Oral & Maxillofacial Surg, NL-1105 AZ Amsterdam, Netherlands. [Raber-Durlacher, Judith] Acad Ctr Dent Amsterdam, Dept Med Dent Interact, Amsterdam, Netherlands. [Gerber, Peter Arne] Univ Dusseldorf, Dusseldorf, Germany. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Rapoport, Bernardo] Rosebank, Med Oncol Ctr, Johannesburg, South Africa. [LeBoeuf, Nicole] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sibaud, Vincent] Canc Univ Inst Toulouse Oncopole, Toulouse, France. [Lacouture, Mario E.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Lacouture, ME (reprint author), Mem Sloan Kettering Canc Ctr, Rockefeller Outpatient Pavil,Suite 228, New York, NY 10065 USA. EM lacoutum@mskcc.org RI Chan, Alexandre/D-5035-2016; OI Chan, Alexandre/0000-0003-4391-4219; Rapoport, Bernardo/0000-0001-7610-3653; Chan, Raymond/0000-0003-0248-7046 FU Onyx Pharmaceuticals; Hoffman La Roche; Berg; Roche; BMS FX Dr. Choi has received remuneration from Onyx Pharmaceuticals and has a consultant role with Biotest AG.; Dr. Gerber has a consultant role with Galderma International. He is also receiving research funding from Hoffman La Roche.; Dr. Lacouture has a consultant role with AstraZeneca, Roche, Bayer, Janssen, Exelixis, Advancell, BMS, Amgen and Genentech. He is also receiving research funding from Berg, Roche and BMS. NR 30 TC 4 Z9 4 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD AUG PY 2015 VL 23 IS 8 BP 2231 EP 2244 DI 10.1007/s00520-014-2564-x PG 14 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA CL4ZQ UT WOS:000356968100007 PM 25564221 ER PT J AU Schlunk, F Greenberg, SM AF Schlunk, Frieder Greenberg, Steven M. TI The Pathophysiology of Intracerebral Hemorrhage Formation and Expansion SO TRANSLATIONAL STROKE RESEARCH LA English DT Review DE Intracerebral hemorrhage; Hematoma expansion; Pathophysiology; Animal models ID CEREBRAL AMYLOID ANGIOPATHY; HEMATOMA EXPANSION; CONTRAST EXTRAVASATION; PRECLINICAL MODELS; AUTOLOGOUS BLOOD; FACTOR-VII; SPOT SIGN; GROWTH; STROKE; VOLUME AB Intracerebral hemorrhage is a devastating disease. Despite its clinical importance, the pathophysiology of intracerebral hemorrhage is not well understood. Hematoma expansion occurs in a large subset of patients and is a predictor of poor outcomes. Since hematoma growth provides a potential opportunity for therapeutic intervention, a thorough understanding of its biological mechanisms is of key importance. After vessel rupture, an initial hematoma forms. Following this initial phase, accumulating evidence suggests that the mass effect causes secondary vessel rupture, which contributes to the hematoma and may trigger an avalanche of further vessel ruptures. The circumstances under which this occurs and to what extent secondary hemorrhage contributes to final hematoma volume remain unknown, however. To address these questions, a translational approach seems most suitable. Current experimental models include intracranial injections of collagenase or autologous blood. Each has individual strengths and weaknesses in its ability to simulate human intracerebral hemorrhage. The ultimate goal for improved understanding and modeling of the pathophysiology of hematoma expansion is to identify new treatment approaches. C1 [Schlunk, Frieder; Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. RP Schlunk, F (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, 175 Cambridge St, Boston, MA 02114 USA. EM sgreenberg@mgh.harvard.edu; fschlunk@gmail.com NR 62 TC 9 Z9 9 U1 4 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD AUG PY 2015 VL 6 IS 4 BP 257 EP 263 DI 10.1007/s12975-015-0410-1 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CL5YD UT WOS:000357040400002 PM 26073700 ER PT J AU Coe, TM Chang, DC Sicklick, JK AF Coe, Taylor M. Chang, David C. Sicklick, Jason K. TI Small bowel volvulus in the adult populace of the United States: results from a population-based study SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Intestinal malrotation; Small bowel volvulus; Acute abdomen; National inpatient sample; Charlson comorbidity ID SMALL-INTESTINE; MALROTATION; OBSTRUCTION; ROTATION AB BACKGROUND: Small bowel volvulus is a rare entity in Western adults. Greater insight into epidemiology and outcomes may be gained from a national database inquiry. METHODS: The Nationwide Inpatient Sample (1998 to 2010), a 20% stratified sample of United States hospitals, was retrospectively reviewed for small bowel volvulus cases (International Classification of Diseases, 9th Edition [ICD-9] code 560.2 excluding gastric/colonic procedures) in patients greater than or equal to 18 years old. RESULTS: There were 2,065,599 hospitalizations for bowel obstruction (ICD-9 560.x). Of those, there were 20,680 (1.00%) small bowel volvulus cases; 169 were attributable to intestinal malrotation. Most cases presented emergently (89.24%) and operative management was employed more frequently than nonoperative (65.21% vs 34.79%, P < .0001). Predictors of mortality included age greater than 50 years, Charlson comorbidity index greater than or equal to 1, emergent admission, peritonitis, acute vascular insufficiency, coagulopathy, and nonoperative management (P < .0001). CONCLUSION: As the first population-based epidemiological study of small bowel volvulus, our findings provide a robust representation of this rare cause of small bowel obstruction in American adults. (C) 2015 Elsevier Inc. All rights reserved. C1 [Coe, Taylor M.; Sicklick, Jason K.] Univ Calif San Diego, Dept Surg, UC San Diego Hlth Syst, San Diego, CA 92103 USA. [Chang, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. RP Sicklick, JK (reprint author), Univ Calif San Diego, Dept Surg, UC San Diego Hlth Syst, San Diego, CA 92103 USA. EM jsicklick@ucsd.edu FU NCI NIH HHS [K08 CA168999] NR 19 TC 3 Z9 3 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD AUG PY 2015 VL 210 IS 2 BP 201 EP U232 DI 10.1016/j.amjsurg.2014.12.048 PG 12 WC Surgery SC Surgery GA CK4YY UT WOS:000356230500001 PM 26002189 ER PT J AU Hidrue, MK Parsons, GR AF Hidrue, Michael K. Parsons, George R. TI Is there a near-term market for vehicle-to-grid electric vehicles? SO APPLIED ENERGY LA English DT Article DE Vehicle-to-grid (V2G); Electric vehicles; Willingness to pay ID CONTINGENT VALUATION; CHOICE; DEMAND; V2G; PENETRATION; MODELS AB We assess the near-term market for vehicle-to-grid electric vehicles (V2G-EV5) using an internet-based contingent-valuation survey. V2G-EV5 are a special breed of electric vehicles used to return power to the grid for ancillary service support or during periods of peak electricity demand. Whether or not these vehicles are economically viable is of interest to policy makers and utility companies. We estimate a demand function for V2G-EVs, consider the importance of different vehicle attributes on demand, and then assess their likelihood of near-term success on the market. To assess the potential market, we compared consumer's willingness to pay for V2G-EVs with the estimated cost of V2G-EV5 under different scenarios of battery cost projection. We found, in all scenarios, WTP estimates are lower than projected costs. Range anxiety, stringent V2G contract, and high battery costs are the primary reasons for the outcome. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hidrue, Michael K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Parsons, George R.] Univ Delaware, Sch Marine Sci & Policy, Newark, DE 19716 USA. [Parsons, George R.] Univ Delaware, Dept Econ, Newark, DE 19716 USA. RP Hidrue, MK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mkessete@udel.edu FU U.S. Department of Energy, Office of Electricity [DE-FC26-08NT01905] FX The authors wish to thank Willett Kempton, Meryl P. Gardner, and Jonathan Lilley for their contribution in the design and development of the survey. This research was supported by funding from the U.S. Department of Energy, Office of Electricity (DE-FC26-08NT01905). NR 28 TC 10 Z9 10 U1 4 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0306-2619 EI 1872-9118 J9 APPL ENERG JI Appl. Energy PD AUG 1 PY 2015 VL 151 BP 67 EP 76 DI 10.1016/j.apenergy.2015.04.051 PG 10 WC Energy & Fuels; Engineering, Chemical SC Energy & Fuels; Engineering GA CK4MU UT WOS:000356198700008 ER PT J AU Sosenko, JM Skyler, JS Palmer, JP AF Sosenko, Jay M. Skyler, Jay S. Palmer, Jerry P. CA Diabet Type 1 TrialNet Grp Diabet Prevention Trial-Type 1 TI The Development, Validation, and Utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) SO CURRENT DIABETES REPORTS LA English DT Article DE Type 1 diabetes; Glucose; C-peptide; Prediction; Diagnosis ID GLUCOSE-TOLERANCE; RELATIVES; INSULIN; TRIAL-TYPE-1; PREDICTION; ACCURACY; MELLITUS AB This report details the development, validation, and utility of the Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score (DPTRS) for type 1 diabetes (T1D). Proportional hazards regression was used to develop the DPTRS model which includes the glucose and C-peptide sums from oral glucose tolerance tests at 30, 60, 90, and 120 min, the log fasting C-peptide, age, and the log BMI. The DPTRS was externally validated in the TrialNet Natural History Study cohort (TNNHS). In a study of the application of the DPTRS, the findings showed that it could be used to identify normoglycemic individuals who were at a similar risk for T1D as those with dysglycemia. The DPTRS could also be used to identify lower risk dysglycemic individuals. Risk estimates of individuals deemed to be at higher risk according to DPTRS values did not differ significantly between the DPT-1 and the TNNHS; whereas, the risk estimates for those with dysglycemia were significantly higher in DPT-1. Individuals with very high DPTRS values were found to be at such marked risk for T1D that they could reasonably be considered to be in a pre-diabetic state. The findings indicate that the DPTRS has utility in T1D prevention trials and for identifying pre-diabetic individuals. C1 [Sosenko, Jay M.; Skyler, Jay S.] Univ Miami, Div Endocrinol, Miami, FL 33101 USA. [Palmer, Jerry P.] Univ Washington, Div Endocrinol Metab & Nutr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Sosenko, JM (reprint author), Univ Miami, Div Endocrinol, POB 016960,D110, Miami, FL 33101 USA. EM jsosenko@med.miami.edu RI Skyler, Jay/F-4211-2016 FU 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 [U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, HHSN267200800019C]; National Center for Research Resources, through Clinical Translational Science Awards [UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, P30 DK017047]; General Clinical Research Center Award [M01 RR00400]; Juvenile Diabetes Research Foundation International (JDRF); American Diabetes Association (ADA) FX The sponsor of the trial was the Type 1 Diabetes TrialNet Study Group (see Appendix 1). Type 1 Diabetes TrialNet Study Group is a clinical trial 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 U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085505, U01 DK085509, and a contract HHSN267200800019C; the National Center for Research Resources, through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, P30 DK017047, and General Clinical Research Center Award M01 RR00400; the Juvenile Diabetes Research Foundation International (JDRF); and the American Diabetes Association (ADA). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, JDRF, or ADA. NR 16 TC 1 Z9 2 U1 1 U2 4 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 AUG PY 2015 VL 15 IS 8 DI 10.1007/s11892-015-0626-1 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CK6NB UT WOS:000356343700003 PM 26077017 ER PT J AU Nordio, F Zanobetti, A Colicino, E Kloog, I Schwartz, J AF Nordio, Francesco Zanobetti, Antonella Colicino, Elena Kloog, Itai Schwartz, Joel TI Changing patterns of the temperature-mortality association by time and location in the US, and implications for climate change SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Climate change; Health effects; Temperature; Meta-smoothing ID HEAT-RELATED MORTALITY; AIR-POLLUTION; UNITED-STATES; MULTIVARIATE METAANALYSIS; AMBIENT-TEMPERATURE; WEATHER; CITIES; SERIES; WAVES; HETEROGENEITY AB The shape of the non-linear relationship between temperature and mortality varies among cities with different climatic conditions. There has been little examination of how these curves change over space and time. We evaluated the short-term effects of hot and cold temperatures on daily mortality over six 7-year periods in 211 US cities, comprising over 42 million deaths. Cluster analysis was used to group the cities according to similar temperatures and relative humidity. Temperature-mortality functions were calculated using B-splines to model the heat effect (lag 0) and the cold effect on mortality (moving average lags 1-5). The functions were then combined through meta-smoothing and subsequently analyzed by meta-regression. We identified eight clusters. At lag 0, Cluster 5 (West Coast) had a RR of 1.14 (95% CI: 1.11,1.17) for temperatures of 27 degrees C vs 15.6 degrees C, and Cluster 6 (Gulf Coast) has a RR of 1.04 (95% CI: 1.03,1.05), suggesting that people are acclimated to their respective climates. Controlling for cluster effect in the multivariate-meta regression we found that across the US, the excess mortality from a 24-h temperature of 27 degrees C decreased over time from 10.6% to 0.9%. We found that the overall risk due to the heat effect is significantly affected by summer temperature mean and air condition usage, which could be a potential predictor in building climate-change scenarios. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Nordio, Francesco] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,TIMI Study Grp, Boston, MA 02115 USA. [Nordio, Francesco; Zanobetti, Antonella; Colicino, Elena; Schwartz, Joel] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth Exposure Epidemiol & Risk Prog, Boston, MA 02115 USA. [Kloog, Itai] Ben Gurion Univ Negev, Dept Geog & Environm Dev, IL-84105 Beer Sheva, Israel. RP Schwartz, J (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Dept Epidemiol, 665 Huntington Ave,Landmark Ctr Room 415, Boston, MA 02115 USA. EM jschwrtz@hsph.harvard.edu RI Colicino, Elena/Q-4973-2016 OI Colicino, Elena/0000-0002-1875-8448 FU [ES020695]; [ES000002] FX We thank Steve Melly from Harvard T. H. Chan School of Public Health for providing the temperature data and city-specific variables. We also thank Dominique J. Monlezun from Tulane School of Public Health for manuscript review. This work was supported by grants ES020695 and ES000002. NR 39 TC 12 Z9 12 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD AUG PY 2015 VL 81 BP 80 EP 86 DI 10.1016/j.envint.2015.04.009 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA CL2BP UT WOS:000356748900009 PM 25965185 ER PT J AU Naraghi, L Mejaddam, AY Birkhan, OA Chang, Y Cropano, CM Mesar, T Larentzakis, A Peev, M Sideris, AC Van der Wilden, GM Imam, AM Hwabejire, JO Velmahos, GC Fagenholz, PJ Yeh, D de Moya, MA King, DR AF Naraghi, L. Mejaddam, A. Y. Birkhan, O. A. Chang, Y. Cropano, C. M. Mesar, T. Larentzakis, A. Peev, M. Sideris, A. C. Van der Wilden, G. M. Imam, A. M. Hwabejire, J. O. Velmahos, G. C. Fagenholz, P. J. Yeh, D. de Moya, M. A. King, D. R. TI Sample entropy predicts lifesaving interventions in trauma patients with normal vital signs SO JOURNAL OF CRITICAL CARE LA English DT Article DE Entropy; Vital; Trauma; Noninvasive; Screening ID HEART-RATE-VARIABILITY; DIMINISHED PHYSIOLOGICAL RESERVE; RATE COMPLEXITY; PERIOD VARIABILITY; COMBAT CASUALTIES; HEMORRHAGIC-SHOCK; MORTALITY; TRIAGE; INDICATOR AB Introduction: Heart rate complexity, commonly described as a "new vital sign," has shown promise in predicting injury severity, but its use in clinical practice is not yet widely adopted. We previously demonstrated the ability of this noninvasive technology to predict lifesaving interventions (LSIs) in trauma patients. This study was conducted to prospectively evaluate the utility of real-time, automated, noninvasive, instantaneous sample entropy (SampEn) analysis to predict the need for an LSI in a trauma alert population presenting with normal vital signs. Methods: Prospective enrollment of patients who met criteria for trauma team activation and presented with normal vital signs was conducted at a level I trauma center. High-fidelity electrocardiogram recording was used to calculate SampEn and SD of the normal-to-normal R-R interval (SDNN) continuously in real time for 2 hours with a portable, handheld device. Patients who received an LSI were compared to patients without any intervention (non-LSI). Multivariable analysis was performed to control for differences between the groups. Treating clinicians were blinded to results. Results: Of 129 patients enrolled, 38 (29%) received 136 LSIs within 24 hours of hospital arrival. Initial systolic blood pressure was similar in both groups. Lifesaving intervention patients had a lower Glasgow Coma Scale. The mean SampEn on presentation was 0.7 (0.4-1.2) in the LSI group compared to 1.5 (1.1-2.0) in the non-LSI group (P < .0001). The area under the curve with initial SampEn alone was 0.73 (95% confidence interval [CI], 0.64-0.81) and increased to 0.93 (95% CI, 0.89-0.98) after adding sedation to the model. Sample entropy of less than 0.8 yields sensitivity, specificity, negative predictive value, and positive predictive value of 58%, 86%, 82%, and 65%, respectively, with an overall accuracy of 76% for predicting an LSI. SD of the normal-to-normal R-R interval had no predictive value. Conclusions: In trauma patients with normal presenting vital signs, decreased SampEn is an independent predictor of the need for LSI. Real-time SampEn analysis may be a useful adjunct to standard vital signs monitoring. Adoption of real-time, instantaneous SampEn monitoring for trauma patients, especially in resource-constrained environments, should be considered. (C) 2015 Elsevier Inc. All rights reserved. C1 [King, D. R.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02141 USA. [King, D. R.] Harvard Univ, Sch Med, Boston, MA 02141 USA. RP King, DR (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02141 USA. EM Dking3@partners.org OI King, David/0000-0003-1028-1478 NR 32 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD AUG PY 2015 VL 30 IS 4 BP 705 EP 710 DI 10.1016/j.jcrc.2015.03.018 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA CK2TO UT WOS:000356066100009 PM 25858820 ER PT J AU Sahin-Efe, A Polyzos, SA Dincer, F Zaichenko, L McGovern, R Schneider, B Mantzoros, CS AF Sahin-Efe, Ayse Polyzos, Stergios A. Dincer, Fadime Zaichenko, Lesya McGovern, Rosemary Schneider, Benjamin Mantzoros, Christos S. TI Intracellular leptin signaling following effective weight loss SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Leptin; Leptin signaling; Obesity; STAT3; Weight loss ID FATTY LIVER-DISEASE; ALL-CAUSE MORTALITY; HUMAN PHYSIOLOGY; SOLUBLE LEPTIN; IN-VITRO; EX-VIVO; HUMANS; PATHWAYS; OBESE; METRELEPTIN AB Aim. To investigate the effect of ex-vivo leptin treatment before and after weight loss on key-molecules of intracellular leptin signaling in peripheral blood mononuclear cells (PBMCs) of obese women. Materials and methods. Five healthy obese women underwent a 12-week medical nutrition treatment aiming at inducing 10% weight loss. Isolated PBMCs at baseline, and at weeks 8 and 12 were treated with increasing leptin doses (0, 25 and 75 ng/ml) for 30 min. The phosphorylation of signal transducer and activator of transcription (STAT)3, extracellular-signal-regulated kinase (ERK), protein kinase B (Ala) and 5' adenosine monophosphate-activated protein kinase (AMPK) of PBMCs was analyzed using Western blotting. Results. Women lost 10 +/- 1% and 13 +/- 1% of weight at week 8 and 12, respectively. Circulating leptin and insulin significantly decreased from 39.5. 7.7 to 12.2 2.4 ng/ml (p = 0.026) and from 13.0 +/- 1.6 to 5.4 +/- 0.9 mu U/ml (p = 0.005) at week 12, respectively. In the ex vivo study, a significant decrease in STAT3 phosphorylation was observed in the control group after weight loss. Treatment of PBMCs with leptin 75 ng/ml increased significantly ERK, STAT3 and Akt phosphorylation, but no weight loss induced change was observed in response to leptin treatment ex vivo. Conclusions. A 10%-15% weight loss decreases baseline STAT3 phosphorylation ex vivo, but does not alter the effect of increasing doses of leptin on the incremental intracellular phosphorylation of STAT3, ERK, Akt and AMPK. Supraphysiologic leptin doses (75 ng/ml) result in higher protein phosphorylation compared to either physiologic doses or no treatment, before and after weight loss. (C) 2015 Elsevier Inc. All rights reserved. C1 [Sahin-Efe, Ayse; Polyzos, Stergios A.; Dincer, Fadime; Zaichenko, Lesya; McGovern, Rosemary; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab,Dept Med, Boston, MA USA. [Sahin-Efe, Ayse; Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. [Schneider, Benjamin] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Minimally Invas Surg, Boston, MA USA. RP Polyzos, SA (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02163 USA. EM stergios@endo.gr FU Clinical Science Research and Development Service of the VA Office of Research and Development [1I01CX000422-01A1] FX This study was supported by the Award 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development. NR 43 TC 4 Z9 4 U1 5 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2015 VL 64 IS 8 BP 888 EP 895 DI 10.1016/j.metabol.2015.04.006 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CK7HB UT WOS:000356402300005 PM 25998856 ER PT J AU Li, B Wang, J Yang, SY Zhou, C Wu, MX AF Li, Bo Wang, Ji Yang, Seung Yun Zhou, Chang Wu, Mei X. TI Sample-free quantification of blood biomarkers via laser-treated skin SO BIOMATERIALS LA English DT Article DE Sample-free; Microneedles; Laser; Circulating biomarkers ID SELECTIVE PHOTOTHERMOLYSIS; MICROPROJECTION ARRAYS; DYE-LASER; KTP LASER; DISEASE; DIAGNOSTICS; PROTEINS; CAPTURE; TISSUES; PLASMA AB Surface modified microneedle (MN) arrays are being developed to capture circulating biomarkers from the skin, but inefficiency and unreliability of the current method limit its clinical applications. We describe here that illumination of a tiny area of the skin with hemoglobin-preferably absorbent laser increased the amount of circulating biomarkers in the upper dermis by more than 1000-fold. The hemoglobin-specific light altered the permeability of capillaries leading to extravasation of molecules but not blood cells beneath the skin involved. When specific probe-coated MN arrays were applied into the laser-treated skin, the biomarkers accumulated in the upper dermis were reliably, accurately, and sufficiently captured as early as 15 min of the assay. The maximal binding occurred in 1 h in a manner independent of penetration depth or a molecular mass of the biomarker. With anti-fluorescein isothiocyanate (FITC)-MNs, we were able to measure blood concentrations of FITC in mice receiving FITC intravenously. The sensitivity and accuracy were comparable to those attained by fluorescence spectrophotometer. Likewise, MNs containing influenza hemagglutinin (HA) could detect anti-HA antibody in mice or swine receiving influenza vaccines as effectively as standard immunoassays. The novel, minimally invasive approach holds great promise for measurement of multiple biomarkers by a single array for point-of-care diagnosis. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Li, Bo; Wang, Ji; Zhou, Chang; Wu, Mei X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. [Yang, Seung Yun] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Biomed Engn,Dept Med, Boston, MA 02115 USA. [Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02142 USA. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St,Edwards 222, Boston, MA 02114 USA. EM mwu5@mgh.harvard.edu RI Yang, Seung Yun/B-5974-2016 OI Yang, Seung Yun/0000-0002-1233-8960 FU National Institutes of Health [AI089779, AI070785, AI097696, DA028378] FX This work was supported by the National Institutes of Health grants AI089779, AI070785, AI097696, and DA028378 (to M.X.W.). The authors would like to thank Prot Jeffrey M. Karp at Brigham and Women's Hospital, Harvard Medical School and the Center for Nanoscale Systems at Harvard University for their help in fabricating microneedle patches. The authors are also grateful to Jeffrey H. Wu for his editing and to the Photopathology Core at Wellman Center for Photomedicine in Massachusetts General Hospital for their microscopy services. NR 28 TC 4 Z9 4 U1 3 U2 36 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 AUG PY 2015 VL 59 BP 30 EP 38 DI 10.1016/j.biomaterials.2015.04.040 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CK3NL UT WOS:000356122700004 PM 25950985 ER PT J AU Mistridis, P Egli, SC Iverson, GL Berres, M Willmes, K Welsh-Bohmer, KA Monsch, AU AF Mistridis, Panagiota Egli, Simone C. Iverson, Grant L. Berres, Manfred Willmes, Klaus Welsh-Bohmer, Kathleen A. Monsch, Andreas U. TI Considering the base rates of low performance in cognitively healthy older adults improves the accuracy to identify neurocognitive impairment with the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB) SO EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE LA English DT Article DE Neuropsychology; Normal aging; Diagnosis; Neurocognitive disorders; Dementia; Mild cognitive impairment ID LOW SCORES; VERBAL CONCEPTUALIZATION; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; MEMORY SCORES; VARIABILITY; RECOMMENDATIONS; ADOLESCENTS; POPULATION AB It is common for some healthy older adults to obtain low test scores when a battery of neuropsychological tests is administered, which increases the risk of the clinician misdiagnosing cognitive impairment. Thus, base rates of healthy individuals' low scores are required to more accurately interpret neuropsychological results. At present, this information is not available for the German version of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB), a frequently used battery in the USA and in German-speaking Europe. This study aimed to determine the base rates of low scores for the CERAD-NAB and to tabulate a summary figure of cut-off scores and numbers of low scores to aid in clinical decision making. The base rates of low scores on the ten German CERAD-NAB subscores were calculated from the German CERAD-NAB normative sample (N = 1,081) using six different cut-off scores (i.e., 1st, 2.5th, 7th, 10th, 16th, and 25th percentile). Results indicate that high percentages of one or more "abnormal" scores were obtained, irrespective of the cut-off criterion. For example, 60.6 % of the normative sample obtained one or more scores at or below the 10th percentile. These findings illustrate the importance of considering the prevalence of low scores in healthy individuals. The summary figure of CERAD-NAB base rates is an important supplement for test interpretation and can be used to improve the diagnostic accuracy of neurocognitive disorders. C1 [Mistridis, Panagiota; Egli, Simone C.; Monsch, Andreas U.] Univ Ctr Med Aging Basel, Felix Platter Hosp, Memory Clin, CH-4031 Basel, Switzerland. [Mistridis, Panagiota; Egli, Simone C.; Monsch, Andreas U.] Univ Basel, Dept Psychol, CH-4055 Basel, Switzerland. [Iverson, Grant L.] Harvard Univ, Dept Phys Med & Rehabil, Sch Med, Boston, MA 02114 USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA 02114 USA. [Iverson, Grant L.] Massachusetts Gen Hosp Home Base Program, Boston, MA 02114 USA. [Berres, Manfred] Univ Appl Sci Koblenz, Dept Math & Technol, D-53424 Remagen, Germany. [Willmes, Klaus] Rhein Westfal TH Aachen, Sect Neuropsychol, Dept Neurol, D-52074 Aachen, Germany. [Welsh-Bohmer, Kathleen A.] Duke Univ, Joseph & Kathleen Bryan Alzheimers Dis Ctr, Durham, NC 27705 USA. RP Monsch, AU (reprint author), Univ Ctr Med Aging Basel, Felix Platter Hosp, Memory Clin, Schanzenstr 55, CH-4031 Basel, Switzerland. EM Andreas.Monsch@unibas.ch FU Swiss National Science Foundation [3200-049107]; Novartis Foundation, Basel, Switzerland; GlaxoSmithKline FX This work was supported by grants from the Swiss National Science Foundation (Grant No. 3200-049107 to A.U.M), from the Novartis Foundation, Basel (A.U.M.), Switzerland, and from GlaxoSmithKline (A.U.M.). We gratefully acknowledge the continuous enthusiasm of the participants of the BAsel Study on the ELderly project. A part of this paper has been presented as a poster at the Alzheimer's Association International Conference in Boston, MA, USA (July 13-18, 2013). NR 49 TC 3 Z9 3 U1 1 U2 14 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0940-1334 EI 1433-8491 J9 EUR ARCH PSY CLIN N JI Eur. Arch. Psych. Clin. Neurosci. PD AUG PY 2015 VL 265 IS 5 BP 407 EP 417 DI 10.1007/s00406-014-0571-z PG 11 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CK1CJ UT WOS:000355942700006 PM 25555899 ER PT J AU Ladeiras-Lopes, R Agewall, S Tawakol, A Staels, B Stein, E Mentz, RJ Leite-Moreira, A Zannad, F Koenig, W AF Ladeiras-Lopes, Ricardo Agewall, Stefan Tawakol, Ahmed Staels, Bart Stein, Evan Mentz, Robert J. Leite-Moreira, Adelino Zannad, Faiez Koenig, Wolfgang TI Atherosclerosis: Recent trials, new targets and future directions SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Atherosclerosis; Pharmacology; Clinical research ID HIGH-DENSITY-LIPOPROTEIN; TRIGLYCERIDE TRANSFER PROTEIN; ACUTE CORONARY SYNDROME; SUBTILISIN/KEXIN TYPE 9; PLACEBO-CONTROLLED TRIAL; APOLIPOPROTEIN-A-I; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; RANDOMIZED CONTROLLED-TRIAL; ESTER TRANSFER PROTEIN; SECRETORY PHOSPHOLIPASE A(2) AB Mortality from cardiovascular diseases (CVD) represents the primary cause of death worldwide. Prevention or treatment of atherosclerosis and its clinical sequelae is a central goal in the management of patients with established vascular disease or those at high-risk for vascular events. This paper provides a review of the contemporary pharmacological armamentarium targeting atherosclerosis and also highlights strategies to support future clinical trial design. Powering future trials targeting LDL-cholesterol to its absolute reduction and including patients with a higher LDL-C despite optimal medical therapy (or unable to tolerate statins) will increase the odds of meaningful results. Mendelian randomization studies may identify new causal risk factors for CVD that would help in the selection of the patients most likely to benefit from a specific new compound. Furthermore, imaging techniques integrating a morphological and functional assessment such as IVUS, OCT, PET/CT and PET/MRI may represent in a near future robust "soft" endpoints to support successful translation of early research into meaningful phase III clinical outcome trials. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Ladeiras-Lopes, Ricardo; Leite-Moreira, Adelino] Univ Porto, Fac Med, Cardiovasc Res & Dev Ctr, Dept Physiol & Cardiothorac Surg, Oporto, Portugal. [Ladeiras-Lopes, Ricardo] Gaia Espinho Hosp Ctr, Dept Cardiol, Vila Nova De Gaia, Portugal. [Agewall, Stefan] Univ Oslo, Oslo Univ Hosp Ulleval, Dept Cardiol, Oslo, Norway. [Agewall, Stefan] Univ Oslo, Inst Clin Med, Oslo, Norway. [Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Tawakol, Ahmed] Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. [Staels, Bart] Univ Lille 2, INSERM, EGID, Inst Pasteur Lille,UMR1011, Lille, France. [Stein, Evan] Metab & Atherosclerosis Res Ctr, Cincinnati, OH USA. [Mentz, Robert J.] Duke Univ Hosp, Duke Clin Res Inst, Durham, NC USA. [Mentz, Robert J.] Duke Univ Hosp, Div Cardiol, Durham, NC USA. [Zannad, Faiez] Univ Lorraine, Ctr Invest Clin 9501, INSERM, Nancy, France. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Koenig, Wolfgang] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Koenig, Wolfgang] German Ctr Cardiovasc Res, DZHK, Partner Site Munich Heart Alliance, Munich, Germany. RP Koenig, W (reprint author), Tech Univ Munich, Deutsch Herzzentrum Munchen, Klin Herz & Kreislauferkrankungen, Lazarettstr 36, D-80636 Munich, Germany. EM ricardoladeiraslopes@gmail.com; koenig@dhm.mhn.de OI Leite-Moreira, Adelino/0000-0001-7808-3596; Ladeiras-Lopes, Ricardo/0000-0002-5260-5613; Staels, Bart/0000-0002-3784-1503 FU Astra Zeneca; Thermo Fisher; Takeda; Genentech; Amgen; BMS; Regeneron/Sanofi; Roche/Genetech; Gemphire; Catabasis; Cymabay; AZ; Roche Diagnostics; Bayer; Boston Scientific; Janssen; Novartis; Pfizer; Resmed; Roche; diaDexus; Cerenis; The Medicines Company; Genzyme; Abbott; Beckmann; Singulex FX R.L.L., B.S. and A.L.M. have no conflicts of interest to declare. S.A., honoraria and consultancy, advisory board fees, from Astra Zeneca and Thermo Fisher. A.T., grant support from Takeda and Genentech; consulting Takeda, Actelion, Amgen. E.S., consultant fees in the last 3 years from Amgen, BMS, Regeneron/Sanofi, Roche/Genetech, AstraZeneca, Gemphire, Catabasis and Cymabay. R.J.M., research support from AZ. F.Z., grants to institution: Roche Diagnostics; steering committee fees: Bayer, Boston Scientific, Janssen, Novartis, Pfizer, Resmed and Takeda; consultant/scientific advisory board: Air Liquide, Amgen, CVRx, Servier, St Jude, Stealth peptide. W.K., consulting fees from Roche, diaDexus, Cerenis, Novartis, Amgen, The Medicines Company, Genzyme, AstraZeneca and Pfizer, honoraria for lectures from AstraZeneca, Amgen, Novartis and MSD, and research support from Roche Diagnostics, Abbott, Beckmann and Singulex. NR 125 TC 14 Z9 14 U1 1 U2 46 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 1 PY 2015 VL 192 BP 72 EP 81 DI 10.1016/j.ijcard.2015.05.013 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK2PR UT WOS:000356053700019 PM 26002254 ER PT J AU Winter, L Moriarty, HJ Atte, F Gitlin, LN AF Winter, Laraine Moriarty, Helene J. Atte, Faith Gitlin, Laura N. TI Depressed Affect and Dimensions of Religiosity in Family Caregivers of Individuals with Dementia SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Depression; Religiosity; Dementia caregiving ID OLDER DUTCH CITIZENS; MENTAL-HEALTH; LIFE EVENTS; ADULTS; SPIRITUALITY; INVOLVEMENT; SYMPTOMS; OUTCOMES; REACH; RESOURCES AB Religiosity and mood have long been recognized as associated, but some patterns of associations suggest complex relationships. Using a multidimensional measure of religiosity, we explored the possibility that dimensions of religiosity may have (1) different strengths of association and (2) directions of association with depressed mood. We measured five dimensions of religiosity in 1227 family caregivers of persons with dementia, testing associations of each dimension to caregivers' depressive symptoms. In zero-order associations, higher scores on each religiosity dimension were associated with lower depression. Yet in hierarchical multiple regressions models, adjusting for other religiosity dimensions, different dimensions showed either no independent association, an independent association, or an inverse association with depressed mood. Frequency of prayer reversed directions of association-showing higher depression in caregivers who prayed more. Findings underscore the complex and sometimes bidirectional association between depressed mood and religiosity and argue for recognition of distinct dimensions of religiosity. C1 [Winter, Laraine] Philadelphia VA Med Ctr, Dept Vet Affairs Med Ctr, Philadelphia Res & Educ Fdn, Philadelphia, PA 19104 USA. [Winter, Laraine; Moriarty, Helene J.] Dept Vet Affairs Med Ctr, Nursing Serv, Philadelphia, PA 19104 USA. [Moriarty, Helene J.; Atte, Faith] Villanova Univ Coll Nursing, Villanova, PA USA. [Gitlin, Laura N.] Johns Hopkins Univ, Sch Nursing, Ctr Innovat Care Aging, Baltimore, MD USA. RP Winter, L (reprint author), Philadelphia VA Med Ctr, Dept Vet Affairs Med Ctr, Philadelphia Res & Educ Fdn, Philadelphia, PA 19104 USA. EM laraine.winter@gmail.com NR 52 TC 0 Z9 0 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD AUG PY 2015 VL 54 IS 4 BP 1490 EP 1502 DI 10.1007/s10943-015-0033-6 PG 13 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA CK0YN UT WOS:000355931900027 PM 25794545 ER PT J AU Heinz, AJ Bui, L Thomas, KM Blonigen, DM AF Heinz, Adrienne J. Bui, Leena Thomas, Katherine M. Blonigen, Daniel M. TI Distinct Facets of Impulsivity Exhibit Differential Associations with Substance Use Disorder Treatment Processes: A Cross-Sectional and Prospective Investigation Among Military Veterans SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Impulsivity; Substance use disorder; Treatment; Executive functioning; Treatment processes; Veterans ID ALCOHOL-USE DISORDERS; 5 FACTOR MODEL; INTERPERSONAL PROBLEMS; BEHAVIOR SCALE; SELF-EFFICACY; EXECUTIVE FUNCTION; DRUG-ADDICTION; NEURAL SYSTEMS; 4-FACTOR MODEL; COPING SKILLS AB Impulsivity, a multi-faceted construct characterized by rash, unplanned actions and a disregard for long-term consequences, is associated with poor substance use disorder (SUD) treatment outcomes. Little is known though about the influence of impulsivity on treatment process variables critical for initiating and maintaining behavioral change. This knowledge gap is important as different aspects of impulsivity may be susceptible to diverse cognitive, behavioral and pharmacological influences. The present study examined two distinct facets of impulsivity (lack of planning and immoderation a proxy of urgency) as predictors of processes that impact SUD treatment success (active coping, avoidant coping, self-efficacy, and interpersonal problems). Participants were 200 Veterans who completed impulsivity and treatment process assessments upon entering an SUD treatment program and treatment process assessments at treatment discharge. Results from multivariate models revealed that lack of planning was associated with lower active coping and higher avoidant coping and interpersonal problems at intake, though not with lower self-efficacy to abstain from substances. Immoderation was associated with higher avoidant coping and lower self-efficacy to abstain from substances at intake, but not with lower active coping or higher interpersonal problems. Higher immoderation, but not lack of planning, predicted lower self-efficacy to abstain from substances at treatment discharge. These findings suggest that different facets of impulsivity confer risk for different SUD treatment process indicators and that clinicians should consider the behavioral expression of patients' impulse control problems in treatment planning and delivery. Published by Elsevier Inc. C1 [Heinz, Adrienne J.; Bui, Leena; Blonigen, Daniel M.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Heinz, Adrienne J.] Vet Affairs Palo Alto Hlth Care Syst, Natl Ctr Posttraumat Stress Disorder, Menlo Pk, CA USA. [Thomas, Katherine M.] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [Thomas, Katherine M.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Heinz, AJ (reprint author), 795 Willow Rd 152-MPD, Menlo Pk, CA 94025 USA. EM adrienneheinz@gmail.com FU VA Clinical Science Research and Development (CSR&D) Career Development Award-2; VA Rehabilitation Research and Development (RR&D) Career Development Award-2 FX Support for this research was provided by a VA Clinical Science Research and Development (CSR&D) Career Development Award-2 granted to Dr. Blonigen and a VA Rehabilitation Research and Development (RR&D) Career Development Award-2 granted to Dr. Heinz. The expressed views do not necessarily represent those of the Department of Veterans Affairs. NR 85 TC 3 Z9 3 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD AUG PY 2015 VL 55 BP 21 EP 28 DI 10.1016/j.jsat.2015.02.005 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CK2FT UT WOS:000356026900004 PM 25770869 ER PT J AU Frakt, AB Trafton, J Pizer, SD AF Frakt, Austin B. Trafton, Jodie Pizer, Steven D. TI Maintenance of Access as Demand for Substance Use Disorder Treatment Grows SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Substance use disorder treatment; Veterans; Veterans Health Administration; Process quality ID MENTAL-HEALTH; ABUSE TREATMENT; BLOCK GRANTS; DRUG-ABUSE; CARE; QUALITY; ALCOHOL; STATE; PERFORMANCE; SPECIALTY AB Due to the Affordable Care Act and other recent laws and regulations, funding for substance use disorder (SUD) treatment is on the rise. In the 2000s, the Veterans Health Administration (VA) implemented several initiatives that increased funding for SUD treatment during a period of growth in demand for it. A key question is whether access to and intensity of treatment kept pace or declined. Using VA SUD treatment funding data and patient-level records to construct performance measures, we studied the relationship between funding and access during the VA expansion. Overall, we observed-an-increase in access to and intensity-of VA SUB-care associated-with increased funding. The VA was able to increase funding for and expand the population to which it offered SUD treatment without diminishing internal access and intensity. Published by Elsevier Inc. C1 [Frakt, Austin B.] Boston Univ, Healthcare Financing & Econ, VA Boston Healthcare Syst, Boston, MA 02130 USA. [Frakt, Austin B.] Boston Univ, Sch Med, Boston, MA 02130 USA. [Trafton, Jodie] VA Palo Alto Healthcare Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Pizer, Steven D.] Northeastern Univ, Healthcare Financing & Econ, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Pizer, Steven D.] Northeastern Univ, Sch Pharm, Boston, MA 02115 USA. [Pizer, Steven D.] Northeastern Univ, Dept Econ, Boston, MA 02115 USA. RP Frakt, AB (reprint author), Boston Univ, Healthcare Financing & Econ, VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM frakt@bu.edu FU Department of Veterans Affairs, Health Services Research and Development grant [CRE 12-023] FX This work was funded by a Department of Veterans Affairs, Health Services Research and Development grant (CRE 12-023).The views expressed are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, Boston University, or Northeastern University. NR 29 TC 1 Z9 1 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD AUG PY 2015 VL 55 BP 58 EP 63 DI 10.1016/j.jsat.2015.02.009 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CK2FT UT WOS:000356026900009 PM 25795602 ER PT J AU Waterford, SD Williams, M Siegert, CJ Fisichella, PM Lebenthal, A AF Waterford, Stephen D. Williams, Mallory Siegert, Charles J. Fisichella, P. Marco Lebenthal, Abraham TI Trauma education in a state of emergency: a curriculum-based analysis SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Trauma; Education; Curriculum; Medical school ID SENIOR MEDICAL-STUDENTS; INJURY AB Background: Trauma is the leading cause of death from ages 1-44-y in the United States and the fifth leading cause of death overall, but there are few studies quantifying trauma education in medical school. This study reviews curriculum hours devoted to trauma education at a northeastern medical school. Materials and methods: We reviewed the preclinical curriculum at a northeastern medical school affiliated with three adult and two pediatric level I trauma centers verified by the American College of Surgeons. We reviewed curricular hours and we categorized them according to the leading ten causes of death in the United States. We also compared the number of educational hours devoted to trauma to other leading causes of death. Results: The total amount of time devoted to trauma education in the first 2 y of medical school was 6.5 h. No lectures were given on the fundamentals of trauma management, traumatic brain injury, or chest or abdominal trauma. The most covered topic was heart disease (128 h), followed by chronic lower respiratory disease (80 h). Curricular time for heart disease, chronic lower respiratory disease, cancer, diabetes, renal disease, and influenza and pneumonia far exceeded that devoted to trauma, after adjusting for the mortality burden of these diseases (P < 0.05 for all). Conclusions: Our study demonstrates that trauma education at a northeastern medical school is nearly absent. With the large burden of trauma and rise in mass casualty incidence, the preclinical curriculum might not be sufficient to expose students to the fundamentals of trauma management. A broader multi-institutional study may shed more insight on these curricular deficiencies in trauma education and detect if these deficiencies are widespread nationally. Published by Elsevier Inc. C1 [Waterford, Stephen D.] Massachusetts Gen Hosp, Dept Gen Surg, Boston, MA 02114 USA. [Williams, Mallory] US Army, Joint Task Force Bravo, Soto Cano Air Base, Honduras. [Siegert, Charles J.; Fisichella, P. Marco; Lebenthal, Abraham] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Siegert, Charles J.; Fisichella, P. Marco; Lebenthal, Abraham] Boston VA Healthcare Syst, Boston, MA USA. [Siegert, Charles J.; Lebenthal, Abraham] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. RP Lebenthal, A (reprint author), Brigham & Womens Hosp, Dept Surg, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. EM alebenthal@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD AUG PY 2015 VL 197 IS 2 BP 236 EP 239 DI 10.1016/j.jss.2015.03.002 PG 4 WC Surgery SC Surgery GA CK3CZ UT WOS:000356095100004 PM 25937566 ER PT J AU Collins, CE Pringle, PL Santry, HP AF Collins, Courtney E. Pringle, Patricia L. Santry, Heena P. TI Innovation or rebranding, acute care surgery diffusion will continue SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Surgery; Resource allocation; Acute care surgery; Health care delivery; Health care innovation; Diffusion of innovation ID EMERGENCY GENERAL-SURGERY; TRAUMA SURGEONS; UNITED-STATES; SERVICE; MODEL; IMPLEMENTATION; APPENDICITIS; WORKFORCE; FUTURE; REGIONALIZATION AB Background: Patterns of adoption of acute care surgery (ACS) as a strategy for emergency general surgery (EGS) care are unknown. Methods: We conducted a qualitative study comprising face-to-face interviews with senior surgeons responsible for ACS at 18 teaching hospitals chosen to ensure diversity of opinions and practice environment (three practice types [community, public or charity, and university] in each of six geographic regions [Mid-Atlantic, Midwest, New England, Northeast, South, and West]). Interviews were recorded, transcribed, and analyzed using NVivo (QSR International, Melbourne, Australia). We applied the methods of investigator triangulation using an inductive approach to develop a final taxonomy of codes organized by themes related to respondents' views on the future of ACS as a strategy for EGS. We applied our findings to a conceptual model on diffusion of innovation. Results: We found a paradox between ACS viewed as a health care delivery innovation versus a rebranding of comprehensive general surgery. Optimism for the future of ACS because of increased desirability for trauma and critical care careers as well as improved EGS outcomes was tempered by fear over lack of continuity, poor institutional resources, and uncertainty regarding financial viability. Our analysis suggests that the implementation of ACS, whether a true health care delivery innovation or an innovative rebranding, fits into the Rogers' diffusion of innovation theory. Conclusions: Despite concerns over resource allocation and the definition of the specialty, from the perspective of senior surgeons deeply entrenched in executing this care delivery model, ACS represents the new face of general surgery that will likely continue to diffuse from these early adopters. Published by Elsevier Inc. C1 [Collins, Courtney E.; Santry, Heena P.] Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA USA. [Pringle, Patricia L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Santry, HP (reprint author), Univ Massachusetts, Med Ctr, Dept Surg, Room S3-731,55 Lake Ave North, Worcester, MA 01655 USA. EM heena@santry.org FU National Institutes of Health [UL1RR031982, 1KL2RR031981-01, 1KL2RR031981-02, 8KL2TR000160-03] FX Heena P. Santry received partial salary support from a grant from the National Institutes of Health (UL1RR031982, 1KL2RR031981-01 (02), and 8KL2TR000160-03). NR 49 TC 0 Z9 0 U1 1 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD AUG PY 2015 VL 197 IS 2 BP 354 EP 362 DI 10.1016/j.jss.2015.03.046 PG 9 WC Surgery SC Surgery GA CK3CZ UT WOS:000356095100021 PM 25891673 ER PT J AU Wylie, KP Kronberg, E Maharajh, K Smucny, J Cornier, MA Tregellas, JR AF Wylie, Korey P. Kronberg, Eugene Maharajh, Keeran Smucny, Jason Cornier, Marc-Andre Tregellas, Jason R. TI Between-network connectivity occurs in brain regions lacking layer IV input SO NEUROIMAGE LA English DT Article DE fMRI; Cytology; Independent components analysis; Resting state; Paralimbic ID INTRINSIC FUNCTIONAL CONNECTIVITY; HUMAN CEREBRAL-CORTEX; CORTICOCORTICAL CONNECTIONS; CORTICAL AREAS; ORGANIZATION; CYTOARCHITECTURE; CINGULATE; CIRCUITS; DYNAMICS; INSULA AB To better understand the cortical circuitry underlying connectivity between large-scale neural networks, we develop a novel, data-driven approach to identify potential integration subregions. Between-network connectivity (BNC) associated with any anatomical region is the amount of connectivity between that point and all large-scale networks, as measured using simple and multiple correlations. It is straightforward to calculate and applicable to functional networks identified using independent components analysis. We calculated BNC for all fMRI voxels within the brain and compared the results to known regional cytoarchitectural patterns. Based on previous observations of the relationship between macroscopic connectivity and microscopic cytoarchitecture, we predicted that areas with high BNC will be located in paralimbic subregions with an undifferentiated laminar structure. Results suggest that the anterior insula and dorsal posterior cingulate cortices play prominent roles in information integration. Cytoarchitecturely, these areas show agranular or dysgranular cytologies with absent or disrupted cortical layer IV. Since layer IV is the primary recipient of feed-forward thalamocortical connections, and due to the exclusive nature of driving connections to this layer, we suggest that the absence of cortical layer IV might allow for information to be exchanged across networks, and is an organizational characteristic of brain-subregions serving as inter-network communication hubs. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wylie, Korey P.; Kronberg, Eugene; Maharajh, Keeran; Smucny, Jason; Tregellas, Jason R.] Univ Colorado, Dept Psychiat, Aurora, CO 80045 USA. [Cornier, Marc-Andre] Univ Colorado, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA. [Tregellas, Jason R.] Denver VA Med Ctr, Res Serv 151, Res Serv, Denver, CO 80220 USA. RP Tregellas, JR (reprint author), Anschutz Med Campus Bldg 500,Mail Stop F546, Aurora, CO 80045 USA. EM Jason.Tregellas@UCDenver.edu RI Tregellas, Jason/J-3637-2015; OI Kronberg, Eugene/0000-0002-5166-1875; Smucny, Jason/0000-0001-5656-7987 FU Veterans Administration Biomedical Laboratory and Clinical Science Research and Development Service; National Institutes of Mental Health [R01DK089095, MH-086383]; Brain and Behavior Research Foundation; Blowitz-Ridgeway Foundation FX This work was supported by the Veterans Administration Biomedical Laboratory and Clinical Science Research and Development Service, the National Institutes of Mental Health grants R01DK089095 and MH-086383, the Brain and Behavior Research Foundation, and the Blowitz-Ridgeway Foundation. NR 52 TC 2 Z9 2 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2015 VL 116 BP 50 EP 58 DI 10.1016/j.neuroimage.2015.05.010 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CK0XY UT WOS:000355930200005 PM 25979667 ER PT J AU Beliveau, V Svarer, C Frokjaer, VG Knudsen, GM Greve, DN Fisher, PM AF Beliveau, Vincent Svarer, Claus Frokjaer, Vibe G. Knudsen, Gitte M. Greve, Douglas N. Fisher, Patrick M. TI Functional connectivity of the dorsal and median raphe nuclei at rest SO NEUROIMAGE LA English DT Article DE Serotonin; Resting-state; Functional connectivity; Dorsal raphe; Median raphe ID SEROTONIN TRANSPORTER AVAILABILITY; CORTISOL AWAKENING RESPONSE; SURFACE-BASED ANALYSIS; HUMAN BRAIN-STEM; CORTICAL SURFACE; PREFRONTAL CORTEX; COORDINATE SYSTEM; STATE NETWORKS; BASAL GANGLIA; FMRI DATA AB Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [C-11] DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined with structural MRI from 49 healthy volunteers, we delineated DR and MR and performed a seed-based resting-state FC analysis. The DR and MR seeds produced largely similar FC maps: significant positive FC with brain regions involved in cognitive and emotion processing including anterior cingulate, amygdala, insula, hippocampus, thalamus, basal ganglia and cerebellum. Significant negative FC was observed within pre- and postcentral gyri for the DR but not for the MR seed. We observed a significant association between DR and MR FC and regional 5-HTT binding. Our results provide evidence for a resting-state network related to DR and MR and comprising regions receiving serotonergic innervation and centrally involved in 5-HT related behaviors including emotion, cognition and reward processing. These findings provide a novel advance in estimating resting-state FC related to 5-HT signaling, which can benefit our understanding of its role in behavior and neuro-psychiatric illnesses. (C) 2015 Elsevier Inc. All rights reserved. C1 [Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G.; Knudsen, Gitte M.; Fisher, Patrick M.] Rigshosp, Neurobiol Res Unit, DK-2100 Copenhagen O, Denmark. [Beliveau, Vincent; Svarer, Claus; Frokjaer, Vibe G.; Knudsen, Gitte M.; Fisher, Patrick M.] Rigshosp, Ctr Integrated Mol Brain Imaging, DK-2100 Copenhagen O, Denmark. [Knudsen, Gitte M.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Greve, Douglas N.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Greve, Douglas N.] Harvard Univ, Sch Med, Boston, MA USA. RP Fisher, PM (reprint author), Rigshosp, Copenhagen Univ Hosp, Neurobiol Res Unit, NRU 6931,Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. EM patrick@nru.dk RI Knudsen, Gitte/C-1368-2013; OI Knudsen, Gitte/0000-0003-1508-6866; Fisher, Patrick/0000-0002-8115-0611; Beliveau, Vincent/0000-0001-7805-279X FU Danish Council for Independent Research [09-073884]; Lundbeck Foundation (Cimbi) [R90-A7722]; Capital Region of Denmark, Foundation for Health Research [R133 A4412]; National Institutes of Health [1R21EB018964-01, 1R01NS083534-01A1] FX We wish to thank Dorthe Givard, Peter Jensen, Anna Pors Nielsen, Maria Heede, Kenda Christensen, Susanne Henningsson and Sussi Larsen for their superb technical assistance. The study was funded by the Danish Council for Independent Research (09-073884), the Lundbeck Foundation (Cimbi) (R90-A7722), and the Capital Region of Denmark, Foundation for Health Research (R133 A4412). Support for this research was also provided in part by the National Institutes of Health (1R21EB018964-01 and 1R01NS083534-01A1). NR 93 TC 6 Z9 6 U1 4 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2015 VL 116 BP 187 EP 195 DI 10.1016/j.neuroimage.2015.04.065 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CK0XY UT WOS:000355930200018 PM 25963733 ER PT J AU Reitzel, LR Langdon, KJ Nguyen, NT Zvolensky, MJ AF Reitzel, Lorraine R. Langdon, Kirsten J. Nguyen, Nga T. Zvolensky, Michael J. TI Financial strain and smoking cessation among men and women within a self-guided quit attempt SO ADDICTIVE BEHAVIORS LA English DT Article DE Financial strain; Smoking cessation; Self-guided quit attempt; Sex differences; Smoking disparities; Socioeconomic status ID STRESS; ADULTS; RELAPSE; SMOKERS; SAMPLE; GENDER AB Introduction: Financial strain, defined as an unfavorable asset-to-needs ratio, has been associated with reduced odds of smoking cessation in the context of a structured clinical study providing cessation assistance. This study reports on a secondary data analysis that assessed the association of financial strain and biochemically-verified smoking abstinence within a structured clinical study of smokers making a self-guided cessation attempt. Methods: Participants (N = 58; 65.5% men) were enrolled in a study about anxiety sensitivity and smoking cessation whereby they were instructed to initiate a self-guided quit attempt. Relations between financial strain and biochemically-verified smoking abstinence on the quit day and at Days 3, 7, 14, 28, and 90 post-quit were assessed using generalized estimating equations controlling for age, sex, race, education, partner status, pre-quit cigarettes smoked per day, and time. Results: Associations between financial strain and abstinence in the whole sample were marginal (aOR = .94,95% CI = .87-1.01, observations = 293; p = .07). However, sex was a significant moderator: greater financial strain was associated with lower odds of abstinence for men (aOR = .90, 95% Cl = .80-1.00, observations = 201; p = .05), but not women (aOR = 1.05,95% Cl = .91-1.21, observations = 92; p = .48). Conclusions: Results indicated that financial strain was associated with lower odds of cessation among men undergoing a self-guided quit attempt in the context of a structured clinical study. These data suggest that financial strain may be an important socioeconomic determinant of smoking cessation and support its relevance for better understanding socioeconomic-based smoking-related health disparities. Future work may benefit by exploring sex-specific models of financial strain in the context of smoking cessation. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Reitzel, Lorraine R.] Univ Houston, Coll Educ, Dept Psychol Hlth & Learning Sci, Houston, TX 77204 USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, VA Boston Healthcare Syst, Natl Ctr PTSD,Womens Hlth Sci Div, Boston, MA 02118 USA. [Nguyen, Nga T.] Istat Solut, Houston, TX 77346 USA. [Zvolensky, Michael J.] Univ Houston, Coll Liberal Arts & Social Sci, Dept Psychol, Houston, TX 77204 USA. RP Reitzel, LR (reprint author), Univ Houston, Coll Educ, Dept Psychol Hlth & Learning Sci, 491 Farish Hall, Houston, TX 77204 USA. EM Lrreitzel@uh.edu FU National Research Service Award by the National Institute on Drug Abuse [F31DA026634]; University of Houston FX This work was supported by a National Research Service Award to Dr. Langdon by the National Institute on Drug Abuse (F31DA026634) and by institutional funds from the University of Houston provided to Dr. Reitzel. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the sponsoring organizations. NR 28 TC 1 Z9 1 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD AUG PY 2015 VL 47 BP 66 EP 69 DI 10.1016/j.addbeh.2015.03.026 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA CJ3GR UT WOS:000355371900012 PM 25879712 ER PT J AU Fazeli, PK Faje, AT Cross, EJ Lee, H Rosen, CJ Bouxsein, ML Klibanski, A AF Fazeli, Pouneh K. Faje, Alexander T. Cross, Ela J. Lee, Hang Rosen, Clifford J. Bouxsein, Mary L. Klibanski, Anne TI Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa SO BONE LA English DT Article DE FGF-21; Anorexia nervosa; Bone microarchitecture; Bone strength ID QUANTITATIVE COMPUTED-TOMOGRAPHY; GROWTH-HORMONE; DISTAL RADIUS; PPAR-ALPHA; FGF21; FIBROBLAST-GROWTH-FACTOR-21; MICE; OSTEOPOROSIS; METABOLISM; STARVATION AB Background: Anorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation and low body weight. Women with AN have impaired bone formation, low bone mass and an increased risk of fracture. FGF-21 is a hormone secreted by the liver in starvation and FGF-21 transgenic mice have significant bone loss due to an uncoupling of bone resorption and bone formation. We hypothesized that FGF-21 may contribute to the low bone mass state of AN. Subjects and methods: We studied 46 women: 20 with AN (median age [interquartile range]: 27.5 [25, 30.75] years) and 26 normal-weight controls (NWC) of similar age (25 [24, 28.5] years). We investigated associations between serum FGF-21 and 1) aBMD measured by dual energy X-ray absorptiometry, 2) parameters of bone microarchitecture in the distal radius and tibia measured by high-resolution peripheral quantitative CT and 3) bone strength, estimated by microfinite element analysis. Results: FGF-21 levels were similar in AN and NWC (AN: 33.1 [18.1, 117.0] pg/ml vs. NWC: 57.4 [23.8, 107.1] pg/ml; p = 0.54). There was a significant inverse association between log FGF-21 and trabecular number in the radius in both AN (R = -0.57,p < 0.01) and NWC (R = -0.53, p < 0.01) and a significant positive association between log FGF-21 and trabecular separation in the radius in AN (R = -0.50, p < 0.03) and NVVC (R = 0.52,p < 0.01). Estimates of radial bone strength were inversely associated with log FGF-21 in AN (R = 0.50, p < 0.03 for both stiffness and failure load). There were no associations between FGF-21 and aBMD, cortical parameters or tibial parameters in the AN or NWC groups. Conclusions: FGF-21 may be an important determinant of trabecular skeletal homeostasis in AN. (C) 2015 Elsevier Inc. All rights reserved. C1 [Fazeli, Pouneh K.; Faje, Alexander T.; Cross, Ela J.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Fazeli, Pouneh K.; Faje, Alexander T.; Cross, Ela J.; Lee, Hang; Bouxsein, Mary L.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA USA. [Lee, Hang] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Rosen, Clifford J.] Maine Med Ctr Res Inst, Scarborough, ME USA. [Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. RP Fazeli, PK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM pkfazeli@partners.org FU Harvard Clinical and Translational Science Center [UL1 RR025758]; National Center for Research Resources [1S10RR023405]; NIH [R24 DK084970, K23 DK094820] FX We would like to thank the nurses and bionutritionists of the MGH Clinical Research Center for their expert care. The project described was supported by grant UL1 RR025758 from the Harvard Clinical and Translational Science Center, and 1S10RR023405 from the National Center for Research Resources and NIH grants R24 DK084970 and K23 DK094820 (Fazeli). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 32 TC 3 Z9 3 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD AUG PY 2015 VL 77 BP 6 EP 11 DI 10.1016/j.bone.2015.04.001 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ7ZB UT WOS:000355717800002 PM 25868802 ER PT J AU Singhal, V Maffazioli, GDN Sokoloff, NC Ackerman, KE Lee, H Gupta, N Clarke, H Slattery, M Bredella, MA Misra, M AF Singhal, Vibha Maffazioli, Giovana D. N. Sokoloff, Natalia Cano Ackerman, Kathryn E. Lee, Hang Gupta, Nupur Clarke, Hannah Slattery, Meghan Bredella, Miriam A. Misra, Madhusmita TI Regional fat depots and their relationship to bone density and microarchitecture in young oligo-amenorrheic athletes SO BONE LA English DT Article DE Visceral fat; Marrow fat; Athletes; Oligo-amenorrhea; BMD; Microarchitecture ID POSTMENOPAUSAL OSTEOPOROTIC WOMEN; HUMAN SKELETAL-MUSCLE; VISCERAL FAT; MARROW FAT; ANOREXIA-NERVOSA; TRABECULAR BONE; FEMORAL-NECK; ADOLESCENT GIRLS; MINERAL CONTENT; STRENGTH AB Context: Various fat depots have differential effects on bone. Visceral adipose tissue (VAT) is deleterious to bone, whereas subcutaneous adipose tissue (SAT) has positive effects. Also, marrow adipose tissue (MAT), a relatively newly recognized fat depot is inversely associated with bone mineral density (BMD). Bone mass in athletes depends on many factors including gonadal steroids and muscle mass. Exercise increases muscle mass and BMD, whereas, estrogen deficiency decreases BMD. Thus, the beneficial effects of weight-bearing exercise on areal and volumetric BMD (aBMD and vBMD) in regularly menstruating (eumenorrheic) athletes (EA) are attenuated in oligo-amenorrheic athletes (OA). Of note, data regarding VAT, SAT, MAT and regional muscle mass in OA compared with EA and non-athletes (C), and their impact on bone are lacking. Methods: We used (i) MRI to assess VAT and SAT at the L4 vertebra level, and cross-sectional muscle area (CSA) of the mid-thigh, (ii) 1H-MRS to assess MAT at L4, the proximal femoral metaphysis and mid-diaphysis, (iii) DXA to assess spine and hip aBMD, and (iv) HRpQCT to assess vBMD at the distal radius (non-weight-bearing bone) and tibia (weight-bearing bone) in 41 young women (20 OA, 10 EA and 11 C 18-25 years). All athletes engaged in weight-bearing sports for >= 4 h/week or ran >= 20 miles/week. Main outcome measures: VAT, SAT and MAT at L4; CSA of the mid-thigh; MAT at the proximal femoral metaphysis and mid-diaphysis; aBMD, vBMD and bone microarchitecture. Results: Groups had comparable age, menarchal age, BMI, VAT, VAT/SAT and spine BMD Z-scores. EA had higher femoral neck BMD Z-scores than OA and C. Fat mass was lowest in OA. SAT was lowest in OA (p = 0.048); L4 MAT was higher in OA than EA (p = 0.03). We found inverse associations of (i) VAT/SAT with spine BMD Z-scores (r = -0.42, p = 0.01), (ii) L4 MAT with spine and hip BMD Z-scores (r = -0.44, p = 0.01; r = -036, p = 0.02), and vBMD of the radius and tibia (r = -0.49, p = 0.002; r = -0.41, p = 0.01), and (iii) diaphyseal and metaphyseal MAT with vBMD of the radius (r <= -0.42, p <= -0.01) and tibia (r <= -0.34, p <= -0.04). In a multivariate model including VAT/SAT, L4 MAT and thigh CSA, spine and hip BMD Z-scores were predicted inversely by L4 MAT and positively by thigh CSA, and total and cortical radius and total tibial vBMD were predicted inversely by L4 MAT. VAT/SAT did not predict radius or tibia total vBMD in this model, but inversely predicted spine BMD Z-scores. When L4 MAT was replaced with diaphyseal or metaphyseal MAT in the model, diaphyseal and metaphyseal MAT did not predict aBMD Z-scores, but diaphyseal MAT inversely predicted total vBMD of the radius and tibia. These results did not change after adding percent body fat to the model. Conclusions: VAT/SAT is an inverse predictor of lumbar spine aBMD Z-scores, while L4 MAT is an independent inverse predictor of aBMD Z-scores at the spine and hip and vBMD measures at the distal tibia and radius in athletes and non-athletes. Diaphyseal MAT independently predicts vBMD measures of the distal tibia and radius. (C) 2015 Elsevier Inc. All rights reserved. C1 [Singhal, Vibha; Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Singhal, Vibha; Maffazioli, Giovana D. N.; Sokoloff, Natalia Cano; Ackerman, Kathryn E.; Lee, Hang; Gupta, Nupur; Clarke, Hannah; Slattery, Meghan; Bredella, Miriam A.; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Singhal, Vibha; Maffazioli, Giovana D. N.; Sokoloff, Natalia Cano; Ackerman, Kathryn E.; Clarke, Hannah; Slattery, Meghan; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kathryn E.] Boston Childrens Hosp, Div Sports Med, Boston, MA 02115 USA. [Lee, Hang] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Gupta, Nupur] Massachusetts Gen Hosp, Dept Adolescent Med, Boston, MA 02114 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Singhal, V (reprint author), 55 Fruit St,Bulfinch Bldg BUL 457B, Boston, MA 02114 USA. EM vsinghal1@partners.org; gmaffazioli@partners.org; ncanosokoloff@partners.org; keackerman@partners.org; hlee5@partners.org; ngupta3@mgh.harvard.edu; clarke.hannahm@gmail.com; mslattery@partners.org; mbredella@partners.org; mmisra@partners.org FU National Institutes of Health [1UL1RR025758-01, 1UL1TR001102-01, 1R01HD060827-01A1, K24HD071843]; [216492] FX We would like to thank our patients, the nurses and bionutritionists in the Massachusetts General Hospital Clinical Research Center. This work was supported by the National Institutes of Health grants 1UL1RR025758-01, 1UL1TR001102-01, 1R01HD060827-01A1 and K24HD071843, and the HRpQCT Core facility was supported by grant 216492. NR 34 TC 4 Z9 4 U1 3 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD AUG PY 2015 VL 77 BP 83 EP 90 DI 10.1016/j.bone.2015.04.005 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ7ZB UT WOS:000355717800012 PM 25868796 ER PT J AU Wagers, AJ AF Wagers, Amy J. TI Systemic regulation of aging phenotypes in mammalian tissues SO EXPERIMENTAL GERONTOLOGY LA English DT Meeting Abstract CT 12th International Symposium on the Neurobiology and Neuroendocrinology of Aging CY JUL 27-AUG 01, 2014 CL Bregenz, AUSTRIA C1 [Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, HHMI Early Career Scientist, Cambridge, MA 02138 USA. [Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 1 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 AUG PY 2015 VL 68 BP 94 EP 94 DI 10.1016/j.exger.2015.01.012 PG 1 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CJ9PQ UT WOS:000355835100024 ER PT J AU Rosenthal, SL Bamne, MN Wang, XB Berman, S Snitz, BE Klunk, WE Sweet, RA Demirci, FY Lopez, OL Kamboh, MI AF Rosenthal, Samantha L. Bamne, Mikhil N. Wang, Xingbin Berman, Sarah Snitz, Beth E. Klunk, William E. Sweet, Robert A. Demirci, F. Yesim Lopez, Oscar L. Kamboh, M. Ilyas TI More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk SO NEUROBIOLOGY OF AGING LA English DT Article DE TREM2; Rare variants; LOAD ID GENOME-WIDE ASSOCIATION; FRONTOTEMPORAL DEMENTIA; COMMON VARIANTS; ONSET; PSYCHOSIS; EXPRESSION; CELLS; INDIVIDUALS; PREVENTION; MICROGLIA AB Over 20 risk loci have been identified for late-onset Alzheimer's disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer's disease risk, we also examined the association of R47H with Alzheimer's diseaseerelated phenotypes, including age-at-onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration. (C) 2015 Elsevier Inc. All rights reserved. C1 [Rosenthal, Samantha L.; Bamne, Mikhil N.; Wang, Xingbin; Demirci, F. Yesim; Kamboh, M. Ilyas] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Berman, Sarah; Snitz, Beth E.; Sweet, Robert A.; Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15261 USA. [Klunk, William E.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 4, Pittsburgh, PA USA. RP Kamboh, MI (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. EM kamboh@pitt.edu OI Demirci, F. Yesim/0000-0001-6907-9843; Kamboh, M. Ilyas/0000-0002-3453-1438 FU National Institute on Aging [AG041718, AG030653, AG027224, AG005133, P01 AG025204]; National Center for Complementary and Alternative Medicine [U01 AT000162] FX This study was supported by the National Institute on Aging grants AG041718, AG030653, AG027224, AG005133, and P01 AG025204, and by U01 AT000162 from the National Center for Complementary and Alternative Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government. NR 50 TC 4 Z9 4 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2015 VL 36 IS 8 AR 2443.e26 DI 10.1016/j.neurobiolaging.2015.04.012 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CJ8RL UT WOS:000355771100013 ER PT J AU Denckla, CA Bornstein, RF AF Denckla, Christy A. Bornstein, Robert F. TI Toward a more nuanced conceptualization of interpersonal distancing: Differential relationships of adaptive and dysfunctional detachment to stress-based anxiety in college students SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Detachment; Personality; Coping; Stress; Anxiety ID RELATIONSHIP PROFILE TEST; PERSONALITY-DISORDER; CONSTRUCT-VALIDITY; DEPENDENCY; GENDER; PERSPECTIVE; EXPERIENCES; RESILIENCE; VALIDATION; BEHAVIOR AB This study investigates the utility of a model for disambiguating the risk vs. protective features associated with detachment in moderating stress-based anxiety. The model distinguishes adaptive detachment (the ability to engage in flexible, goal-directed cognitive distancing accompanied by the capacity to moderate affective arousal and maintain functional levels of interpersonal connectedness) from dysfunctional detachment (a more generalized detached interpersonal style characterized by pervasive social isolation and negative emotionality). College students (N = 104, 71.4% female, mean age = 19.20 (SD = 3.54)) completed measures of detachment, mental health symptoms, and daily hassles; moderator hypotheses were tested by conducting a series of regression analyses. Findings indicate that individuals who report higher levels of adaptive detachment but not dysfunctional detachment experienced reduced anxiety in the context of elevated daily stressors. Results suggest that certain aspects of detachment may serve protective functions by reducing anxiety in the context of stressful events. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Denckla, Christy A.; Bornstein, Robert F.] Adelphi Univ, Gordon F Demer Inst Adv Psychol Studies, Garden City, NY USA. RP Denckla, CA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 15 Parkman St, Boston, MA 02114 USA. EM cdenckla@mgh.harvard.edu FU International Psychoanalytic Association FX This research was supported with a Grant from the International Psychoanalytic Association awarded to the first author. NR 47 TC 1 Z9 1 U1 6 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD AUG PY 2015 VL 82 BP 148 EP 152 DI 10.1016/j.paid.2015.03.008 PG 5 WC Psychology, Social SC Psychology GA CH6OZ UT WOS:000354157200026 ER PT J AU Thames, AD Briones, MS Magpantay, LI Martinez-Maza, O Singer, EJ Hinkin, CH Morgello, S Gelman, BB Moore, DJ Heizerling, K Levine, AJ AF Thames, April D. Briones, Marisa S. Magpantay, Larry I. Martinez-Maza, Otoniel Singer, Elyse J. Hinkin, Charles H. Morgello, Susan Gelman, Benjamin B. Moore, David J. Heizerling, Keith Levine, Andrew J. TI The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients SO AIDS LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; MILD COGNITIVE IMPAIRMENT; SOLUBLE TNF RECEPTORS; ALZHEIMERS-DISEASE; AIDS DEMENTIA; MCP-1; ASTROCYTES; EXPRESSION; CELLS; INFLAMMATION AB Objectives:We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4(+) cell count and neurocognitive functioning among HIV-infected adults. We hypothesized that HIV-positive carriers of the risk' CCL2 -2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning. Design:A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available. Methods:Genomic DNA was extracted from peripheral blood mononuclear cells and/or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-), interferon-gamma (IFN-), soluble tumor necrosis factor receptor 2, sIL-6R, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests. Results:Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 -2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups. Conclusion:Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition. C1 [Thames, April D.; Hinkin, Charles H.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Briones, Marisa S.; Heizerling, Keith] Univ Calif Los Angeles, Dept Family Med, Los Angeles, CA USA. [Magpantay, Larry I.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Dept Obstet & Gynecol, Los Angeles, CA 90024 USA. [Magpantay, Larry I.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Dept Epidemiol & Microbiol, Los Angeles, CA USA. [Magpantay, Larry I.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, Dept Immunol & Human Genet, Los Angeles, CA USA. [Singer, Elyse J.; Levine, Andrew J.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Hinkin, Charles H.] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. [Morgello, Susan] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Morgello, Susan] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Morgello, Susan] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Gelman, Benjamin B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Gelman, Benjamin B.] Univ Texas Med Branch, Dept Neurosci, Galveston, TX 77555 USA. [Gelman, Benjamin B.] Univ Texas Med Branch, Dept Cell Biol, Galveston, TX 77555 USA. [Moore, David J.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. RP Thames, AD (reprint author), 740 Westwood Plaza,C8-746, Los Angeles, CA 90095 USA. EM athames@mednet.ucla.edu RI Martinez-Maza, Otoniel/B-2667-2009 OI Martinez-Maza, Otoniel/0000-0003-1364-0675 FU National Institute of Mental Health (NIMH) [R25 MH080661, NIMH K23 MH096551]; Translational Research in NeuroAIDS and Mental Health [NIH K23 MH096551]; California HIV/AIDS Research Program grant [ID06-LA-187]; Texas NeuroAIDS Research Center [U24MH100930]; California NeuroAIDS Tissue Network [U24MH100928]; National Neurological AIDS Bank [U24MH100929]; Manhattan HIV Brain Bank [U24MH100931]; Data Coordinating Center [U24MH100925] FX This work was supported by the National Institute of Mental Health (NIMH) grant R25 MH080661 (subaward PI: A.T.). A.T. is also currently supported by a career development award from the National Institute of Mental Health (NIMH K23 MH096551). A.T., M.B., C.H. and A.J. designed the current study. A.T. and M. B. drafted the manuscript. A.T. performed statistical analysis and prepared figures. L.I.M. and O.M.M. performed the multiplex assays for CSF samples. B.B.G., S.M., E.J.S and D.J.M. supervised and managed clinical cohorts that were used in this study. All authors read, participated in editing the manuscript, providing scientific input on the study design and approved the final manuscript.; R25 MH080661; PI: J. MacArthur subaward PI: A. Thames Translational Research in NeuroAIDS and Mental Health, NIH K23 MH096551 (PI: A. Thames); California HIV/AIDS Research Program grant ID06-LA-187 (Levine); Texas NeuroAIDS Research Center: U24MH100930; California NeuroAIDS Tissue Network: U24MH100928; National Neurological AIDS Bank: U24MH100929; Manhattan HIV Brain Bank: U24MH100931; Data Coordinating Center: U24MH100925. NR 47 TC 1 Z9 2 U1 0 U2 2 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 JUL 31 PY 2015 VL 29 IS 12 BP 1483 EP 1491 DI 10.1097/QAD.0000000000000706 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CV6QL UT WOS:000364395000001 PM 26244388 ER PT J AU Kim, Y Lee, JH Ryu, H AF Kim, Yunha Lee, Junghee Ryu, Hoon TI Modulation of autophagy by miRNAs SO BMB REPORTS LA English DT Editorial Material DE Autophagy; EWSR1; miR125a; miR351; UVRAG AB MicroRNAs (miRNAs) can regulate the expression of genes that are involved in multiple cellular pathways. However, their targets and mechanism of action associated with the autophagy pathway are not fully investigated yet. EWSR1 (EWS RNA-Binding Protein 1/Ewing Sarcoma Break Point Region 1) gene encodes a RNA/DNA binding protein that is ubiquitously expressed and plays roles in numerous cellular processes. Recently, our group has shown that EWSR1 deficiency leads to developmental failure and accelerated senescence via processing of miRNAs, but its role in the regulation of autophagy remains elusive. In this context, we further investigated and found that EWSR1 deficiency triggers the activation of the DROSHA-mediated microprocessor complex and increases the levels of miR125a and miR351, which directly target Uvrag. Interestingly, the miR125a- and miR351-targeted reduction of Uvrag led to the inhibition of autophagy in both ewsr1 knockout (KO) MEFs and ewsr1 KO mice. In summary, our study demonstrates that EWSR1 is associated with the posttranscriptional regulation of Uvrag via miRNA processing. The regulation of autophagy pathway in miRNAs-Uvrag-dependent manner provides a novel mechanism of EWSR1 deficiency-related cellular dysfunction. C1 [Kim, Yunha] Korea Inst Sci & Technol, Ctr Neuromed, Seoul 136791, South Korea. [Lee, Junghee; Ryu, Hoon] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Ryu, H (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA. EM hoonryu@bu.edu FU NINDS NIH HHS [R01 NS067283] NR 0 TC 1 Z9 2 U1 0 U2 0 PU KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER, # 801, 635-4 , YEOKSAM-DONG, KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-6696 EI 1976-670X J9 BMB REP JI BMB Rep. PD JUL 31 PY 2015 VL 48 IS 7 BP 371 EP 372 DI 10.5483/BMBRep.2015.48.7.121 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CO2RV UT WOS:000359005200003 PM 26129673 ER PT J AU Xian, Y Wu, JJ Obrien, EC Fonarow, GC Olson, DM Schwamm, LH Bhatt, DL Smith, EE Suter, RE Hannah, D Lindholm, B Maisch, L Greiner, MA Lytle, BL Pencina, MJ Peterson, ED Hernandez, AF AF Xian, Ying Wu, Jingjing Obrien, Emily C. Fonarow, Gregg C. Olson, DaiWai M. Schwamm, Lee H. Bhatt, Deepak L. Smith, Eric E. Suter, Robert E. Hannah, Deidre Lindholm, Brianna Maisch, Lesley Greiner, Melissa A. Lytle, Barbara L. Pencina, Michael J. Peterson, Eric D. Hernandez, Adrian F. TI Real world effectiveness of warfarin among ischemic stroke patients with atrial fibrillation: observational analysis from Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID HEALTH-CARE PROFESSIONALS; GUIDELINES-STROKE; ORAL ANTICOAGULATION; PATIENTS PERSPECTIVE; UNCERTAINTY LIFE; DOSE WARFARIN; PREVENTION; MORTALITY; ATTACK; RISK AB OBJECTIVE To examine the association between warfarin treatment and longitudinal outcomes after ischemic stroke in patients with atrial fibrillation in community practice. DESIGN Observational study. SETTING Hospitals (n=1487) participating in the Get With The Guidelines (GWTG)-Stroke program in the United States, from 2009 to 2011. PARTICIPANTS 12552 warfarin naive atrial fibrillation patients admitted to hospital for ischemic stroke and treated with warfarin compared with no oral anticoagulant at discharge, linked to Medicare claims for longitudinal outcomes. MAIN OUTCOME MEASURES Major adverse cardiovascular events (MACE) and home time, a patient centered outcomes measure defined as the total number of days free from institutional care after discharge. A propensity score inverse probability weighting method was used to account for all differences in observed characteristics between treatment groups. RESULTS Among 12 552 survivors of stroke, 11 039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke. CONCLUSIONS Among ischemic stroke patients with atrial fibrillation, warfarin treatment was associated with improved long term clinical outcomes and more days at home. C1 [Xian, Ying; Wu, Jingjing; Obrien, Emily C.; Greiner, Melissa A.; Lytle, Barbara L.; Pencina, Michael J.; Peterson, Eric D.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC 27705 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Olson, DaiWai M.] Univ Texas SW Med Ctr Dallas, Dept Neurol & Neurotherapeut, Neurol Surg, Dallas, TX 75390 USA. [Schwamm, Lee H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke Serv, Boston, MA USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Brigham & Womens Hosp Heart & Vasc Ctr, Boston, MA USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Suter, Robert E.] Univ Texas SW Med Ctr Dallas, Amer Heart Assoc, Dallas, TX 75390 USA. RP Xian, Y (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM ying.xian@duke.edu RI Smith, Eric/C-5443-2012; Hernandez, Adrian F./A-7818-2016 OI Smith, Eric/0000-0003-3956-1668; Hernandez, Adrian F./0000-0003-3387-9616 NR 39 TC 11 Z9 11 U1 1 U2 10 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 JUL 31 PY 2015 VL 351 AR h3786 DI 10.1136/bmj.h3786 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CO2UE UT WOS:000359011300002 PM 26232340 ER PT J AU Lei, LL West, J Yan, ZJ Gao, XL Fang, P Dennis, JH Gnatovskiy, L Wang, WD Kingston, RE Wang, Z AF Lei, Lenglam West, Jason Yan, Zhijiang Gao, Xiaolin Fang, Peng Dennis, Jonathan H. Gnatovskiy, Leonid Wang, Weidong Kingston, Robert E. Wang, Zhong TI BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; TRANSCRIPTIONAL NETWORK; SELF-RENEWAL; PLURIPOTENCY; GENOME; ESBAF; PROMOTERS; COMPONENT; CLUSTERS; REGIONS AB The unique chromatin signature of ES cells is fundamental to the pluripotency and differentiation of ES cells. One key feature is the poised chromatin state of master developmental genes that are transcriptionally repressed in ES cells but ready to be activated in response to differentiation signals. Poised chromatin in ES cells contains both H3 Lys-4 trimethylation (H3K4me3) and H3 Lys-27 trimethylation (H3K27me3) methylation, indicating activating and repressing potential. However, the contribution of non-covalent chromatin structure to the poised state is not well understood. To address whether remodeling of nucleosomes is important to the poised state, we characterized the function of BAF250a, a key regulatory subunit of the ES cell ATP-dependent Brahma-associated factor (BAF) chromatin remodeling complex (esBAF). Acute deletion of BAF250a disrupted the differentiation potential of ES cells by altering the expression timing of key developmental genes and pluripotent genes. Our genome-wide nucleosome and histone modification analyses indicated that the disruption of gene expression timing was largely due to changes of chromatin structures at poised genes, particularly those key developmental genes mediated by BAF250a. Specifically, BAF250a deletion caused a nucleosome occupancy increase at H3K4me3- and/or H3K27me3-associated promoters. Moreover, H3K27me3 levels and the number of bivalent promoter genes were reduced in BAF250aKOES cells. We revealed that BAF250a ablation led to elevated Brg1 but reduced Suz12 recruitment at nucleosome occupancy-increased regions, indicating an unexpected and complicated role of BAF250a in regulating esBAF and Polycomb repressive complex (PRC) activities. Together, our studies identified that BAF250a mediates esBAF and PRC functions to establish the poised chromatin configuration in ES cells, which is essential for the proper differentiation of ES cells. C1 [Lei, Lenglam; Gnatovskiy, Leonid; Wang, Zhong] Univ Michigan, Dept Cardiac Surg, Cardiovasc Res Ctr, Ann Arbor, MI 48109 USA. [West, Jason; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Gao, Xiaolin; Fang, Peng] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Yan, Zhijiang; Wang, Weidong] NIA, Genome Instabil & Chromatin Remodeling Sect, NIH, Baltimore, MD 21224 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. RP Wang, Z (reprint author), Univ Michigan, Dept Cardiac Surg, Cardiovasc Res Ctr, 2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM zhongw@med.umich.edu RI Regan, Clinton/E-6250-2012; West, Jason/I-4445-2014 OI West, Jason/0000-0002-7252-8651 FU National Institutes of Health [HL109054]; Intramural Research Program of the NIA/National Institutes of Health [AG000650-10]; Samuel and Jean Frankel Cardiovascular Center, University of Michigan (Inaugural Fund) FX This work was supported, in whole or in part, by National Institutes of Health Grant HL109054 (to W. Z.) and Intramural Research Program of the NIA/National Institutes of Health Grant AG000650-10 (to W. W.). This work was also supported by the Samuel and Jean Frankel Cardiovascular Center, University of Michigan (Inaugural Fund) (to W. Z.). The authors declare that they have no conflicts of interest with the contents of this article. NR 35 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 31 PY 2015 VL 290 IS 31 BP 19343 EP 19352 DI 10.1074/jbc.M115.637389 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN9PK UT WOS:000358781100045 ER PT J AU Samir, AE Allegretti, AS Zhu, QL Dhyani, M Anvari, A Sullivan, DA Trottier, CA Dougherty, S Williams, WW Babitt, JL Wenger, J Thadhani, RI Lin, HY AF Samir, Anthony E. Allegretti, Andrew S. Zhu, Qingli Dhyani, Manish Anvari, Arash Sullivan, Dorothy A. Trottier, Caitlin A. Dougherty, Sarah Williams, Winfred W. Babitt, Jodie L. Wenger, Julia Thadhani, Ravi I. Lin, Herbert Y. TI Shear wave elastography in chronic kidney disease: a pilot experience in native kidneys SO BMC NEPHROLOGY LA English DT Article DE Chronic kidney disease; Stiffness; Fibrosis; Shear wave elastography; Ultrasound ID RADIATION FORCE IMPULSE; RENAL-ALLOGRAFT FIBROSIS; TISSUE ELASTICITY QUANTIFICATION; GLOMERULAR-FILTRATION-RATE; TRANSIENT ELASTOGRAPHY; ULTRASOUND ELASTOGRAPHY; DIFFERENT FREQUENCIES; SERUM CREATININE; HEPATITIS-C; LIVER AB Background: There currently is a need for a non-invasive measure of renal fibrosis. We aim to explore whether shear wave elastography (SWE)-derived estimates of tissue stiffness may serve as a non-invasive biomarker that can distinguish normal and abnormal renal parenchymal tissue. Methods: Participants with CKD (by estimated GFR) and healthy volunteers underwent SWE. Renal elasticity was estimated as Young's modulus (YM) in kilopascals (kPa). Univariate Wilcoxon rank-sum tests were used. Results: Twenty-five participants with CKD (median GFR 38 mL/min; quartile 1, quartile 3 28, 42) and 20 healthy controls without CKD underwent SWE performed by a single radiologist. CKD was associated with increased median YM (9.40 [5.55, 22.35] vs. 4.40 [3.68, 5.70] kPa; p = 0.002) and higher median intra-subject inter-measurement estimated YM's variability (4.27 [2.89, 9.90] vs. 1.51 [1.21, 2.05] kPa; p < 0.001). Conclusions: SWE-derived estimates of renal stiffness and intra-subject estimated stiffness variability are higher in patients with CKD than in healthy controls. Renal fibrosis is a plausible explanation for the observed difference in YM. Further studies are required to determine the relationship between YM, estimated renal stiffness, and renal fibrosis severity. C1 [Samir, Anthony E.; Zhu, Qingli; Dhyani, Manish; Anvari, Arash] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Allegretti, Andrew S.; Sullivan, Dorothy A.; Trottier, Caitlin A.; Dougherty, Sarah; Williams, Winfred W.; Babitt, Jodie L.; Wenger, Julia; Thadhani, Ravi I.; Lin, Herbert Y.] Massachusetts Gen Hosp, Div Nephrol, Dept Med, Boston, MA 02114 USA. RP Allegretti, AS (reprint author), Massachusetts Gen Hosp, Div Nephrol, Dept Med, 185 Cambridge St,Suite 8-216, Boston, MA 02114 USA. EM AALLEGRETTI@partners.org; Lin.Herbert@mgh.harvard.edu RI Anvari, Arash/B-4329-2014; OI Anvari, Arash/0000-0001-5887-581X; Dhyani, Manish/0000-0002-2651-1859 FU NIH [5T32DK007540-29, RO1 DK 069533, RO1 071837] FX The authors would like to thank the Thadhani Lab for their feedback on the study design and data analysis. ASA is supported by NIH grant 5T32DK007540-29. HYL is supported in part by NIH grant RO1 DK 069533 and RO1 071837. NR 39 TC 7 Z9 8 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 31 PY 2015 VL 16 AR 119 DI 10.1186/s12882-015-0120-7 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CN8QP UT WOS:000358706700001 PM 26227484 ER PT J AU Hu, LT Tsibris, AM Branda, JA AF Hu, Linden T. Tsibris, Athe M. Branda, John A. TI Case 24-2015: A 28-Year-Old Pregnant Woman with Fever, Chills, Headache, and Fatigue SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN GRANULOCYTIC ANAPLASMOSIS; BORRELIA-MIYAMOTOI INFECTION; NORTHEASTERN UNITED-STATES; CONFIRMED ERYTHEMA MIGRANS; LYME BORRELIOSIS; RELAPSING FEVER; SENSU-LATO; DISEASE; PCR; BURGDORFERI C1 [Hu, Linden T.] Tufts Med Ctr, Dept Geog Med & Infect Dis, Boston, MA 02111 USA. [Tsibris, Athe M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tsibris, Athe M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hu, LT (reprint author), Tufts Med Ctr, Dept Geog Med & Infect Dis, Boston, MA 02111 USA. RI Hu, Linden/L-6314-2016 OI Hu, Linden/0000-0003-1659-5558 FU Abzyme; FoodSource Lure; DynaMed/EBSCO; AdvanDx; bioMerieux; Immunetics; Alere; DiaSorin FX Dr. Hu reports receiving consulting fees from Abzyme and grant support to his institution from FoodSource Lure; Dr. Tsibris, consulting and editing fees from DynaMed/EBSCO; and Dr. Branda, consulting fees from AdvanDx and grant support to his institution from bioMerieux, Immunetics, Alere, and DiaSorin. No other potential conflict of interest relevant to this article was reported. NR 18 TC 1 Z9 1 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 JUL 30 PY 2015 VL 373 IS 5 BP 468 EP 475 DI 10.1056/NEJMcpc1501763 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CN8BO UT WOS:000358662200012 PM 26222563 ER PT J AU Basak, SK Zinabadi, A Wu, AW Venkatesan, N Duarte, VM Kang, JJ Dalgard, CL Srivastava, M Sarkar, FH Wang, MB Srivatsan, ES AF Basak, Saroj K. Zinabadi, Alborz Wu, Arthur W. Venkatesan, Natarajan Duarte, Victor M. Kang, James J. Dalgard, Clifton L. Srivastava, Meera Sarkar, Fazlul H. Wang, Marilene B. Srivatsan, Eri S. TI Liposome encapsulated curcumin-difluorinated (CDF) inhibits the growth of cisplatin resistant head and neck cancer stem cells SO ONCOTARGET LA English DT Article DE head and neck cancer; cisplatin; drug resistance; curcumin-difluorinated (CDF); cancer stem cell (CSC) ID NF-KAPPA-B; IN-VITRO; SIGNALING PATHWAYS; PANCREATIC-CANCER; SUPPRESSES GROWTH; COLON-CANCER; ORAL-CANCER; BETA KINASE; CARCINOMA; SENESCENCE AB Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with 600,000 new cases every year worldwide. Although chemotherapeutics exist, five-year survival is only 50%. New strategies to overcome drug resistance are required to improve HNSCC treatment. Curcumin-difluorinated (CDF), a synthetic analog of curcumin, was packaged in liposomes and used to evaluate growth inhibition of cisplatin resistant HNSCC cell lines CCL-23R and UM-SCC-1R generated from the parental cell lines CCL-23 and UM-SCC-1 respectively. Growth inhibition in vitro and expression levels of the CD44 (cancer stem cell marker), cytokines, and growth factors were investigated after liposomal CDF treatment. The in vivo growth inhibitory effect of liposomal CDF was evaluated in the nude mice xenograft tumor model of UM-SCC1R and the inhibition of CD44 was measured. Treatment of the resistant cell lines in vitro with liposomal CDF resulted in a statistically significant growth inhibition (p<0.05). The nude mice xenograft study showed a statistically significant tumor growth inhibition of UM-SCC-1R cells and a reduction in the expression of CD44 (p<0.05), indicating an inhibitory effect of liposomal CDF on CSCs. Our results demonstrate that delivery of CDF through liposomes may be an effective method for the treatment of cisplatin resistant HNSCC. C1 [Basak, Saroj K.; Zinabadi, Alborz; Wu, Arthur W.; Venkatesan, Natarajan; Duarte, Victor M.; Kang, James J.; Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Duarte, Victor M.; Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, Los Angeles, CA 90095 USA. [Dalgard, Clifton L.; Srivastava, Meera] Uniformed Serv Univ Hlth Sci, Dept Anat, Bethesda, MD 20814 USA. [Dalgard, Clifton L.; Srivastava, Meera] Uniformed Serv Univ Hlth Sci, Dept Physiol & Genet, Bethesda, MD 20814 USA. [Dalgard, Clifton L.; Srivastava, Meera] Uniformed Serv Univ Hlth Sci, Dept Mol & Cell Biol, Bethesda, MD 20814 USA. [Sarkar, Fazlul H.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RP Srivatsan, ES (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. EM esrivats@g.ucla.edu FU VAGLAHS; West Los Angeles Surgical Education Research Center; UCLA Academic Senate grants; Merit; Veterans Administration, Washington, D.C. FX The study was supported by funds from VAGLAHS, West Los Angeles Surgical Education Research Center, UCLA Academic Senate grants (M. B. Wang), and Merit grant from the Veterans Administration, Washington, D.C. (E.S. Srivatsan). NR 42 TC 12 Z9 12 U1 2 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 30 PY 2015 VL 6 IS 21 BP 18504 EP 18517 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2VW UT WOS:000359015900025 PM 26098778 ER PT J AU Chen, C Cai, JJ Zhang, S Gan, L Dong, YL Zhu, T Ma, G Li, T Zhang, XY Li, Q Cheng, X Wu, CM Yang, J Zuo, YX Liu, J AF Chen, Chan Cai, Jingjing Zhang, Shu Gan, Lu Dong, Yuanlin Zhu, Tao Ma, Gang Li, Tao Zhang, Xiyang Li, Qian Cheng, Xu Wu, Chaomeng Yang, Jing Zuo, Yunxia Liu, Jin TI Protective Effect of RNase on Unilateral Nephrectomy-Induced Postoperative Cognitive Dysfunction in Aged Mice SO PLOS ONE LA English DT Article ID EXTRACELLULAR RNA; SURGERY; DECLINE; RESPONSES; DELIRIUM; BRAIN; DRUGS AB Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice. C1 [Chen, Chan; Cai, Jingjing; Gan, Lu; Zhu, Tao; Ma, Gang; Li, Tao; Zhang, Xiyang; Li, Qian; Cheng, Xu; Wu, Chaomeng; Yang, Jing; Zuo, Yunxia; Liu, Jin] Sichuan Univ, West China Hosp, Dept Anesthesiol, Chengdu 610064, Sichuan, Peoples R China. [Chen, Chan; Cai, Jingjing; Gan, Lu; Zhu, Tao; Ma, Gang; Li, Tao; Zhang, Xiyang; Li, Qian; Cheng, Xu; Wu, Chaomeng; Yang, Jing; Zuo, Yunxia; Liu, Jin] Sichuan Univ, West China Hosp, Translat Neurosci Ctr, Chengdu 610064, Sichuan, Peoples R China. [Zhang, Shu] Sichuan Univ, West China Hosp, Dept Emergency Med, Chengdu 610064, Sichuan, Peoples R China. [Dong, Yuanlin] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Boston, MA 02114 USA. [Dong, Yuanlin] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Li, T (reprint author), Sichuan Univ, West China Hosp, Dept Anesthesiol, Chengdu 610064, Sichuan, Peoples R China. EM xwtao_zhu@yahoo.com FU China Medical Board [0082827601157]; Science and Technology Pillar Program of Sichuan Province Research Grant [2014sz0056] FX This work was financially supported by Distinguished Professorships Awards (no. 0082827601157, to JL) from the China Medical Board (URLs: http://www.chinamedicalboard.org/active_grants), and the Science and Technology Pillar Program of Sichuan Province Research Grant (no. 2014sz0056, to CC) (URLs: http://xmgl.scst.gov.cn/index.html). NR 28 TC 3 Z9 3 U1 1 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 JUL 30 PY 2015 VL 10 IS 7 AR e0134307 DI 10.1371/journal.pone.0134307 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO0JT UT WOS:000358837700071 PM 26225860 ER PT J AU Curie, A Yang, K Kirsch, I Gollub, RL Portes, VD Kaptchuk, TJ Jensen, KB AF Curie, Aurore Yang, Kathy Kirsch, Irving Gollub, Randy L. Portes, Vincent des Kaptchuk, Ted J. Jensen, Karin B. TI Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis SO PLOS ONE LA English DT Article ID FRAGILE-X-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; IRRITABLE-BOWEL-SYNDROME; DOWN-SYNDROME; DOUBLE-BLIND; ALZHEIMERS-DISEASE; CLINICAL-TRIALS; WILLI-SYNDROME; FOLINIC ACID; YOUNG MALES AB Background Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. Objective To determine if placebo response exists in patients with genetically determined ID. Data sources and Study selection We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. Data extraction and synthesis Two investigators extracted outcome data independently. Main outcomes and measures Bias-corrected standardized mean difference (Hedge's g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient subgroups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression Results Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for "subjective outcomes" (a third-person's evaluation of the patient) (g = 0.563, p = 0.022) and "objective outcomes" (direct evaluation of the patient's abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. Conclusions and relevance Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and "placebo-by-proxy" induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID. C1 [Curie, Aurore; Yang, Kathy; Gollub, Randy L.; Jensen, Karin B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Martinos Ctr Biomed Imaging, Boston, MA 02138 USA. [Curie, Aurore; Portes, Vincent des] CNRS, Inst Cognit Sci, L2C2, UMR5304, Bron, France. [Curie, Aurore; Portes, Vincent des] Hosp Civils Lyon, Hop Femmes Meres Enfants, Ctr Reference Deficiences Intellectuelles Causes, Bron, France. [Curie, Aurore; Portes, Vincent des] Univ Lyon 1, F-69365 Lyon, France. [Curie, Aurore] INSERM, EPICIME CIC1407, F-69500 Bron, France. [Kirsch, Irving; Kaptchuk, Ted J.; Jensen, Karin B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA USA. [Kirsch, Irving] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Jensen, Karin B.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Curie, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Martinos Ctr Biomed Imaging, Boston, MA 02138 USA. EM aurorecurie@yahoo.fr OI Jensen, Karin/0000-0003-2521-3160 FU COFAS Marie Curie Postdoc Program; Swedish Society for Medical Research; Jerome Lejeune's Foundation; Xtraordinaire Association; Foundation for Science and Therapeutic Encounter; NIH/NCCIH [K24 AT004095, R01AT005280] FX This work is supported by the COFAS Marie Curie Postdoc Program (KBJ), Swedish Society for Medical Research (KBJ), Jerome Lejeune's Foundation (Postdoctoral Fellowship AC), Xtraordinaire Association (Postdoctoral Fellowship AC), Foundation for Science and Therapeutic Encounter (TJK), K24 AT004095 (from NIH/NCCIH) (TJK), R01AT005280 (from NIH/NCCIH) (RG/TJK). NR 84 TC 2 Z9 2 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2015 VL 10 IS 7 AR e0133316 DI 10.1371/journal.pone.0133316 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO0JT UT WOS:000358837700017 PM 26226597 ER PT J AU Alonso, TO Santos, JM Teran, LO Hernandez, MB Broto, JP de Erausquin, GA AF Ortiz Alonso, Tomas Matias Santos, Juan Teran, Laura Ortiz Borrego Hernandez, Mayelin Poch Broto, Joaquin de Erausquin, Gabriel Alejandro TI Differences in Early Stages of Tactile ERP Temporal Sequence (P100) in Cortical Organization during Passive Tactile Stimulation in Children with Blindness and Controls SO PLOS ONE LA English DT Article ID SOMATOSENSORY EVOKED-POTENTIALS; CROSS-MODAL PLASTICITY; MEDIAN NERVE-STIMULATION; SIGHTED INDIVIDUALS; MENTAL-IMAGERY; CORTEX; SHAPE; ATTENTION; RESPONSES; HUMANS AB Compared to their seeing counterparts, people with blindness have a greater tactile capacity. Differences in the physiology of object recognition between people with blindness and seeing people have been well documented, but not when tactile stimuli require semantic processing. We used a passive vibrotactile device to focus on the differences in spatial brain processing evaluated with event related potentials (ERP) in children with blindness (n = 12) vs. normally seeing children (n = 12), when learning a simple spatial task (lines with different orientations) or a task involving recognition of letters, to describe the early stages of its temporal sequence (from 80 to 220 msec) and to search for evidence of multi-modal cortical organization. We analysed the P100 of the ERP. Children with blindness showed earlier latencies for cognitive (perceptual) event related potentials, shorter reaction times, and (paradoxically) worse ability to identify the spatial direction of the stimulus. On the other hand, they are equally proficient in recognizing stimuli with semantic content (letters). The last observation is consistent with the role of P100 on somatosensory-based recognition of complex forms. The cortical differences between seeing control and blind groups, during spatial tactile discrimination, are associated with activation in visual pathway (occipital) and task-related association (temporal and frontal) areas. The present results show that early processing of tactile stimulation conveying cross modal information differs in children with blindness or with normal vision. C1 [Ortiz Alonso, Tomas] Univ Complutense Madrid, Fac Med, Dept Psychiat, Madrid, Spain. [Matias Santos, Juan] Univ Atacama, Dept Psychol, Copiapo, Chile. [Matias Santos, Juan] Fdn J Robert Cade, CONICET, Cordoba, Argentina. [Teran, Laura Ortiz] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr, Boston, MA 02115 USA. [Borrego Hernandez, Mayelin] Ctr Neurociencias Cuba, Havana, Cuba. [Poch Broto, Joaquin] Univ Complutense Madrid, Hosp Clin Univ San Carlos, Dept Ear Nose & Throat ENT, Madrid, Spain. [de Erausquin, Gabriel Alejandro] Univ S Florida, Ctr Neuromodulat, Tampa, FL 33620 USA. [de Erausquin, Gabriel Alejandro] Univ S Florida, Roskamp Lab Brain Dev Modulat & Repair, Dept Psychiat, Tampa, FL USA. [de Erausquin, Gabriel Alejandro] Univ S Florida, Dept Neurol, Tampa, FL 33620 USA. [de Erausquin, Gabriel Alejandro] Univ S Florida, Dept Neurosurg, Tampa, FL USA. RP de Erausquin, GA (reprint author), Univ S Florida, Ctr Neuromodulat, Tampa, FL 33620 USA. EM gdeeraus@health.usf.edu FU Comunidad Autonoma de Madrid/Madrid Regional Government [CAM-4131308]; Fundacion Mutua Madrilena [MM-4131220]; NIMH [7K08MH077220]; Roskamp Endowment at USF FX This research has been made possible through grants from the Comunidad Autonoma de Madrid/Madrid Regional Government (grant #CAM-4131308) and the Fundacion Mutua Madrilena (grants #MM-4131220). GdE was funded in part by NIMH 7K08MH077220 and the Roskamp Endowment at USF. GdE is a Stephen and Constance Lieber Investigator and Sidney R. Baer Jr. Investigator. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 53 TC 0 Z9 0 U1 3 U2 12 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 JUL 30 PY 2015 VL 10 IS 7 AR e0124527 DI 10.1371/journal.pone.0124527 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO0JT UT WOS:000358837700001 ER PT J AU Sullivan, LB Gui, DY Hosios, AM Bush, LN Freinkman, E Vander Heiden, MG AF Sullivan, Lucas B. Gui, Dan Y. Hosios, Aaron M. Bush, Lauren N. Freinkman, Elizaveta Vander Heiden, Matthew G. TI Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells SO CELL LA English DT Article ID ASCITES TUMOR-CELLS; MAMMALIAN-CELLS; MITOCHONDRIAL-DNA; CANCER-CELLS; REDUCTIVE CARBOXYLATION; GLUTAMINE-METABOLISM; NUCLEOTIDE SYNTHESIS; ALPHA-KETOGLUTARATE; AEROBIC GLYCOLYSIS; REDOX STATE AB Mitochondrial respiration is important for cell proliferation; however, the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here, we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis. C1 [Sullivan, Lucas B.; Gui, Dan Y.; Hosios, Aaron M.; Bush, Lauren N.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Sullivan, Lucas B.; Gui, Dan Y.; Hosios, Aaron M.; Bush, Lauren N.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Freinkman, Elizaveta] Whitehead Inst Biomed Res, Nine Cambridge Ctr, Cambridge, MA 02142 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. EM mvh@mit.edu FU Burroughs Wellcome Fund; NIH [P30CA1405141, GG006413, R01 CA168653, T32 GM007753]; American Cancer Society [PF-15-096-01-TBE]; HHMI International Student Research fellowship; Vertex Scholars Program; Alex's Lemonade Stand Undergraduate Research Fellowship FX This work was supported by the Burroughs Wellcome Fund and the NIH (P30CA1405141, GG006413, and R01 CA168653) to M.G.V.H., a postdoctoral fellowship, PF-15-096-01-TBE from the American Cancer Society to L.B.S., NIH (T32 GM007753) to D.Y.G., HHMI International Student Research fellowship and the Vertex Scholars Program to A.M.H., and Alex's Lemonade Stand Undergraduate Research Fellowship to L.N.B., We thank Alena Heath for graphic design and members of the Vander Heiden lab for thoughtful discussion. We also thank C. Moraes, I.F.M. de Coo, and Navdeep Chandel for the 143B CytB and 143B WT cybrid cell lines. M.G.V.H. is a consultant and SAB member for Agios Pharmaceuticals which seeks to target metabolism for cancer therapy. NR 49 TC 83 Z9 84 U1 11 U2 32 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 JUL 30 PY 2015 VL 162 IS 3 BP 552 EP 563 DI 10.1016/j.cell.2015.07.017 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN9WS UT WOS:000358801800015 PM 26232225 ER PT J AU Parnas, O Jovanovic, M Eisenhaure, TM Herbst, RH Dixit, A Ye, CJ Przybylski, D Platt, RJ Tirosh, I Sanjana, NE Shalem, O Satija, R Raychowdhury, R Mertins, P Carr, SA Zhang, F Hacohen, N Regev, A AF Parnas, Oren Jovanovic, Marko Eisenhaure, Thomas M. Herbst, Rebecca H. Dixit, Atray Ye, Chun Jimmie Przybylski, Dariusz Platt, Randall J. Tirosh, Itay Sanjana, Neville E. Shalem, Ophir Satija, Rahul Raychowdhury, Raktima Mertins, Philipp Carr, Steven A. Zhang, Feng Hacohen, Nir Regev, Aviv TI A Genome-wide CRISPR Screen in Primary Immune Cells to Dissect Regulatory Networks SO CELL LA English DT Article ID GENE-EXPRESSION; DENDRITIC CELLS; PAF1 COMPLEX; PROTEIN; MACROPHAGES; DIFFERENTIATION; ACTIVATION; CANCER; TRANSCRIPTION; RESPONSES AB Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells and provide a genetic approach for dissection of mammalian cell circuits. C1 [Parnas, Oren; Jovanovic, Marko; Eisenhaure, Thomas M.; Herbst, Rebecca H.; Dixit, Atray; Przybylski, Dariusz; Platt, Randall J.; Tirosh, Itay; Sanjana, Neville E.; Shalem, Ophir; Raychowdhury, Raktima; Mertins, Philipp; Carr, Steven A.; Zhang, Feng; Hacohen, Nir; Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Eisenhaure, Thomas M.; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Herbst, Rebecca H.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. [Dixit, Atray] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Ye, Chun Jimmie] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Dept Epidemiol & Biostat, Inst Human Genet, San Francisco, CA 94143 USA. [Platt, Randall J.; Sanjana, Neville E.; Shalem, Ophir; Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Platt, Randall J.; Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Platt, Randall J.; Sanjana, Neville E.; Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Sanjana, Neville E.; Zhang, Feng] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Satija, Rahul] New York Genome Ctr, New York, NY 10013 USA. [Satija, Rahul] NYU, Ctr Genom & Syst Biol, New York, NY 10012 USA. [Hacohen, Nir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02140 USA. RP Hacohen, N (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM nhacohen@broadinstitute.org; aregev@broadinstitute.org OI , /0000-0003-2193-9001; Sanjana, Neville/0000-0002-1504-0027 FU NHGRI CEGS [P50 HG006193]; Broad Institute Funds; Klarman Cell Obervatory; HHMI; MGH Research Scholars Program; Swiss National Science Foundation (SNF); Marie Sklodowska-Curie IOF; National Institutes of Health through NIMH [5DP1-MH100706]; National Institutes of Health through NIDDK [5R01-DK097768]; National Science Foundation; Keck Foundation; New York Stem Cell Foundation; Damon Runyon Foundation; Searle Scholars Foundation; Merkin Foundation; Vallee Foundation; Simons Center for the Social Brain Postdoctoral Fellowship; NIH NHGRI [K99-HG008171]; National Science Foundation [1122374]; Human Frontier Science Program fellowship; National Space Biomedical Research Institute through NASA [NCC 9-58]; National Defense Science and Engineering Fellowship; Herchel Smith Fellowship FX We thank Max Artyomov and Laurie Glimcher for help and data related to Xbp1 targets and Jonathan Weissman for very helpful discussions on ER stress. We thank the Broad's Genomic Perturbation Platform for help in design of the secondary library and Broad Technology labs (Tarjei Mikkelssen) for help with synthesis of the secondary library. We thank Dave Gennert, Carl De Boer, Alex Shalek, John Trombetta, Schraga Schwartz, Maxwell Mumbach, Dawn Thompson, Timothy Tickle, Brian Haas, Chloe Villani, and all members of the Regev, Hacohen, Carr, and Zhang groups for input and discussions. We thank Terry Means for discussions and advice. We thank Leslie Gaffney for help with figure preparation and the Broad Genomics Platform for all sequencing. FACS sorting was performed at the Bauer Core Laboratory, Harvard FAS Center for Systems Biology, with great help from Patricia Rogers. This work was supported by NHGRI CEGS P50 HG006193 (A.R., N.H., and S.A.C.) and Broad Institute Funds. A.R. was supported by the Klarman Cell Obervatory and HHMI. N.H. was supported by the MGH Research Scholars Program. M.J. was supported by fellowships of the Swiss National Science Foundation for advanced researchers (SNF) and the Marie Sklodowska-Curie IOF. F.Z. is supported by the National Institutes of Health through NIMH (5DP1-MH100706) and NIDDK (5R01-DK097768), a Waterman Award from the National Science Foundation, the Keck, New York Stem Cell, Damon Runyon, Searle Scholars, Merkin, and Vallee Foundations, and Bob Metcalfe. F.Z. is a New York Stem Cell Foundation Robertson Investigator. N.E.S. is supported by a Simons Center for the Social Brain Postdoctoral Fellowship and NIH NHGRI award K99-HG008171. O.S. is a fellow of the Klarman Cell Observatory. R.J.P. is supported by a National Science Foundation Graduate Research Fellowship under grant number 1122374. I.T. was supported by a Human Frontier Science Program fellowship. A.D. is supported by the National Space Biomedical Research Institute through NASA NCC 9-58 and the National Defense Science and Engineering Fellowship. R.H.H. receives support from the Herchel Smith Fellowship. A.R. is on the scientific advisory board for Thermo Fisher Scientific. F.Z. is a founder and scientific advisor of Editas Medicine and a scientific advisor for Horizon Discovery. NR 48 TC 53 Z9 54 U1 14 U2 78 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 JUL 30 PY 2015 VL 162 IS 3 BP 675 EP 686 DI 10.1016/j.cell.2015.06.059 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN9WS UT WOS:000358801800024 PM 26189680 ER PT J AU Muralidhar, V Mahal, BA Nguyen, PL AF Muralidhar, Vinayak Mahal, Brandon A. Nguyen, Paul L. TI Conditional cancer-specific mortality in T4, N1, or M1 prostate cancer: implications for long-term prognosis SO RADIATION ONCOLOGY LA English DT Article DE Prostate cancer; Conditional survival; Racial disparities ID RADICAL PROSTATECTOMY; TUMOR SIZE; SURVIVAL AB Background: The risk of prostate cancer-specific mortality (PCSM) following a diagnosis of prostate cancer may improve after patients have survived a number of years after diagnosis. We sought to determine long-term conditional PCSM for patients with stage T4, N1, or M1 prostate cancer. Methods: We identified 66,817 patients diagnosed with stage IV (T4N0M0, N1M0, or M1) prostate cancer between 1973 and 2011 using the Surveillance, Epidemiology, and End Results (SEER) database. Conditional five-year PCSM was evaluated for each group of patients at 5, 10, and 15 years of survival according to the Fine & Gray model for competing risks after adjusting for tumor grade, age, income level, and marital status. Race-stratified analyses were also performed. Results: There were 13,345 patients with T4 disease, 12,450 patients with N1 disease, and 41,022 patients with M1 disease. Median follow-up among survivors in the three groups was 123 months (range: 0-382 months), 61 months (range: 0-410 months), and 30 months (range: 0-370 months), respectively. Conditional PCSM improved in all three groups over time. Among patients with T4 disease, 5-year PCSM improved from 13.9 % at diagnosis to 11.2, 8.1, and 6.5 % conditioned on 5, 10, or 15 years of survival, respectively (p < 0.001 in all cases). In patients with N1 disease, 5-year PCSM increased within the first five years and decreased thereafter, from 18.9 % at diagnosis to 21.4 % (p < 0.001), 17.6 % (p = 0.055), and 13.8 % (p < 0.001), respectively. In patients with metastatic disease, 5-year PCSM improved from 57.2 % at diagnosis to 41.1, 28.8, and 20.8 %, respectively (p < 0.001). White race was associated with a greater increase in conditional survival compared to non-white race among those with T4 or N1 disease. Conclusions: While patients with T4, N1, or M1 prostate cancer are never "cured," their odds of cancer-specific survival increase substantially after they have survived for 5 or more years. Physicians who take care of patients with prostate cancer can use this data to guide follow-up decisions and to counsel newly diagnosed patients and survivors regarding their long-term prognosis. C1 [Muralidhar, Vinayak] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. [Mahal, Brandon A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Harvard-MIT Division of Health Sciences and Technology at Harvard Medical School; Fitz's Cancer Warriors; Prostate Cancer Foundation FX This work is supported financially by an IDEA2 grant from the Harvard-MIT Division of Health Sciences and Technology at Harvard Medical School, Fitz's Cancer Warriors, David and Cynthia Chapin, the Prostate Cancer Foundation, Hugh Simons in honor of Frank and Anne Simons, Scott Forbes and Gina Ventre, and a grant from an anonymous family foundation. NR 22 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD JUL 30 PY 2015 VL 10 AR 155 DI 10.1186/s13014-015-0470-0 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CN6UN UT WOS:000358569900001 PM 26220664 ER PT J AU Di Narzo, AF Kozlenkov, A Ge, YC Zhang, B Sanelli, L May, Z Li, YQ Fouad, K Cardozo, C Koonin, EV Bennett, DJ Dracheva, S AF Di Narzo, Antonio Fabio Kozlenkov, Alexey Ge, Yongchao Zhang, Bin Sanelli, Leo May, Zacnicte Li, Yanqing Fouad, Karim Cardozo, Christopher Koonin, Eugene V. Bennett, David J. Dracheva, Stella TI Decrease of mRNA Editing after Spinal Cord Injury is Caused by Down-regulation of ADAR2 that is Triggered by Inflammatory Response SO SCIENTIFIC REPORTS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SEROTONIN 2C; CONSTITUTIVE ACTIVITY; PREFRONTAL CORTEX; PERSISTENT SODIUM; EXPRESSION DATA; 2A RECEPTORS; HUMAN BRAIN; MOTONEURONS; RATS AB We recently showed that spinal cord injury (SCI) leads to a decrease in mRNA editing of serotonin receptor 2C (5-HT2CR) contributing to post-SCI spasticity. Here we study post-SCI mRNA editing and global gene expression using massively parallel sequencing. Evidence is presented that the decrease in 5-HT2CR editing is caused by down-regulation of adenosine deaminase ADAR2 and that editing of at least one other ADAR2 target, potassium channel Kv1.1, is decreased after SCI. Bayesian network analysis of genome-wide transcriptome data indicates that down-regulation of ADAR2 (1) is triggered by persistent inflammatory response to SCI that is associated with activation of microglia and (2) results in changes in neuronal gene expression that are likely to contribute both to post-SCI restoration of neuronal excitability and muscle spasms. These findings have broad implications for other diseases of the Central Nervous System and could open new avenues for developing efficacious antispastic treatments. C1 [Di Narzo, Antonio Fabio; Zhang, Bin] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kozlenkov, Alexey; Dracheva, Stella] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Kozlenkov, Alexey; Dracheva, Stella] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Kozlenkov, Alexey; Cardozo, Christopher; Dracheva, Stella] James J Peters VA Med Ctr, Bronx, NY USA. [Ge, Yongchao] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Sanelli, Leo; May, Zacnicte; Li, Yanqing; Fouad, Karim; Bennett, David J.] Univ Alberta, Fac Rehabil Med, Ctr Neurosci, Edmonton, AB, Canada. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Dracheva, S (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. EM Stella.Dracheva@mssm.edu FU VISN3 Mental Illness Research and Education Clinical Center (MIRECC); VA Merit Review Award [BX002343]; intramural funds of the US Department of Health and Human Services FX The work was supported with resources and the use of facilities at the James J Peters VA Medical Center, Bronx, New York and funded by: VISN3 Mental Illness Research and Education Clinical Center (MIRECC) and VA Merit Review Award (BX002343 to S.D.). E.V.K. is supported by intramural funds of the US Department of Health and Human Services to National Library of Medicine. NR 57 TC 4 Z9 4 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 30 PY 2015 VL 5 AR 12615 DI 10.1038/srep12615 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO0UY UT WOS:000358870200001 PM 26223940 ER PT J AU Pardo-Saganta, A Tata, PR Law, BM Saez, B Chow, RDW Prabhu, M Gridley, T Rajagopal, J AF Pardo-Saganta, Ana Tata, Purushothama Rao Law, Brandon M. Saez, Borja Chow, Ryan Dz-Wei Prabhu, Mythili Gridley, Thomas Rajagopal, Jayaraj TI Parent stem cells can serve as niches for their daughter cells SO NATURE LA English DT Article ID SIGNALING CONTROLS; AIRWAY EPITHELIUM; TRANSGENIC MICE; MOUSE TRACHEA; IN-VIVO; LUNG; MAINTENANCE; CLARA; DIFFERENTIATION; REGENERATION AB Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance(1,2), while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation(3-6). Recently, stem cells have been shown to regulate themselves using an autocrine mechanism(7). The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells1. Since then, an increasing body of work has focused on defining stem cell niches(1-6). Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells(8,9). Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells(9,10). Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche. C1 [Pardo-Saganta, Ana; Tata, Purushothama Rao; Law, Brandon M.; Saez, Borja; Chow, Ryan Dz-Wei; Prabhu, Mythili; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Pardo-Saganta, Ana; Tata, Purushothama Rao; Law, Brandon M.; Chow, Ryan Dz-Wei; Prabhu, Mythili; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Pardo-Saganta, Ana; Tata, Purushothama Rao; Law, Brandon M.; Chow, Ryan Dz-Wei; Prabhu, Mythili; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Pediat, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Pardo-Saganta, Ana; Tata, Purushothama Rao; Law, Brandon M.; Saez, Borja; Chow, Ryan Dz-Wei; Prabhu, Mythili; Rajagopal, Jayaraj] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Saez, Borja] Harvard Univ, Stem Cell & Regenerat Biol Dept, Cambridge, MA 02138 USA. [Gridley, Thomas] Maine Med Ctr, Res Inst, Ctr Mol Med, Scarborough, ME 04074 USA. RP Rajagopal, J (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA. EM jrajagopal@mgh.harvard.edu FU New York Stem Cell Foundation; National Institutes of Health-National Heart, Lung, and Blood Institute Early Career Research New Faculty (P30) award [5P30HL101287-02]; NIH-NHLBI [RO1HL118185]; Harvard Stem Cell Institute (HSCI) Junior Investigator Grant FX We thank A. Glick for providing the CK5rtTA mice, B. Hogan for providing CK5creER and SCGB1A1creER mice and Y.-Y. Kong for sharing the Mib1 floxed mice. B. Z. Stanger provided the RBPjk floxed mice and shared protocols for the immunohistochemical detection of Notch components. We also thank B. Stripp for providing the goat anti-SCGB1A1 antibody. We wish to extend our thanks to all of the members of the Rajagopal laboratory and the HSCI flow cytometry core facility. This research was supported by the New York Stem Cell Foundation (J.R. is a New York Stem Cell Foundation-Robertson Investigator), by a National Institutes of Health-National Heart, Lung, and Blood Institute Early Career Research New Faculty (P30) award (5P30HL101287-02), an RO1 (RO1HL118185) from NIH-NHLBI (to J.R.) and a Harvard Stem Cell Institute (HSCI) Junior Investigator Grant (to J.R.). J.R. is also the Maroni Research Scholar at Massachusetts General Hospital. NR 37 TC 23 Z9 23 U1 0 U2 24 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 JUL 30 PY 2015 VL 523 IS 7562 BP 597 EP + DI 10.1038/nature14553 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN7ZL UT WOS:000358655200046 PM 26147083 ER PT J AU Chabner, B Richon, V AF Chabner, Bruce Richon, Victoria TI Focus on Research Structural Approaches to Cancer Drug Development SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Chabner, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Richon, Victoria] Sanofi Aventis, Cambridge, MA USA. RP Chabner, B (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 1 Z9 1 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 30 PY 2015 VL 373 IS 5 BP 402 EP 403 DI 10.1056/NEJMp1503567 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CN8BO UT WOS:000358662200003 PM 26222556 ER PT J AU Tap, WD Wainberg, ZA Anthony, SP Ibrahim, PN Zhang, C Healey, JH Chmielowski, B Staddon, AP Cohn, AL Shapiro, GI Keedy, VL Singh, AS Puzanov, I Kwak, EL Wagner, AJ Von Hoff, DD Weiss, GJ Ramanathan, RK Zhang, J Habets, G Zhang, Y Burton, EA Visor, G Sanftner, L Severson, P Nguyen, H Kim, MJ Marimuthu, A Tsang, G Shellooe, R Gee, C West, BL Hirth, P Nolop, K van de Rijn, M Hsu, HH Peterfy, C Lin, PS Tong-Starksen, S Bollag, G AF Tap, W. D. Wainberg, Z. A. Anthony, S. P. Ibrahim, P. N. Zhang, C. Healey, J. H. Chmielowski, B. Staddon, A. P. Cohn, A. L. Shapiro, G. I. Keedy, V. L. Singh, A. S. Puzanov, I. Kwak, E. L. Wagner, A. J. Von Hoff, D. D. Weiss, G. J. Ramanathan, R. K. Zhang, J. Habets, G. Zhang, Y. Burton, E. A. Visor, G. Sanftner, L. Severson, P. Nguyen, H. Kim, M. J. Marimuthu, A. Tsang, G. Shellooe, R. Gee, C. West, B. L. Hirth, P. Nolop, K. van de Rijn, M. Hsu, H. H. Peterfy, C. Lin, P. S. Tong-Starksen, S. Bollag, G. TI Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PIGMENTED VILLONODULAR SYNOVITIS; RHEUMATOID-ARTHRITIS; MACROPHAGES; EXPRESSION; TRANSLOCATION; INHIBITION; EFFICACY; IMPROVES; THERAPY; GROWTH AB BACKGROUND Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the auto-inhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. C1 [Tap, W. D.; Healey, J. H.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Tap, W. D.] Weill Cornell Med Coll, New York, NY USA. [Wainberg, Z. A.; Chmielowski, B.; Singh, A. S.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Ibrahim, P. N.; Zhang, C.; Zhang, J.; Habets, G.; Zhang, Y.; Burton, E. A.; Visor, G.; Sanftner, L.; Severson, P.; Nguyen, H.; Kim, M. J.; Marimuthu, A.; Tsang, G.; Shellooe, R.; Gee, C.; West, B. L.; Hirth, P.; Nolop, K.; Hsu, H. H.; Lin, P. S.; Tong-Starksen, S.; Bollag, G.] Plexxikon, Berkeley, CA USA. [van de Rijn, M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Anthony, S. P.] Evergreen Hematol & Oncol, Spokane, WA USA. [Staddon, A. P.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Cohn, A. L.] Rocky Mt Canc Ctr, Denver, CO USA. [Shapiro, G. I.; Wagner, A. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kwak, E. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Keedy, V. L.; Puzanov, I.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Von Hoff, D. D.; Weiss, G. J.; Ramanathan, R. K.] Scottsdale Healthcare, Virginia G Piper Canc Ctr, Translat Genom Res Inst TGen, Scottsdale, AZ USA. [Peterfy, C.] Spire Sci, Boca Raton, FL USA. RP Tap, WD (reprint author), Mem Sloan Kettering Canc Ctr, 300 E 66th St,Suite 1001, New York, NY 10065 USA. EM tapw@mskcc.org OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Plexxikon FX Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861. NR 23 TC 34 Z9 35 U1 3 U2 13 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 JUL 30 PY 2015 VL 373 IS 5 BP 428 EP 437 DI 10.1056/NEJMoa1411366 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CN8BO UT WOS:000358662200006 PM 26222558 ER PT J AU Miller, BL Dickerson, BC AF Miller, Bruce L. Dickerson, Bradford C. TI Case 9-2015: A Man with Personality Changes and Progressive Neurologic Decline Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Miller, Bruce L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Miller, BL (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 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 JUL 30 PY 2015 VL 373 IS 5 BP 486 EP 486 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CN8BO UT WOS:000358662200027 PM 26222576 ER PT J AU Betensky, RA Szymonifka, J Lee, EQ Nutt, CL Batchelor, TT AF Betensky, Rebecca A. Szymonifka, Jackie Lee, Eudocia Q. Nutt, Catherine L. Batchelor, Tracy T. TI Computationally simple analysis of matched, outcome-based studies of ordinal disease states SO STATISTICS IN MEDICINE LA English DT Article DE adjacent categories model; conditional logistic regression; glioblastoma; outcome-based sampling; pseudo-likelihood ID LONG-TERM; GLIOBLASTOMA-MULTIFORME; ANTIANGIOGENIC THERAPY; ADJUVANT TEMOZOLOMIDE; SURVIVORS; MODELS; NORMALIZATION; RADIOTHERAPY; VASCULATURE; CONCOMITANT AB Outcome-based sampling is an efficient study design for rare conditions, such as glioblastoma. It is often used in conjunction with matching, for increased efficiency and to potentially avoid bias due to confounding. A study was conducted at the Massachusetts General Hospital that involved retrospective sampling of glioblastoma patients with respect to multiple-ordered disease states, as defined by three categories of overall survival time. To analyze such studies, we posit an adjacent categories logit model and exploit its allowance for prospective analysis of a retrospectively sampled study and its advantageous removal of set and level specific nuisance parameters through conditioning on sufficient statistics. This framework allows for any sampling design and is not limited to one level of disease within each set, such as in previous publications. We describe how this ordinal conditional model can be fit using standard conditional logistic regression procedures. We consider an alternative pseudo-likelihood approach that potentially offers robustness under partial model misspecification at the expense of slight loss of efficiency under correct model specification for small sample sizes. We apply our methods to the Massachusetts General Hospital glioblastoma study. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Betensky, Rebecca A.; Szymonifka, Jackie] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Lee, Eudocia Q.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Nutt, Catherine L.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Brain Tumor Ctr, Boston, MA 02114 USA. RP Betensky, RA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM betensky@hsph.harvard.edu FU NIH [R01-CA075971, K12-CA090354, P30-CA06516, R01-CA129371, K24-CA125440] FX This work is granted by the NIH (R01-CA075971, K12-CA090354, P30-CA06516, R01-CA129371, and K24-CA125440). NR 29 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2015 VL 34 IS 17 BP 2514 EP 2527 DI 10.1002/sim.6503 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CM1GQ UT WOS:000357429700003 PM 25900819 ER PT J AU Lajnef, T Chaibi, S Ruby, P Aguera, PE Eichenlaub, JB Samet, M Kachouri, A Jerbi, K AF Lajnef, Tarek Chaibi, Sahbi Ruby, Perrine Aguera, Pierre-Emmanuel Eichenlaub, Jean-Baptiste Samet, Mounir Kachouri, Abdennaceur Jerbi, Karim TI Learning machines and sleeping brains: Automatic sleep stage classification using decision-tree multi-class support vector machines SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Electroencephalography (EEG); Sleep scoring; Oscillations; Polysomnography; Decision-tree; Support vector machine (SVM); Linear Discriminant Analysis (LDA); Hierarchical clustering; Machine learning; Dendrogram ID HIGH-FREQUENCY OSCILLATIONS; ARTIFICIAL NEURAL-NETWORKS; SPINDLE DETECTION; PERMUTATION ENTROPY; GAMMA OSCILLATIONS; EEG SIGNAL; OPTIMAL COMBINATION; K-COMPLEX; ELECTROENCEPHALOGRAM; RECORDINGS AB Background: Sleep staging is a critical step in a range of electrophysiological signal processing pipelines used in clinical routine as well as in sleep research. Although the results currently achievable with automatic sleep staging methods are promising, there is need for improvement, especially given the time-consuming and tedious nature of visual sleep scoring. New method: Here we propose a sleep staging framework that consists of a multi-class support vector machine (SVM) classification based on a decision tree approach. The performance of the method was evaluated using polysomnographic data from 15 subjects (electroencephalogram (EEG), electrooculogram (EGG) and electromyogram (EMG) recordings). The decision tree, or dendrogram, was obtained using a hierarchical clustering technique and a wide range of time and frequency-domain features were extracted. Feature selection was carried out using forward sequential selection and classification was evaluated using k-fold cross-validation. Results: The dendrogram-based SVM (DSVM) achieved mean specificity, sensitivity and overall accuracy of 0.92, 0.74 and 0.88 respectively, compared to expert visual scoring. Restricting DSVM classification to data where both experts' scoring was consistent (76.73% of the data) led to a mean specificity, sensitivity and overall accuracy of 0.94, 0.82 and 0.92 respectively. Comparison with existing methods: The DSVM framework outperforms classification with more standard multi-class "one-against-all" SVM and linear-discriminant analysis. Conclusion: The promising results of the proposed methodology suggest that it may be a valuable alternative to existing automatic methods and that it could accelerate visual scoring by providing a robust starting hypnogram that can be further fine-tuned by expert inspection. (C) 2015 Elsevier B.V. All rights reserved. C1 [Lajnef, Tarek; Chaibi, Sahbi; Samet, Mounir; Kachouri, Abdennaceur] Univ Sfax, LETI Lab, Sfax Natl Engn Sch ENIS, Sfax, Tunisia. [Chaibi, Sahbi; Ruby, Perrine; Jerbi, Karim] Univ Lyon 1, Lyon Neurosci Res Ctr, DYCOG Lab, INSERM,U1028,UMR 5292, F-69365 Lyon, France. [Eichenlaub, Jean-Baptiste] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kachouri, Abdennaceur] Univ Gabes, Higher Inst Ind Syst Gabes ISSIG, Gabes, Tunisia. [Jerbi, Karim] Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. RP Jerbi, K (reprint author), Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. EM karim.jerbi@umontreal.ca RI Eichenlaub, Jean-Baptiste/E-5864-2015 OI Eichenlaub, Jean-Baptiste/0000-0002-4610-1566 FU EDST doctoral program; LETI Laboratory, Sfax, Tunisia; Fyssen Foundation; Universite de Lyon [ANR-11-LABX-0042, ANR-11-IDEX-0007]; Canada Research Chairs program FX Tarek Lajnef was in part supported by travel funds from EDST doctoral program and the LETI Laboratory, Sfax, Tunisia. Jean-Baptiste Eichenlaub is supported by the Fyssen Foundation. 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. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program. NR 89 TC 12 Z9 12 U1 5 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD JUL 30 PY 2015 VL 250 SI SI BP 94 EP 105 DI 10.1016/j.jneumeth.2015.01.022 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA CL5DB UT WOS:000356978900010 PM 25629798 ER PT J AU Abramovitch, A Mittelman, A Tankersley, AP Abramowitz, JS Schweiger, A AF Abramovitch, Amitai Mittelman, Andrew Tankersley, Amelia P. Abramowitz, Jonathan S. Schweiger, Avraham TI Neuropsychological investigations in obsessive-compulsive disorder: A systematic review of methodological challenges SO PSYCHIATRY RESEARCH LA English DT Review DE Neuropsychology; Statistics; Methodology; Research methods; OCD; Psychiatric disorders; Cognitive function ID COGNITIVE-BEHAVIORAL THERAPY; RESPONSE-INHIBITION; SYMPTOM DIMENSIONS; UNAFFECTED RELATIVES; EXECUTIVE FUNCTIONS; HOARDING DISORDER; EARLY-ONSET; GO/NO-GO; PERFORMANCE; METAANALYSIS AB The inconsistent nature of the neuropsychology literature pertaining to obsessive-compulsive disorder (OCD) has long been recognized. However, individual studies, systematic reviews, and recent meta-analytic reviews were unsuccessful in establishing a consensus regarding a disorder-specific neuropsychological profile. In an attempt to identify methodological factors that may contribute to the inconsistency that is characteristic of this body of research, a systematic review of methodological factors in studies comparing OCD patients and non-psychiatric controls on neuropsychological tests was conducted. This review covered 115 studies that included nearly 3500 patients. Results revealed a range of methodological weaknesses. Some of these weaknesses have been previously noted in the broader neuropsychological literature, while some are more specific to psychiatric disorders, and to OCD. These methodological shortcomings have the potential to hinder the identification of a specific neuropsychological profile associated with OCD as well as to obscure the association between neurocognitive dysfunctions and contemporary neurobiological models. Rectifying these weaknesses may facilitate replicability, and promote our ability to extract cogent, meaningful, and more unified inferences regarding the neuropsychology of OCD. To that end, we present a set of methodological recommendations to facilitate future neuropsychology research in psychiatric disorders in general, and in OCD in particular. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Abramovitch, Amitai] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Abramovitch, Amitai; Mittelman, Andrew; Tankersley, Amelia P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Abramovitch, Amitai] Texas State Univ, Dept Psychol, San Marcos, TX 78666 USA. [Abramowitz, Jonathan S.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Schweiger, Avraham] Acad Coll Tel Aviv, Dept Psychol, Tel Aviv, Israel. 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 NR 81 TC 3 Z9 3 U1 6 U2 28 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2015 VL 228 IS 1 BP 112 EP 120 DI 10.1016/j.psychres.2015.04.025 PG 9 WC Psychiatry SC Psychiatry GA CK9II UT WOS:000356553400019 PM 25957648 ER PT J AU Kang, SH Lee, JI Han, HR Karmacharya, R Jeon, HJ Roh, S AF Kang, Shi Hyun Lee, Jong-il Han, Hye Ree Karmacharya, Rakesh Jeon, Hong Jin Roh, Sungwon TI Effects of LEP, LEAR, ADIPOQ, MC4R and FTO polymorphisms on dyslipidemia in Korean patients with schizophrenia who are taking clozapine SO PSYCHIATRY RESEARCH LA English DT Letter ID ANTIPSYCHOTICS; ASSOCIATION C1 [Kang, Shi Hyun; Lee, Jong-il] Seoul Natl Hosp, Dept Psychiat, Seoul, South Korea. [Han, Hye Ree; Roh, Sungwon] Seoul Natl Hosp, Dept Mental Hlth Res, Seoul, South Korea. [Karmacharya, Rakesh; Jeon, Hong Jin; Roh, Sungwon] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Karmacharya, Rakesh; Jeon, Hong Jin; Roh, Sungwon] Harvard Univ, Sch Med, Boston, MA USA. [Karmacharya, Rakesh] McLean Hosp, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02178 USA. [Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat, Seoul, South Korea. [Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. RP Roh, S (reprint author), Seoul Natl Hosp, Dept Mental Hlth Res, Seoul, South Korea. EM swroh@korea.kr FU National Center for Mental Health Research & Education, Seoul National Hospital, Republic of Korea; NIH [K08MH086846]; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH) [8UL1TR000170-05] FX This study was supported by a grant from the National Center for Mental Health Research & Education, Seoul National Hospital, Republic of Korea. R.K. was supported by an NIH Clinical Scientist Development Award (No. K08MH086846). We would like to acknowledge a biostatistics consultation with Dr. Douglas Hayden of the Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH Award 8UL1TR000170-05). NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2015 VL 228 IS 1 BP 177 EP 178 DI 10.1016/j.psychres.2015.03.007 PG 2 WC Psychiatry SC Psychiatry GA CK9II UT WOS:000356553400030 PM 25841316 ER PT J AU Kacmarek, RM Pirrone, M Berra, L AF Kacmarek, Robert M. Pirrone, Massimiliano Berra, Lorenzo TI Assisted mechanical ventilation: the future is now! SO BMC ANESTHESIOLOGY LA English DT Editorial Material ID ADJUSTABLE GAIN FACTORS; PRESSURE-SUPPORT; PROPORTIONAL ASSIST; TIDAL VOLUME; ASYNCHRONY; WORKLOAD; IMPACT; NAVA AB Assisted ventilation is a highly complex process that requires an intimate interaction between the ventilator and the patient. The complexity of this form of ventilation is frequently underappreciated by the bedside clinician. In assisted mechanical ventilation, regardless of the specific mode, the ventilator's gas delivery pattern and the patient's breathing pattern must match near perfectly or asynchrony between the patient and the ventilator occurs. Asynchrony can be categorized into four general types: flow asynchrony; trigger asynchrony; cycle asynchrony; and mode asynchrony. In an article recently published in BMC Anesthesiology, Hodane et al. have demonstrated reduced asynchrony during assisted ventilation with Neurally Adjusted Ventilatory Assist (NAVA) as compared to pressure support ventilation (PSV). These findings add to the growing volume of data indicating that modes of ventilation that provide proportional assistance to ventilation - e.g., NAVA and Proportional Assist Ventilation (PAV)-markedly reduce asynchrony. As it becomes more accepted that the respiratory center of the patient in most circumstances is the most appropriate determinant of ventilatory pattern and as the negative outcome effects of patient-ventilator asynchrony become ever more recognized, we can expect NAVA and PAV to become the preferred modes of assisted ventilation! C1 [Kacmarek, Robert M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rkacmarek@partners.org NR 19 TC 2 Z9 3 U1 1 U2 5 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 JUL 29 PY 2015 VL 15 AR 110 DI 10.1186/s12871-015-0092-y PG 3 WC Anesthesiology SC Anesthesiology GA CO4BB UT WOS:000359103900001 PM 26215886 ER PT J AU Gagan, J Van Allen, EM AF Gagan, Jeffrey Van Allen, Eliezer M. TI Next-generation sequencing to guide cancer therapy SO GENOME MEDICINE LA English DT Review ID CELL LUNG-CANCER; CIRCULATING TUMOR DNA; COPY NUMBER ALTERATIONS; COLORECTAL-CANCER; INCIDENTAL FINDINGS; PROSTATE-CANCER; RAS MUTATIONS; GENOME; EXOME; RESISTANCE AB As a result of multiple technological and practical advances, high-throughput sequencing, known more commonly as "next-generation" sequencing (NGS), can now be incorporated into standard clinical practice. Whereas early protocols relied on samples that were harvested outside of typical clinical pathology workflows, standard formalin-fixed, paraffin-embedded specimens can more regularly be used as starting materials for NGS. Furthermore, protocols for the analysis and interpretation of NGS data, as well as knowledge bases, are being amassed, allowing clinicians to act more easily on genomic information at the point of care for patients. In parallel, new therapies that target somatically mutated genes identified through clinical NGS are gaining US Food and Drug Administration (FDA) approval, and novel clinical trial designs are emerging in which genetic identifiers are given equal weight to histology. For clinical oncology providers, understanding the potential and the limitations of DNA sequencing will be crucial for providing genomically driven care in this era of precision medicine. C1 [Gagan, Jeffrey] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Van Allen, Eliezer M.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Van Allen, EM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. FU National Institutes of Health [1K08CA188615]; Prostate Cancer Foundation; American Cancer Society FX This work is supported by the National Institutes of Health 1K08CA188615 (EMVA), Prostate Cancer Foundation (EMVA), and the American Cancer Society (EMVA). NR 66 TC 30 Z9 32 U1 7 U2 30 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 JUL 29 PY 2015 VL 7 AR 80 DI 10.1186/s13073-015-0203-x PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CN6UC UT WOS:000358568800003 PM 26221189 ER PT J AU Palombo, DJ Madan, CR AF Palombo, Daniela J. Madan, Christopher R. TI Making Memories That Last SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID POSTENCODING REST; EPISODIC MEMORIES; CONNECTIVITY; HIPPOCAMPAL; CONSOLIDATION; PERSISTENCE; MECHANISMS C1 [Palombo, Daniela J.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Palombo, Daniela J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Madan, Christopher R.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. RP Palombo, DJ (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave,D11-103, Jamaica Plain, MA 02130 USA. EM palombo@bu.edu; madanc@bc.edu OI Madan, Christopher/0000-0003-3228-6501 NR 15 TC 1 Z9 1 U1 1 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 29 PY 2015 VL 35 IS 30 BP 10643 EP 10644 DI 10.1523/JNEUROSCI.1882-15.2015 PG 2 WC Neurosciences SC Neurosciences & Neurology GA CN8GO UT WOS:000358678100001 PM 26224849 ER PT J AU Lajnef, T Chaibi, S Eichenlaub, JB Ruby, PM Aguera, PE Samet, M Kachouri, A Jerbi, K AF Lajnef, Tarek Chaibi, Sahbi Eichenlaub, Jean-Baptiste Ruby, Perrine M. Aguera, Pierre-Emmanuel Samet, Mounir Kachouri, Abdennaceur Jerbi, Karim TI Sleep spindle and K-complex detection using tunable Q-factor wavelet transform and morphological component analysis SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE sleep; spindles; K-complex; automatic detection; electroencephalography (EEG); tunable Q-factor wavelet transform (TQWT); morphological component analysis (MCA); neural oscillations ID SUPPORT VECTOR MACHINES; DREAM-RECALL FREQUENCY; EYE-MOVEMENT SLEEP; MEMORY CONSOLIDATION; GAMMA OSCILLATIONS; AUTOMATIC DETECTION; SLOW OSCILLATIONS; INTRACRANIAL EEG; MOTOR SEQUENCE; DECISION-TREE AB A novel framework for joint detection of sleep spindles and K-complex events, two hallmarks of sleep stage S2, is proposed. Sleep electroencephalography (EEG) signals are split into oscillatory (spindles) and transient (K-complex) components. This decomposition is conveniently achieved by applying morphological component analysis (MCA) to a sparse representation of EEG segments obtained by the recently introduced discrete tunable 0-factor wavelet transform (TQVVT). Tuning the 0-factor provides a convenient and elegant tool to naturally decompose the signal into an oscillatory and a transient component. The actual detection step relies on thresholding (i) the transient component to reveal K-complexes and (ii) the time-frequency representation of the oscillatory component to identify sleep spindles. Optimal thresholds are derived from ROC-like curves (sensitivity vs. FDR) on training sets and the performance of the method is assessed on test data sets. We assessed the performance of our method using full-night sleep EEG data we collected from 14 participants. In comparison to visual scoring (Expert 1), the proposed method detected spindles with a sensitivity of 83.18% and false discovery rate (FDR) of 39%, while K-complexes were detected with a sensitivity of 81.57% and an FDR of 29.54%. Similar performances were obtained when using a second expert as benchmark. In addition, when the TQVVT and MCA steps were excluded from the pipeline the detection sensitivities dropped down to 70% for spindles and to 76.97% for K-complexes, while the FDR rose up to 43.62 and 49.09%, respectively. Finally, we also evaluated the performance of the proposed method on a set of publicly available sleep EEG recordings. Overall, the results we obtained suggest that the TQVVT-MCA method may be a valuable alternative to existing spindle and K-complex detection methods. Paths for improvements and further validations with large-scale standard open-access benchmarking data sets are discussed. C1 [Lajnef, Tarek; Chaibi, Sahbi; Samet, Mounir; Kachouri, Abdennaceur] Univ Sfax, Sfax Natl Engn Sch, LETI Lab, Sfax, Tunisia. [Eichenlaub, Jean-Baptiste] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Ruby, Perrine M.; Aguera, Pierre-Emmanuel; Jerbi, Karim] Univ Lyon 1, DYCOG Lab, Lyon Neurosci Res Ctr, INSERM,U1028,UMR 5292, F-69365 Lyon, France. [Kachouri, Abdennaceur] Univ Gabes, Higher Inst Ind Syst Gabes, Elect Engn Dept, Gabes, Tunisia. [Jerbi, Karim] Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. RP Jerbi, K (reprint author), Univ Montreal, Dept Psychol, Pavillon Marie Victorin CP 6128,Succursale Ctr Vi, Montreal, PQ H3C 3J7, Canada. EM karim.jerbi@umontreal.ca FU EDST doctoral program; LETI Laboratory, Sfax, Tunisia; Fyssen Foundation; Universite de Lyon [ANR-11-LABX-0042, ANR-11-IDEX-0007]; Canada Research Chairs program FX Tarek Lajnef was supported in part by travel funds from EDST doctoral program and the LETI Laboratory, Sfax, Tunisia. Jean-Baptiste Eichenlaub is supported by the Fyssen Foundation. This study 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. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program. NR 104 TC 5 Z9 5 U1 6 U2 25 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUL 28 PY 2015 VL 9 AR 414 DI 10.3389/fnhum.2015.00414 PG 17 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CQ0DR UT WOS:000360265900001 PM 26283943 ER PT J AU Raffeld, MR Biffi, A Battey, TWK Ayres, AM Viswanathan, A Greenberg, SM Rosand, J Anderson, CD AF Raffeld, Miriam R. Biffi, Alessandro Battey, Thomas W. K. Ayres, Alison M. Viswanathan, Anand Greenberg, Steven M. Rosand, Jonathan Anderson, Christopher D. TI APOE epsilon 4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; APOLIPOPROTEIN-E GENOTYPE; METAANALYSIS; STROKE; LOBAR; MICE; LIPOPROTEINS; ASTROCYTES; DEEP; E3 AB Objective: Genetic variants epsilon 2/epsilon 4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE epsilon 4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association. Methods: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH. Results: We observed 29 nonlobar ICH recurrences among 363 survivors. APOE epsilon 4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02-2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE epsilon 4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE epsilon 2 and recurrent nonlobar ICH. Conclusion: APOE epsilon 4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE epsilon 4 in nonlobar ICH. C1 [Raffeld, Miriam R.; Biffi, Alessandro; Battey, Thomas W. K.; Ayres, Alison M.; Viswanathan, Anand; Greenberg, Steven M.; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Raffeld, Miriam R.; Biffi, Alessandro; Battey, Thomas W. K.; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Dept Neurol, Boston, MA 02114 USA. [Raffeld, Miriam R.; Biffi, Alessandro; Battey, Thomas W. K.; Rosand, Jonathan; Anderson, Christopher D.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Anderson, CD (reprint author), Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. EM cdanderson@partners.org FU National Institute for Neurologic Disorders and Stroke [R01 NS063925, R01 NS059727, P50 NS051343, K23 NS086873, AG26484] FX The authors' work on this study was supported by funding from the National Institute for Neurologic Disorders and Stroke (R01 NS063925, R01 NS059727, P50 NS051343, K23 NS086873, and AG26484). All funding entities had no involvement in study design, data collection, analysis, and interpretation, writing of the report, and in the decision to submit the paper for publication. NR 22 TC 3 Z9 3 U1 2 U2 5 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 JUL 28 PY 2015 VL 85 IS 4 BP 349 EP 356 DI 10.1212/WNL.0000000000001790 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CO7MK UT WOS:000359343300008 PM 26115730 ER PT J AU Roccaro, AM Mishima, Y Sacco, A Moschetta, M Tai, YT Shi, JT Zhang, Y Reagan, MR Huynh, D Kawano, Y Sahin, I Chiarini, M Manier, S Cea, M Aljawai, Y Glavey, S Morgan, E Pan, C Michor, F Cardarelli, P Kuhne, M Ghobrial, IM AF Roccaro, Aldo M. Mishima, Yuji Sacco, Antonio Moschetta, Michele Tai, Yu-Tzu Shi, Jiantao Zhang, Yong Reagan, Michaela R. Huynh, Daisy Kawano, Yawara Sahin, Ilyas Chiarini, Marco Manier, Salomon Cea, Michele Aljawai, Yosra Glavey, Siobhan Morgan, Elizabeth Pan, Chin Michor, Franziska Cardarelli, Pina Kuhne, Michelle Ghobrial, Irene M. TI CXCR4 Regulates Extra-Medullary Myeloma through Epithelial-Mesenchymal-Transition-like Transcriptional Activation SO CELL REPORTS LA English DT Article ID EXTRAMEDULLARY MULTIPLE-MYELOMA; TUMOR PROGRESSION; BETA-CATENIN; BONE-MARROW; LEUKEMIA CELLS; STROMAL CELLS; CANCER CELLS; STEM-CELLS; EXPRESSION; METASTASIS AB Extra-medullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. However, molecular alterations that lead to EMD have not been well defined. We developed bone marrow (BM)- and EMD-prone MM syngeneic cell lines; identified that epithelial-to-mesenchymal transition (EMT) transcriptional patterns were significantly enriched in both clones compared to parental cells, together with higher levels of CXCR4 protein; and demonstrated that CXCR4 enhanced the acquisition of an EMT-like phenotype in MM cells with a phenotypic conversion for invasion, leading to higher bone metastasis and EMD dissemination in vivo. In contrast, CXCR4 silencing led to inhibited tumor growth and reduced survival. Ulocuplumab, a monoclonal anti-CXCR4 antibody, inhibited MM cell dissemination, supported by suppression of the CXCR4-driven EMT-like phenotype. These results suggest that targeting CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression. C1 [Roccaro, Aldo M.; Mishima, Yuji; Sacco, Antonio; Moschetta, Michele; Tai, Yu-Tzu; Zhang, Yong; Reagan, Michaela R.; Huynh, Daisy; Kawano, Yawara; Sahin, Ilyas; Chiarini, Marco; Manier, Salomon; Cea, Michele; Aljawai, Yosra; Glavey, Siobhan; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shi, Jiantao; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Shi, Jiantao; Michor, Franziska] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Chiarini, Marco] Ctr Ric Oncoematol AIL CREA, Spedali Civili Brescia, I-25123 Brescia, Italy. [Morgan, Elizabeth] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Pan, Chin; Cardarelli, Pina; Kuhne, Michelle] Bristol Myers Squibb Co, Redwood City, CA 94063 USA. [Mishima, Yuji] Japanese Fdn Canc Res, Canc Chemotherapy Ctr, Tokyo 1358550, Japan. [Reagan, Michaela R.] MMCRI, Scarborough, ME 04074 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; Chiarini, Marco/K-4983-2016; OI Sacco, Antonio/0000-0003-2945-9416; Chiarini, Marco/0000-0003-1000-0461; Roccaro, Aldo/0000-0002-1872-5128; Reagan, Michaela/0000-0003-2884-6481 FU NIH/National Cancer Institute [RO1CA181683]; Leukemia & Lymphoma Society; Dana-Farber Cancer Institute Physical Sciences Oncology Center (NCI) [U54CA143798] FX The following support is acknowledged: NIH/National Cancer Institute (RO1CA181683); The Leukemia & Lymphoma Society; and the Dana-Farber Cancer Institute Physical Sciences Oncology Center (NCI grant U54CA143798). M.K., P.C., and C.P. are employees at Bristol-Myers Squibb. I.M.G. is a member of the BMS advisory board and received research support. NR 54 TC 10 Z9 10 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 28 PY 2015 VL 12 IS 4 BP 622 EP 635 DI 10.1016/j.celrep.2015.06.059 PG 14 WC Cell Biology SC Cell Biology GA CN9BZ UT WOS:000358742300009 PM 26190113 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Progress in the Noninvasive Detection of High-Risk Coronary Plaques SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE acute coronary syndrome(s); computed tomographic angiography; coronary disease ID ARTERY-DISEASE; VULNERABLE PLAQUE; ATHEROSCLEROSIS; ANGIOGRAPHY; THROMBOSIS; LESIONS C1 [Braunwald, Eugene] Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Div Cardiovasc, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Off Floor, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 16 TC 0 Z9 1 U1 0 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 JUL 28 PY 2015 VL 66 IS 4 BP 347 EP 349 DI 10.1016/j.jacc.2015.05.067 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CN7FV UT WOS:000358600500002 PM 26205590 ER PT J AU Pape, LA Awais, M Woznicki, EM Suzuki, T Trimarchi, S Evangelista, A Myrmel, T Larsen, M Harris, KM Greason, K Di Eusanio, M Bossone, E Montgomery, DG Eagle, KA Nienaber, CA Isselbacher, EM O'Gara, P AF Pape, Linda A. Awais, Mazen Woznicki, Elise M. Suzuki, Toru Trimarchi, Santi Evangelista, Arturo Myrmel, Truls Larsen, Magnus Harris, Kevin M. Greason, Kevin Di Eusanio, Marco Bossone, Eduardo Montgomery, Daniel G. Eagle, Kim A. Nienaber, Christoph A. Isselbacher, Eric M. O'Gara, Patrick TI Presentation, Diagnosis, and Outcomes of Acute Aortic Dissection 17-Year Trends From the International Registry of Acute Aortic Dissection SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute aortic dissection; management; outcomes ID ENDOVASCULAR REPAIR; THORACIC AORTA; IRAD; REOPERATIONS; MORTALITY; SURVIVAL; ANEURYSM; THERAPY; DISEASE AB BACKGROUND Diagnosis, treatment, and outcomes of acute aortic dissection (AAS) are changing. OBJECTIVES This study examined 17-year trends in the presentation, diagnosis, and hospital outcomes of AAD from the International Registry of Acute Aortic Dissection (IRAD). METHODS Data from 4,428 patients enrolled at 28 IRAD centers between December 26, 1995, and February 6, 2013, were analyzed. Patients were divided according to enrollment date into 6 equal groups and by AAD type: A (n = 2,952) or B (n = 1,476). RESULTS There was no change in the presenting complaints of severe or worst-ever pain for type A and type B AAD (93% and 94%, respectively), nor in the incidence of chest pain (83% and 71%, respectively). Use of computed tomography (CT) for diagnosis of type A increased from 46% to 73% (p < 0.001). Surgical management for type A increased from 79% to 90% (p < 0.001). Endovascular management of type B increased from 7% to 31% (p < 0.001). Type A in-hospital mortality decreased significantly (31% to 22%; p < 0.001), as surgical mortality (25% to 18%; p = 0.003). There was no significant trend in in-hospital mortality in type B (from 12% to 14%). CONCLUSIONS Presenting symptoms and physical findings of AAD have not changed significantly. Use of chest CT increased for type A. More patients in both groups were managed with interventional procedures: surgery in type A and endovascular therapy in type B. A significant decrease in overall in-hospital mortality was seen for type A but not for type B. (C) 2015 by the American College of Cardiology Foundation. C1 [Pape, Linda A.] Univ Massachusetts Hosp, Dept Med, Worcester, MA 01655 USA. [Awais, Mazen; Woznicki, Elise M.; Montgomery, Daniel G.; Eagle, Kim A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Awais, Mazen] Botsford Hosp, Dept Internal Med, Farmington Hills, MI USA. [Suzuki, Toru] Univ Tokyo, Dept Cardiovasc Med, Tokyo, Japan. [Trimarchi, Santi] IRCCS Policlin San Donato, Res Ctr Thorac Aort Dis, San Donato Milanese, Italy. [Evangelista, Arturo] Hosp Gen Univ Vall DHebron, Serv Cardiol, Barcelona, Spain. [Myrmel, Truls; Larsen, Magnus] Univ Tromso Hosp, Dept Thorac & Cardiovasc Surg, N-9012 Tromso, Norway. [Harris, Kevin M.] Minneapolis Heart Inst, Div Cardiovasc, Minneapolis, MN USA. [Greason, Kevin] Mayo Clin, Dept Cardiovasc Surg, Rochester, MN USA. [Di Eusanio, Marco] Univ Hosp S Orsola, Dept Cardiac Surg, Bologna, Italy. [Bossone, Eduardo] Univ Salerno, Div Cardiol, I-84100 Salerno, Italy. [Nienaber, Christoph A.] Univ Rostock, Dept Internal Med, D-18055 Rostock, Germany. [Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [O'Gara, Patrick] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. RP Pape, LA (reprint author), Univ Massachusetts Hosp, Cardiovasc Med, 55 Lake Ave North, Worcester, MA 01655 USA. EM linda.pape@umassmed.edu RI Trimarchi, Santi/J-7361-2016 OI Trimarchi, Santi/0000-0001-5996-3264 FU W.L. Gore & Associates, Inc.; Medtronic; Varbedian Aortic Research Fund; Hewlett Foundation; UM Faculty Group Practice; Terumo; Ann and Bob Aikens; Gore FX This research was supported by W.L. Gore & Associates, Inc., Medtronic, the Varbedian Aortic Research Fund, the Hewlett Foundation, UM Faculty Group Practice, Terumo, and Ann and Bob Aikens. Dr. Trimarchi has been a consultant for Medtronic and W.L. Gore. Dr. Eagle has a scientific research grant from Gore. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 32 TC 55 Z9 57 U1 3 U2 12 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 JUL 28 PY 2015 VL 66 IS 4 BP 350 EP 358 DI 10.1016/j.jacc.2015.05.029 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CN7FV UT WOS:000358600500003 PM 26205591 ER PT J AU La Fountaine, MF Cirnigliaro, CM Emmons, RR Kirshblum, SC Galea, M Spungen, AM Bauman, WA AF La Fountaine, Michael F. Cirnigliaro, Christopher M. Emmons, Racine R. Kirshblum, Steven C. Galea, Marinella Spungen, Ann M. Bauman, William A. TI Lipoprotein heterogeneity in persons with Spinal Cord Injury: a model of prolonged sitting and restricted physical activity SO LIPIDS IN HEALTH AND DISEASE LA English DT Article DE Cardiovascular disease; Insulin resistance; Lipids and lipoproteins; Nuclear magnetic resonance spectroscopy; Paraplegia; Special populations; Tetraplegia ID HIGH-DENSITY-LIPOPROTEIN; NUCLEAR-MAGNETIC-RESONANCE; CORONARY HEART-DISEASE; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; PARTICLE-SIZE; SKELETAL-MUSCLE; RISK; CHOLESTEROL; ATHEROSCLEROSIS AB Background: Persons with spinal cord injury (SCI) often have low levels of physical activity, which predispose to increased adiposity and decreased high density lipoprotein cholesterol (HDL-C) concentrations, and, generally, normal low density lipoprotein cholesterol (LDL-C) concentrations. In spite of the mixed lipoprotein profile, the SCI population has been reported to have an elevated risk of cardiovascular-related morbidity and mortality. Nuclear magnetic resonance spectroscopy may permit a more precise quantification of lipoprotein particle (P) species, enabling a more accurate inference of risk for cardiovascular disease (CVD) in the SCI population. Methods: Fasting blood samples were obtained on 83 persons with chronic SCI and 62 able-bodied (AB) subjects. Fasting plasma insulin (FPI), triglycerides (TG), and P number and size of VLDL (very low density lipoprotein), LDL, and HDL subclasses were determined. AB and SCI subjects were stratified based on HDL-C (i.e., Low < 40 and Normal >= 40 mg/dl): AB-Normal (n = 48), AB-Low (n = 14), SCI-Normal (n = 49), and SCI-Low (n = 34). Factorial analyses of variance were performed to identify group differences in lipoprotein measurements. Pearson correlations were performed between the number of P by lipoprotein subclass, size, FPI, and TG. Results: The SCI-Normal group was not significantly different from the AB-Normal group for body composition, FPI, TG or LP-IR and had negligible differences in the lipoprotein P profile, except for fewer number and smaller size of HDL-P. The SCI-Low group had a similar lipoprotein profile to that of the AB-Low group, but with a lipid P composition associated with a heightened atherogenic risk and greater tendency toward insulin resistance by the Lipoprotein-Insulin Resistance (LP-IR) score. In the SCI-Low group, the decreased number and reduced size of lipoprotein P were more prevalent and may be associated with increased waist circumference (i.e., abdominal adiposity), relatively elevated TG values (compared to the other subgroups), and an underlying subclinical state of insulin resistance. Conclusions: Prolonged sitting and restricted physical activity in individuals with SCI had the most profound effect on the HDL-C and its lipoprotein P subclasses, but not on LDL-C, however its P subclasses were also unfavorably affected but not to the same degree. The quantification of lipoprotein P characteristics may be a potent tool for the determination of risk for CVD in persons with SCI. C1 [La Fountaine, Michael F.; Cirnigliaro, Christopher M.; Spungen, Ann M.; Bauman, William A.] James J Peters Vet Affairs Med Ctr, Natl Ctr Excellence Med Consequences Spinal Cord, Dept Vet Affairs Rehabil Res & Dev Serv, Bronx, NY 10468 USA. [La Fountaine, Michael F.; Spungen, Ann M.; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [La Fountaine, Michael F.] Seton Hall Univ, Sch Hlth & Med Sci, Inst Adv Study Rehabil & Sports Sci, S Orange, NJ 07079 USA. [La Fountaine, Michael F.] Seton Hall Univ, Sch Hlth & Med Sci, Dept Phys Therapy, S Orange, NJ 07079 USA. [Emmons, Racine R.] William Patterson Univ, Dept Kinesiol, Wayne, NJ USA. [Kirshblum, Steven C.] Kessler Inst Rehabil, W Orange, NJ USA. [Kirshblum, Steven C.] Rutgers New Jersey Med Sch, Dept Phys Med & Rehabil, Newark, NJ USA. [Galea, Marinella] James J Peters VA Med Ctr, SCI Med Serv, Bronx, NY USA. [Spungen, Ann M.; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. RP La Fountaine, MF (reprint author), James J Peters Vet Affairs Med Ctr, Natl Ctr Excellence Med Consequences Spinal Cord, Dept Vet Affairs Rehabil Res & Dev Serv, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM michael.lafountaine@va.gov FU Veterans Affairs Rehabilitation Research and Development Service [B9212-C]; James J. Peters VA Medical Center FX Veterans Affairs Rehabilitation Research and Development Service (#B9212-C) and the James J. Peters VA Medical Center. NR 51 TC 0 Z9 0 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD JUL 28 PY 2015 VL 14 AR 81 DI 10.1186/s12944-015-0084-4 PG 10 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA CN5QL UT WOS:000358484000001 PM 26215870 ER PT J AU Kozono, D Li, J Nitta, M Sampetrean, O Gonda, D Kushwaha, DS Merzon, D Ramakrishnan, V Zhu, S Zhu, KY Matsui, H Harismendy, O Hua, W Mao, Y Kwon, CH Saya, H Nakano, I Pizzo, DP VandenBerg, SR Chen, CC AF Kozono, David Li, Jie Nitta, Masayuki Sampetrean, Oltea Gonda, David Kushwaha, Deepa S. Merzon, Dmitry Ramakrishnan, Valya Zhu, Shan Zhu, Kaya Matsui, Hiroko Harismendy, Olivier Hua, Wei Mao, Ying Kwon, Chang-Hyuk Saya, Hideyuki Nakano, Ichiro Pizzo, Donald P. VandenBerg, Scott R. Chen, Clark C. TI Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epigenomics; glioblastoma; neoplastic stem cells ID STOCHASTIC GENE-EXPRESSION; TUMOR-INITIATING CELLS; STEM-CELLS; C-MYC; HISTONE MODIFICATIONS; MOLECULAR-ORIGINS; EMBRYONIC STEM; CANCER-CELLS; SOLID TUMORS; HUMAN GENOME AB The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development. C1 [Kozono, David; Nitta, Masayuki; Kushwaha, Deepa S.; Merzon, Dmitry; Zhu, Shan; Zhu, Kaya] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Li, Jie; Gonda, David; Ramakrishnan, Valya; Saya, Hideyuki; Chen, Clark C.] Univ Calif San Diego, Div Neurosurg, La Jolla, CA 92093 USA. [Sampetrean, Oltea; Saya, Hideyuki] Keio Univ, Sch Med, Div Gene Regulat, Tokyo 1608582, Japan. [Matsui, Hiroko; Harismendy, Olivier] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Matsui, Hiroko; Harismendy, Olivier] Univ Calif San Diego, Rady Childrens Hosp, La Jolla, CA 92093 USA. [Hua, Wei; Mao, Ying] Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200040, Peoples R China. [Kwon, Chang-Hyuk; Nakano, Ichiro] Ohio State Univ, Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Pizzo, Donald P.; VandenBerg, Scott R.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92037 USA. RP Chen, CC (reprint author), Univ Calif San Diego, Div Neurosurg, La Jolla, CA 92093 USA. EM clarkchen@ucsd.edu RI RAMAKRISHNAN, VALYA/L-6415-2016 FU Doris Duke Charitable Foundation Clinical Scientist Development Award; Sontag Foundation Distinguished Scientist Award; Burroughs Wellcome Fund Career Awards for Medical Scientists; Kimmel Scholar award; American Brain Tumor Association; China National Natural Science Foundation [81001115]; China National Funds for Distinguished Young Scientists [81025013] FX We thank Dr. Bing Ren for his expertise and helpful discussions. C.C.C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award (www.ddcf.org), the Sontag Foundation Distinguished Scientist Award (www.sontagfoundation.org), the Burroughs Wellcome Fund Career Awards for Medical Scientists (www.bwfund.org), the Kimmel Scholar award (www.kimmel.org), and a Discovery Grant from the American Brain Tumor Association (www.abta.org). Y.M. and W.H. are supported by the China National Natural Science Foundation (81001115; www.nsfc.gov.cn) and China National Funds for Distinguished Young Scientists (81025013; www.nsfc.gov.cn). NR 73 TC 7 Z9 7 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 28 PY 2015 VL 112 IS 30 BP E4055 EP E4064 DI 10.1073/pnas.1501967112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN7ZW UT WOS:000358656500013 PM 26159421 ER PT J AU Rajaram, R Chung, JW Kinnier, CV Barnard, C Mohanty, S Pavey, ES McHugh, MC Bilimoria, KY AF Rajaram, Ravi Chung, Jeanette W. Kinnier, Christine V. Barnard, Cynthia Mohanty, Sanjay Pavey, Emily S. McHugh, Megan C. Bilimoria, Karl Y. TI Hospital Characteristics Associated With Penalties in the Centers for Medicare & Medicaid Services Hospital-Acquired Condition Reduction Program SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SURVEILLANCE BIAS; UNITED-STATES; CARE; QUALITY; OUTCOMES; HEALTH; PERFORMANCE; ADJUSTMENT; SURGERY; VOLUME AB IMPORTANCE In fiscal year (FY) 2015, the Centers for Medicare & Medicaid Services (CMS) instituted the Hospital-Acquired Condition (HAC) Reduction Program, which reduces payments to the lowest-performing hospitals. However, it is uncertain whether this program accurately measures quality and fairly penalizes hospitals. OBJECTIVE To examine the characteristics of hospitals penalized by the HAC Reduction Program and to evaluate the association of a summary score of hospital characteristics related to quality with penalization in the HAC program. DESIGN, SETTING, AND PARTICIPANTS Data for hospitals participating in the FY2015 HAC Reduction Program were obtained from CMS' Hospital Compare and merged with the 2014 American Hospital Association Annual Survey and FY2015 Medicare Impact File. Logistic regression models were developed to examine the association between hospital characteristics and HAC program penalization. An 8-point hospital quality summary score was created using hospital characteristics related to volume, accreditations, and offering of advanced care services. The relationship between the hospital quality summary score and HAC program penalization was examined. Publicly reported process-of-care and outcome measures were examined from 4 clinical areas (surgery, acute myocardial infarction, heart failure, pneumonia), and their association with the hospital quality summary score was evaluated. EXPOSURES Penalization in the HAC Reduction Program. MAIN OUTCOMES AND MEASURES Hospital characteristics associated with penalization. RESULTS Of the 3284 hospitals participating in the HAC program, 721 (22.0%) were penalized. Hospitals were more likely to be penalized if they were accredited by the Joint Commission (24.0% accredited, 14.4% not accredited; odds ratio [OR], 1.33; 95% CI, 1.04-1.70); they were major teaching hospitals (42.3%; OR, 1.58; 95% CI, 1.09-2.29) or very major teaching hospitals (62.2%; OR, 2.61; 95% CI, 1.55-4.39; vs nonteaching hospitals, 17.0%); they cared for more complex patient populations based on case mix index (quartile 4 vs quartile 1: 32.8% vs 12.1%; OR, 1.98; 95% CI, 1.44-2.71); or they were safety-net hospitals vs non-safety-net hospitals (28.3% vs 19.9%; OR, 1.36; 95% CI, 1.11-1.68). Hospitals with higher hospital quality summary scores had significantly better performance on 9 of 10 publicly reported process and outcomes measures compared with hospitals that had lower quality scores (all P <= .01 for trend). However, hospitals with the highest quality score of 8 were penalized significantly more frequently than hospitals with the lowest quality score of 0 (67.3%[37/55] vs 12.6%[53/422]; P < .001 for trend). CONCLUSIONS AND RELEVANCE Among hospitals participating in the HAC Reduction Program, hospitals that were penalized more frequently had more quality accreditations, offered advanced services, were major teaching institutions, and had better performance on other process and outcome measures. These paradoxical findings suggest that the approach for assessing hospital penalties in the HAC Reduction Program merits reconsideration to ensure it is achieving the intended goals. C1 [Rajaram, Ravi; Chung, Jeanette W.; Kinnier, Christine V.; Pavey, Emily S.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, SOQIC, Dept Surg, Chicago, IL 60611 USA. [Rajaram, Ravi; Barnard, Cynthia; McHugh, Megan C.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Ctr Healthcare Studies, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Kinnier, Christine V.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Barnard, Cynthia; Bilimoria, Karl Y.] Northwestern Mem HealthCare, Div Qual, Chicago, IL USA. [Mohanty, Sanjay] Henry Ford Hosp, Dept Surg, Detroit, MI 48202 USA. RP Bilimoria, KY (reprint author), Northwestern Univ, Feinberg Sch Med, SOQIC, Dept Surg, 633 N St Clair St,20th Floor, Chicago, IL 60611 USA. EM k-bilimoria@northwestern.edu FU Agency for Healthcare Research and Quality [T32HS000078]; American College of Surgeons Clinical Scholars in Residence Program; Merck FX Dr Rajaramis supported by the Agency for Healthcare Research and Quality (T32HS000078), the American College of Surgeons Clinical Scholars in Residence Program, and an unrestricted educational grant from Merck. NR 34 TC 28 Z9 28 U1 2 U2 8 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 JUL 28 PY 2015 VL 314 IS 4 BP 375 EP 383 DI 10.1001/jama.2015.8609 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CN6YY UT WOS:000358581700019 PM 26219055 ER PT J AU Alfandre, D Sharpe, VA Berkowitz, K AF Alfandre, David Sharpe, Virginia Ashby Berkowitz, Kenneth TI Surrogate Decision Making for Patients Without Nuclear Family SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Alfandre, David; Sharpe, Virginia Ashby; Berkowitz, Kenneth] US Dept Vet Affairs, VHA Natl Ctr Eth Hlth Care, Washington, DC USA. RP Alfandre, D (reprint author), US Dept Vet Affairs, VHA Natl Ctr Eth Hlth Care, 423 E 23rd St, New York, NY 10010 USA. EM david.alfandre@va.gov NR 3 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 JUL 28 PY 2015 VL 314 IS 4 BP 407 EP 408 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CN6YY UT WOS:000358581700027 PM 26219061 ER PT J AU Kao, SY Stankovic, KM AF Kao, Shyan-Yuan Stankovic, Konstantina M. TI Transactivation of human osteoprotegerin promoter by GATA-3 SO SCIENTIFIC REPORTS LA English DT Article ID TRAIL-INDUCED APOPTOSIS; T-CELL DEVELOPMENT; HUMAN HDR SYNDROME; INNER-EAR; TRANSCRIPTION FACTORS; GENE-EXPRESSION; OTIC CAPSULE; HEARING-LOSS; PROSTATE-CANCER; RENAL DYSPLASIA AB Osteoprotegerin (OPG) is a key regulator of bone remodeling. Mutations in OPG are involved in a variety of human diseases. We have shown that cochlear spiral ganglion cells secrete OPG at high levels and lack of OPG causes sensorineural hearing loss in addition to the previously described conductive hearing loss. In order to study the regulation of OPG expression, we conducted a database search on regulatory elements in the promoter region of the OPG gene, and identified two potential GATA-3 binding sites. Using luciferase assays and site directed mutagenesis, we demonstrate that these two elements are GATA-3 responsive and support GATA-3 transactivation in human HEK and HeLa cells. The expression of wild type GATA-3 activated OPG mRNA and protein expression, while the expression of a dominant negative mutant of GATA-3 or a GATA-3 shRNA construct reduced OPG mRNA and protein levels. GATA-3 deficient cells generated by expressing a GATA-3 shRNA construct were sensitive to apoptosis induced by etoposide and TNF-alpha. This apoptotic effect could be partly prevented by the co-treatment with exogenous OPG. Our results suggest new approaches to rescue diseases due to GATA-3 deficiency - such as in hypoparathyroidism, sensorineural deafness, and renal (HDR) syndrome - by OPG therapy. C1 [Kao, Shyan-Yuan; Stankovic, Konstantina M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Eaton Peabody Labs, Boston, MA 02138 USA. [Kao, Shyan-Yuan; Stankovic, Konstantina M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Program Speech & Hearing Biosci & Technol, Boston, MA USA. RP Stankovic, KM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Eaton Peabody Labs, Boston, MA 02138 USA. EM konstantina_stankovic@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders grant [K08DC010419]; Bertarelli Foundation; Nancy Sayles Day Foundation FX This study was supported by the National Institute on Deafness and Other Communication Disorders grant K08DC010419 (K.M.S.), the Bertarelli Foundation (K.M.S.) and Nancy Sayles Day Foundation (K.M.S.). We thank Dr. Shelley Batts for helpful comments on an earlier version of the manuscript and Kris Kristiansen for help with qRT-PCR experiments. NR 52 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 28 PY 2015 VL 5 AR 12479 DI 10.1038/srep12479 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN7AO UT WOS:000358586100001 PM 26216189 ER PT J AU Hosseini, P Sung, YJ Choi, Y Lue, N Yaqoob, Z So, P AF Hosseini, Poorya Sung, Yongjin Choi, Youngwoon Lue, Niyom Yaqoob, Zahid So, Peter TI Scanning color optical tomography (SCOT) SO OPTICS EXPRESS LA English DT Article ID DIGITAL HOLOGRAPHIC MICROSCOPY; PHASE MICROSCOPY; DIFFRACTION TOMOGRAPHY; REFRACTIVE-INDEX; LIVING CELLS; LIVE CELLS; DYNAMICS; DIFFERENTIATION; RESOLUTION; GROWTH AB We have developed an interferometric optical microscope that provides three-dimensional refractive index map of a specimen by scanning the color of three illumination beams. Our design of the interferometer allows for simultaneous measurement of the scattered fields (both amplitude and phase) of such a complex input beam. By obviating the need for mechanical scanning of the illumination beam or detection objective lens; the proposed method can increase the speed of the optical tomography by orders of magnitude. We demonstrate our method using polystyrene beads of known refractive index value and live cells. (C) 2015 Optical Society of America C1 [Hosseini, Poorya; Sung, Yongjin; Lue, Niyom; Yaqoob, Zahid; So, Peter] MIT, Laser Biomed Res Ctr, Cambridge, MA 02139 USA. [Hosseini, Poorya; So, Peter] MIT, Dept Mech & Biol Engn, Cambridge, MA 02139 USA. [Sung, Yongjin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sung, Yongjin] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Choi, Youngwoon] Korea Univ, Sch Biomed Engn, Seoul 136701, South Korea. RP Sung, YJ (reprint author), MIT, Laser Biomed Res Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM yongjin.sung@gmail.com RI Hosseini, Poorya/A-8121-2016 OI Hosseini, Poorya/0000-0001-7347-7887 FU NIH [9P41EB015871-26A1, 1R01HL121386-01A1]; NSF [CBET-0939511]; Singapore-MIT Alliance for Science and Technology Center; MIT SkolTech initiative; Hamamatsu Corp.; Koch Institute for Integrative Cancer Research Bridge Project Initiative; [5P41EB015871-30]; [5R01HL121386-03]; [2R01EY017656-06A1]; [1U01NS090438-01]; [1R21NS091982-01]; [5R01NS051320]; [DP3DK101024-01]; [4R44EB012415-02] FX This work was mainly supported by NIH 9P41EB015871-26A1 and 1R01HL121386-01A1. Peter T.C. So was supported by 5P41EB015871-30, 5R01HL121386-03, 2R01EY017656-06A1, 1U01NS090438-01, 1R21NS091982-01, 5R01NS051320, DP3DK101024-01, 4R44EB012415-02, NSF CBET-0939511, the Singapore-MIT Alliance for Science and Technology Center, the MIT SkolTech initiative, the Hamamatsu Corp. and the Koch Institute for Integrative Cancer Research Bridge Project Initiative. The authors would like to thank Professor George Barbastathis for helpful discussion, and Dr. Jeon Woong Kang for sample preparation and feedback on the manuscript. NR 39 TC 4 Z9 4 U1 1 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 27 PY 2015 VL 23 IS 15 BP 19752 EP 19762 DI 10.1364/OE.23.019752 PG 11 WC Optics SC Optics GA CR0TE UT WOS:000361035300112 PM 26367632 ER PT J AU Rissone, A Weinacht, KG la Marca, G Bishop, K Giocaliere, E Jagadeesh, J Felgentreff, K Dobbs, K Al-Herz, W Jones, M Chandrasekharappa, S Kirby, M Wincovitch, S Simon, KL Itan, Y DeVine, A Schlaeger, T Schambach, A Sood, R Notarangelo, LD Candotti, F AF Rissone, Alberto Weinacht, Katja Gabriele la Marca, Giancarlo Bishop, Kevin Giocaliere, Elisa Jagadeesh, Jayashree Felgentreff, Kerstin Dobbs, Kerry Al-Herz, Waleed Jones, Marypat Chandrasekharappa, Settara Kirby, Martha Wincovitch, Stephen Simon, Karen Lyn Itan, Yuval DeVine, Alex Schlaeger, Thorsten Schambach, Axel Sood, Raman Notarangelo, Luigi D. Candotti, Fabio TI Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ADENYLATE KINASE 2; MYELODYSPLASTIC SYNDROME; TRANSGENIC ZEBRAFISH; VASCULAR DEVELOPMENT; KNOCKOUT HEART; OMENN SYNDROME; GENE; GROWTH; TRANSPLANTATION; EXPRESSION AB Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD. C1 [Rissone, Alberto; Jagadeesh, Jayashree; Simon, Karen Lyn; Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Bishop, Kevin; Sood, Raman] NHGRI, Zebrafish Core, NIH, Bethesda, MD 20892 USA. [Sood, Raman] NHGRI, Oncogenesis & Dev Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Jones, Marypat; Chandrasekharappa, Settara] NHGRI, Genom Core, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Kirby, Martha] NHGRI, Div Intramural Res Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Wincovitch, Stephen] NHGRI, Cytogenet & Microscopy Core, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Weinacht, Katja Gabriele; DeVine, Alex; Schlaeger, Thorsten; Schambach, Axel] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Felgentreff, Kerstin; Dobbs, Kerry; Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Weinacht, Katja Gabriele] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [la Marca, Giancarlo] Univ Florence, Dept Neurosci Psychol Pharmacol & Child Hlth, I-51039 Florence, Italy. [la Marca, Giancarlo; Giocaliere, Elisa] Meyer Childrens Univ Hosp, I-50141 Florence, Italy. [Al-Herz, Waleed] Kuwait Univ, Dept Pediat, Fac Med, Kuwait 13110, Kuwait. [Al-Herz, Waleed] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait 70459, Kuwait. [Itan, Yuval] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Schambach, Axel] Hannover Med Sch, Inst Expt Hematol, D-30625 Hannover, Germany. [Notarangelo, Luigi D.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Candotti, Fabio] Univ Lausanne Hosp, Div Immunol & Allergy, CH-1011 Lausanne, Switzerland. RP Candotti, F (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM Luigi.Notarangelo@childrens.harvard.edu; Fabio.Candotti@chuv.ch RI Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; la marca, giancarlo/0000-0003-3319-7260 FU National Institute of Allergy and Infectious Diseases (NIAID) [5R01AI100887]; Manton Foundation; Intramural Research Program of the National Human Genome Research Institute; UNIL-CHUV grant [CGRB 29583]; EU FP7 program Cellpid and Cluster of Excellence REBIRTH (DFG); Kuwait Foundation for Advancement of Science [2010-1302-05]; Amy Potter Fellowship; Charles King Trust; Primary Immune Deficiency Treatment Consortium; NIAID [1U54AI082973] FX This work was supported in part by grant 5R01AI100887 from the National Institute of Allergy and Infectious Diseases (NIAID) and by the Manton Foundation (to L.D. Notarangelo), by funding from the Intramural Research Program of the National Human Genome Research Institute (to F. Candotti, R. Sood, and S. Chandrasekharappa), by UNIL-CHUV grant CGRB 29583 (to F. Candotti), by EU FP7 program Cellpid and Cluster of Excellence REBIRTH (DFG; to A. Schambach), and by the Kuwait Foundation for Advancement of Science (2010-1302-05; to W. Al-Herz). K.G. Weinacht's work was supported by the Amy Potter Fellowship, the Charles King Trust, and the Primary Immune Deficiency Treatment Consortium and funded by grant 1U54AI082973 from NIAID. NR 61 TC 4 Z9 4 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 27 PY 2015 VL 212 IS 8 BP 1185 EP 1202 DI 10.1084/jem.20141286 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CQ1SO UT WOS:000360379400004 PM 26150473 ER PT J AU Greenblatt, MB Park, KH Oh, H Kim, JM Shin, DY Lee, JM Lee, JW Singh, A Lee, KY Hu, D Xiao, CC Charles, JF Penninger, JM Lotinun, S Baron, R Ghosh, S Shim, JH AF Greenblatt, Matthew B. Park, Kwang Hwan Oh, Hwanhee Kim, Jung-Min Shin, Dong Yeon Lee, Jae Myun Lee, Jin Woo Singh, Anju Lee, Ki-young Hu, Dorothy Xiao, Changchun Charles, Julia F. Penninger, Josef M. Lotinun, Sutada Baron, Roland Ghosh, Sankar Shim, Jae-Hyuck TI CHMP5 controls bone turnover rates by dampening NF-kappa B activity in osteoclasts SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID VALOSIN-CONTAINING PROTEIN; JUVENILE PAGETS-DISEASE; GENOME-WIDE ASSOCIATION; MESENCHYMAL STEM-CELLS; C-SRC; OSTEOBLAST DIFFERENTIATION; GENE-EXPRESSION; ESCRT-III; RESORPTION; COMPLEX AB Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-kappa B signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover. A conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early onset, polyostotic form of human Paget's disease of bone (PDB). These phenotypes are reversed by haploinsufficiency for Rank, as well as by antiresorptive treatments, including alendronate, zolendronate, and OPG-Fc. Accordingly, CHMP5-deficient osteoclasts display increased RANKL-induced NF-kappa B activation and osteoclast differentiation. Biochemical analysis demonstrated that CHMP5 cooperates with the PDB genetic risk factor valosin-containing protein (VCP/p97) to stabilize the inhibitor of NF-kappa B alpha (I kappa B alpha), down-regulating ubiquitination of I kappa B alpha via the deubiquitinating enzyme USP15. Thus, CHMP5 tunes NF-kappa B signaling downstream of RANK in osteoclasts to dampen osteoclast differentiation, osteoblast coupling and bone turnover rates, and disruption of CHMP5 activity results in a PDB-like skeletal disorder. C1 [Greenblatt, Matthew B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Greenblatt, Matthew B.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Park, Kwang Hwan; Oh, Hwanhee; Kim, Jung-Min; Shin, Dong Yeon; Shim, Jae-Hyuck] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Park, Kwang Hwan; Lee, Jae Myun] Yonsei Univ, Coll Med, Brain Korea PLUS Project Med Sci 21, Dept Microbiol, Seoul 120752, South Korea. [Park, Kwang Hwan; Lee, Jin Woo] Yonsei Univ, Coll Med, Dept Orthopaed Surg, Seoul 120752, South Korea. [Singh, Anju] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Lee, Ki-young] Sungkyunkwan Univ, Sch Med, Dept Mol Cell Biol, Suwon 440746, South Korea. [Lee, Ki-young] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Suwon 440746, South Korea. [Hu, Dorothy] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Xiao, Changchun] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Charles, Julia F.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Dept Med, Boston, MA 02115 USA. [Charles, Julia F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Penninger, Josef M.] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Lotinun, Sutada] Chulalongkorn Univ, Dept Physiol, Bangkok 10330, Thailand. [Lotinun, Sutada] Chulalongkorn Univ, STAR Craniofacial & Skeletal Disorders, Fac Dent, Bangkok 10330, Thailand. [Ghosh, Sankar] Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA. RP Shim, JH (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. EM jas2060@med.cornell.edu RI Penninger, Josef/I-6860-2013 OI Penninger, Josef/0000-0002-8194-3777 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health [1 R01 AR068983-01]; Advanced European Research Council grant; Era of Hope/Department of Defense FX This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (J.-H. Shim; 1 R01 AR068983-01). J.M. Penninger was supported by an Advanced European Research Council grant and an Innovator Award from the Era of Hope/Department of Defense. NR 58 TC 3 Z9 3 U1 2 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JUL 27 PY 2015 VL 212 IS 8 BP 1283 EP 1301 DI 10.1084/jem.20150407 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CQ1SO UT WOS:000360379400010 PM 26195726 ER PT J AU Zhao, QC Yetisen, AK Anthony, CJ Fowler, WR Yun, SH Butt, H AF Zhao, Qiancheng Yetisen, Ali K. Anthony, Carl J. Fowler, William R. Yun, Seok Hyun Butt, Haider TI Printable ink holograms SO APPLIED PHYSICS LETTERS LA English DT Article ID PERIODIC STRUCTURES; INTERFERENCE; FABRICATION; STAMPS AB The development of single-step printable holographic recording techniques can enable applications in rapid data storage, imaging, and bio-sensing. The personalized use of holography is limited due to specialist level of knowledge, time consuming recording techniques, and high-cost equipment. Here, we report a rapid and feasible in-line reflection recording strategy for printing surface holograms consisting of ink using a single pulse of a laser light within seconds. The laser interference pattern and periodicity of surface grating as a function of tilt angle are predicted by computationally and demonstrated experimentally to create 2D linear gratings and three-dimensional (3D) images. We further demonstrate the utility of our approach in creating personalized handwritten signatures and 3D images. (C) 2015 AIP Publishing LLC. C1 [Zhao, Qiancheng; Anthony, Carl J.; Fowler, William R.; Butt, Haider] Univ Birmingham, Sch Mech Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. [Yetisen, Ali K.; Yun, Seok Hyun] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yetisen, Ali K.; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Butt, H (reprint author), Univ Birmingham, Sch Mech Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. EM h.butt@bham.ac.uk OI Anthony, Carl/0000-0002-7729-9843; Butt, Haider/0000-0003-2434-9525 FU Leverhulme Trust FX H.B. thanks the Leverhulme Trust for research funding. The authors thank Jeff Blyth, Christopher R. Lowe, and Yunuen Montelongo for their help toward this work. NR 22 TC 8 Z9 8 U1 3 U2 19 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0003-6951 EI 1077-3118 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD JUL 27 PY 2015 VL 107 IS 4 AR 041115 DI 10.1063/1.4928046 PG 5 WC Physics, Applied SC Physics GA CO1OF UT WOS:000358924200015 ER PT J AU Retarekar, R Ramachandran, M Berkowitz, B Harbaugh, RE Hasan, D Rosenwasser, RH Ogilvy, CS Raghavan, ML AF Retarekar, Rohini Ramachandran, Manasi Berkowitz, Benjamin Harbaugh, Robert E. Hasan, David Rosenwasser, Robert H. Ogilvy, Christopher S. Raghavan, Madhavan L. TI Stratification of a population of intracranial aneurysms using blood flow metrics SO COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING LA English DT Article DE computational fluid dynamics; intracranial aneurysms; wall shear stress ID WALL SHEAR-STRESS; MIDDLE CEREBRAL-ARTERY; CONTRAST CINE MR; TRANSCRANIAL DOPPLER; VERTEBRAL ARTERIES; RUPTURE; HEMODYNAMICS; SONOGRAPHY; VELOCITY; RISK AB Indices of the intra-aneurysm hemodynamic environment have been proposed as potentially indicative of their longitudinal outcome. To be useful, the indices need to be used to stratify large study populations and tested against known outcomes. The first objective was to compile the diverse hemodynamic indices reported in the literature. Furthermore, as morphology is often the only patient-specific information available in large population studies, the second objective was to assess how the ranking of aneurysms in a population is affected by the use of steady flow simulation as an approximation to pulsatile flow simulation, even though the former is clearly non-physiological. Sixteen indices of aneurysmal hemodynamics reported in the literature were compiled and refined where needed. It was noted that, in the literature, these global indices of flow were always time-averaged over the cardiac cycle. Steady and pulsatile flow simulations were performed on a population of 198 patient-specific and 30 idealised aneurysm models. All proposed hemodynamic indices were estimated and compared between the two simulations. It was found that steady and pulsatile flow simulations had a strong linear dependence (r >= 0.99 for 14 indices; r >= 0.97 for 2 others) and rank the aneurysms in an almost identical fashion (rho >= 0.99 for 14 indices; rho >= 0.96 for other 2). When geometry is the only measured piece of information available, stratification of aneurysms based on hemodynamic indices reduces to being a physically grounded substitute for stratification of aneurysms based on morphology. Under such circumstances, steady flow simulations may be just as effective as pulsatile flow simulation for estimating most key indices currently reported in the literature. C1 [Retarekar, Rohini; Ramachandran, Manasi; Berkowitz, Benjamin; Raghavan, Madhavan L.] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Harbaugh, Robert E.] Penn State Univ, Penn State Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Hasan, David] Univ Iowa, Dept Neurosurg, Iowa City, IA 52242 USA. [Rosenwasser, Robert H.] Thomas Jefferson Univ, Jefferson Univ Hosp, Dept Neurol Surg, Philadelphia, PA 19107 USA. [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Raghavan, ML (reprint author), Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. EM ml-raghavan@uiowa.edu FU National Institute of Health [R01 HL083475]; National Science Foundation through NCSA [TG-CTS100061] FX This work was supported by the National Institute of Health [grant number #R01 HL083475]. It was also supported in part by the National Science Foundation through Teragrid resources provided by NCSA [grant number #TG-CTS100061]. NR 34 TC 2 Z9 2 U1 0 U2 42 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1025-5842 EI 1476-8259 J9 COMPUT METHOD BIOMEC JI Comput. Methods Biomech. Biomed. Eng. PD JUL 27 PY 2015 VL 18 IS 10 BP 1072 EP 1082 DI 10.1080/10255842.2013.869322 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical SC Computer Science; Engineering GA AW1RD UT WOS:000346066300005 PM 24506436 ER PT J AU Berry, DL Halpenny, B Bosco, JLF Bruyere, J Sanda, MG AF Berry, Donna L. Halpenny, Barbara Bosco, Jaclyn L. F. Bruyere, John, Jr. Sanda, Martin G. TI Usability evaluation and adaptation of the e-health Personal Patient Profile-Prostate decision aid for Spanish-speaking Latino men SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article DE Usability; Adaptation; Spanish; Localized prostate cancer; Disparities; Decision aid ID RADICAL PROSTATECTOMY; CANCER; SUPPORT; DESIGN; TRIAL; DISPARITIES; SURVIVORS; SURGERY; CARE AB Background: The Personal Patient Profile-Prostate (P3P), a web-based decision aid, was demonstrated to reduce decisional conflict in English-speaking men with localized prostate cancer early after initial diagnosis. The purpose of this study was to explore and enhance usability and cultural appropriateness of a Spanish P3P by Latino men with a diagnosis of prostate cancer. Methods: P3P was translated to Spanish and back-translated by three native Spanish-speaking translators working independently. Spanish-speaking Latino men with a diagnosis of localized prostate cancer, who had made treatment decisions in the past 24 months, were recruited from two urban clinical care sites. Individual cognitive interviews were conducted by two bilingual research assistants as each participant used the Spanish P3P. Notes of user behavior, feedback, and answers to direct questions about comprehension, usability and perceived usefulness were analyzed and categorized. Results: Seven participants with a range of education levels identified 25 unique usability issues in navigation, content comprehension and completeness, sociocultural appropriateness, and methodology. Revisions were prioritized to refine the usability and cultural and linguistic appropriateness of the decision aid. Conclusions: Usability issues were discovered that are potential barriers to effective decision support. Successful use of decision aids requires adaptation and testing beyond translation. Our findings led to revisions further refining the usability and linguistic and cultural appropriateness of Spanish P3P. C1 [Berry, Donna L.] Univ Washington, Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Berry, Donna L.; Halpenny, Barbara; Bosco, Jaclyn L. F.] Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. [Bruyere, John, Jr.] Marshall Univ, Joan C Edwards Sch Med, Huntington, WV USA. [Sanda, Martin G.] Emory Univ, Sch Med, Dept Urol, Atlanta, GA 30322 USA. RP Berry, DL (reprint author), Univ Washington, Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. EM donnalb@uw.edu RI Sanda, Martin/B-2023-2015 NR 46 TC 3 Z9 3 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD JUL 24 PY 2015 VL 15 AR 56 DI 10.1186/s12911-015-0180-4 PG 12 WC Medical Informatics SC Medical Informatics GA CN3SM UT WOS:000358346700001 PM 26204920 ER PT J AU Batchelor, TT Chen, YB Rapalino, O Cobos, I AF Batchelor, Tracy T. Chen, Yi-Bin Rapalino, Otto Cobos, Inma TI Case 23-2015: A 51-Year-Old Woman with Headache, Cognitive Impairment, and Weakness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PRIMARY CNS LYMPHOMA; NERVOUS-SYSTEM LYMPHOMA; RECURRENT PRIMARY CNS; WHOLE-BRAIN RADIOTHERAPY; B-CELL LYMPHOMAS; CEREBRAL SCHISTOSOMIASIS; IMMUNOCOMPETENT PATIENTS; GLIOBLASTOMA-MULTIFORME; INTENSIVE CHEMOTHERAPY; CORPUS-CALLOSUM C1 [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol & Radiat Oncol, Boston, MA 02114 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cobos, Inma] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Batchelor, Tracy T.] Harvard Univ, Sch Med, Dept Neurol & Radiat Oncol, Boston, MA USA. [Chen, Yi-Bin] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rapalino, Otto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Cobos, Inma] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Batchelor, TT (reprint author), Massachusetts Gen Hosp, Dept Neurol & Radiat Oncol, Boston, MA 02114 USA. FU Merck; Roche; Kyowa Hakko Kirin; Novartis; Proximagen; Agenus; Spectrum; Amgen; Champions Biotechnology; Advance Medical; Foundation Medicine; Robert Michael Educational Institute; Educational Concepts Group; Research to Practice; Oakstone Publishing; Imedex; Pfizer; AstraZeneca; Millennium; Otsuka Pharmaceuticals; Seattle Genetics; Bayer; Onyx Pharmaceuticals FX Dr. Batchelor reports receiving consulting fees from Merck, Roche, Kyowa Hakko Kirin, Novartis, Proximagen, Agenus, Spectrum, Amgen, Champions Biotechnology, Advance Medical, and Foundation Medicine; lecture fees from Robert Michael Educational Institute, Educational Concepts Group, Research to Practice, Oakstone Publishing, and Imedex; and grant support from Pfizer, AstraZeneca, and Millennium. Dr. Chen reports receiving consulting fees from Otsuka Pharmaceuticals and grant support from Otsuka Pharmaceuticals, Seattle Genetics, Bayer and Onyx Pharmaceuticals, and Novartis. No other potential conflict of interest relevant to this article was reported. NR 62 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 JUL 23 PY 2015 VL 373 IS 4 BP 367 EP 377 DI 10.1056/NEJMcpc1406415 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CN3NL UT WOS:000358333500012 PM 26200983 ER PT J AU Guieze, R Wu, CJ AF Guieze, Romain Wu, Catherine J. TI Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia SO BLOOD LA English DT Review ID IDENTIFIES RECURRENT MUTATIONS; HEMATOPOIETIC STEM-CELL; CLONAL EVOLUTION; SF3B1 MUTATIONS; DISEASE PROGRESSION; DNA METHYLATION; HEMATOLOGICAL MALIGNANCIES; CLINICAL-SIGNIFICANCE; EPIGENETIC CHANGES; DOWN-REGULATION AB Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19(+)CD5(+)CD23(+)sIg(dim) expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity among individuals with CLL but also even within individual patient leukemias. We herein review the rapidly growing series of studies assessing the genetic and epigenetic features of CLL within clinically defined periods of its growth. These studies strongly suggest an evolving spectrum of lesions over time and that these features may have clinical impact. C1 [Guieze, Romain] CHU Clermont Ferrand, Serv Hematol Clin Adulte & Therapie Cellulaire, Clermont Ferrand, France. [Guieze, Romain] Univ Auvergne, Clermont Ferrand, France. [Guieze, Romain; Wu, Catherine J.] Dana Farber Canc Inst, Div Hematol Neoplasia, Boston, MA 02115 USA. [Guieze, Romain; Wu, Catherine J.] Broad Inst, Canc Program, Cambridge, MA USA. [Guieze, Romain; Wu, Catherine J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Guieze, Romain; Wu, Catherine J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Wu, CJ (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, 450 Brookline Ave,540B, Boston, MA 02115 USA. EM cwu@partners.org FU Blavatnik Family Foundation; American Association for Cancer Research; National Institutes of Health, National Heart, Lung, and Blood Institute [1RO1HL103532-01, 1RO1HL116452-01]; National Cancer Institute [1R01CA155010-01A1]; Lymphoma Research Foundation; Leukemia Lymphoma Society; Quest for Cures Award FX C.J.W. acknowledges support from the Blavatnik Family Foundation, American Association for Cancer Research (SU2C Innovative Research Grant), National Institutes of Health, National Heart, Lung, and Blood Institute (1RO1HL103532-01 and 1RO1HL116452-01), National Cancer Institute (1R01CA155010-01A1), and the Lymphoma Research Foundation. C.J.W. is also a recipient of a Leukemia Lymphoma Society Scholar Award and Translational Research Program Award, as well as a Quest for Cures Award. NR 92 TC 17 Z9 18 U1 2 U2 13 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 JUL 23 PY 2015 VL 126 IS 4 BP 445 EP 453 DI 10.1182/blood-2015-02-585042 PG 9 WC Hematology SC Hematology GA CO0UP UT WOS:000358869300008 PM 26065654 ER PT J AU Donato, J Campigotto, F Uhlmann, EJ Coletti, E Neuberg, D Weber, GM Zwicker, JI AF Donato, Jessica Campigotto, Federico Uhlmann, Erik J. Coletti, Erika Neuberg, Donna Weber, Griffin M. Zwicker, Jeffrey I. TI Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study SO BLOOD LA English DT Article ID VENOUS THROMBOEMBOLISM; INTRACEREBRAL HEMORRHAGE; CANCER; MANAGEMENT; TUMORS; SURVIVAL; RISK AB Venous thromboembolism occurs frequently in patients with cancer who have brain metastases, but there is limited evidence supporting the safety of therapeutic anticoagulation. To assess the risk for intracranial hemorrhage associated with the administration of therapeutic doses of low-molecular-weight heparin, we performed a matched, retrospective cohort study of 293 patients with cancer with brain metastases (104 with therapeutic enoxaparin and 189 controls). A blinded review of radiographic imaging was performed, and intracranial hemorrhages were categorized as trace, measurable, and significant. There were no differences observed in the cumulative incidence of intracranial hemorrhage at 1 year in the enoxaparin and control cohorts for measurable (19% vs 21%; Gray test, P = .97; hazard ratio, 1.02; 90% confidence interval [CI], 0.66-1.59), significant (21% vs 22%; P = .87), and total (44% vs 37%; P = .13) intracranial hemorrhages. The risk for intracranial hemorrhage was fourfold higher (adjusted hazard ratio, 3.98; 90% CI, 2.41-6.57; P < .001) in patients with melanoma or renal cell carcinoma (N = 60) than lung cancer (N = 153), but the risk was not influenced by the administration of enoxaparin. Overall survival was similar for the noxaparin and control cohorts (8.4 vs 9.7 months; Log-rank, P = .65). We conclude that intracranial hemorrhage is frequently observed in patients with brain metastases, but that therapeutic anticoagulation does not increase the risk for intracranial hemorrhage. C1 [Donato, Jessica] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. [Campigotto, Federico; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Uhlmann, Erik J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Coletti, Erika; Zwicker, Jeffrey I.] Harvard Univ, Sch Med, Div Hemostasis & Thrombosis, Boston, MA USA. [Coletti, Erika; Zwicker, Jeffrey I.] Harvard Univ, Sch Med, Div Hematol & Oncol, Boston, MA USA. [Weber, Griffin M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Ctr Biomed Informat, Interdisciplinary Med & Biotechnol,Med Sch, Boston, MA 02215 USA. RP Zwicker, JI (reprint author), Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, 330 Brookline Ave, Boston, MA 02115 USA. EM jzwicker@bidmc.harvard.edu OI Zwicker, Jeffrey/0000-0001-5810-6893 FU National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000170-05]; Harvard University and its affiliated academic health care centers; Dana-Farber/Harvard Cancer Center [5P30 CA006516] FX Computerized data collection was supported by the 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 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). Statistical support provided through a Dana-Farber/Harvard Cancer Center Core Grant (5P30 CA006516). NR 21 TC 13 Z9 13 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 23 PY 2015 VL 126 IS 4 BP 494 EP 499 DI 10.1182/blood-2015-02-626788 PG 6 WC Hematology SC Hematology GA CO0UP UT WOS:000358869300014 PM 25987658 ER PT J AU Sakurai, Y Fitch-Tewfik, JL Qiu, YZ Ahn, B Myers, DR Tran, R Fay, ME Ding, LM Spearman, PW Michelson, AD Flaumenhaft, R Lam, WA AF Sakurai, Yumiko Fitch-Tewfik, Jennifer L. Qiu, Yongzhi Ahn, Byungwook Myers, David R. Tran, Reginald Fay, Meredith E. Ding, Lingmei Spearman, Paul W. Michelson, Alan D. Flaumenhaft, Robert Lam, Wilbur A. TI Platelet geometry sensing spatially regulates alpha-granule secretion to enable matrix self-deposition SO BLOOD LA English DT Article ID ACTIN CYTOSKELETON; RHO GTPASES; IN-VITRO; TI-VAMP; MEMBRANE; AGGREGATION; ACTIVATION; FIBRINOGEN; EXOCYTOSIS; STABILITY AB Although the biology of platelet adhesionon subendothelial matrix after vascular injury is well characterized, how the matrix biophysical properties affect platelet physiology is unknown. Here we demonstrate that geometric orientation of the matrix itself regulates platelet alpha-granule secretion, a key component of platelet activation. Using protein micro-contact printing, we show that platelets spread beyond the geometric constraints of fibrinogen or collagen micropatterns with <5-mu m features. Interestingly, alpha-granule exocytosis and deposition of the alpha-granule contents such as fibrinogen and fibronectin were primarily observed in those areas of platelet extension beyond the matrix protein micropatterns. This enables platelets to "self-deposit" additional matrix, provide more cellular membrane to extend spreading, and reinforce platelet-platelet connections. Mechanistically, this phenomenon is mediated by actin polymerization, Rac1 activation, and (alpha parallel to b)beta(3) integrin redistribution and activation, and is attenuated in gray platelet syndrome platelets, which lack alpha-granules, and Wiskott-Aldrich syndrome platelets, which have cytoskeletal defects. Overall, these studies demonstrate how platelets transduce geometric cues of the underlying matrix geometry into intracellular signals to extend spreading, which endows platelets spatial flexibility when spreading onto small sites of exposed subendothelium. C1 [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Emory Univ, Atlanta, GA 30322 USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Aflac Canc Ctr, Atlanta, GA USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Childrens Healthcare Atlanta, Blood Disorders Serv, Atlanta, GA USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Ding, Lingmei; Spearman, Paul W.; Lam, Wilbur A.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Georgia Inst Technol, Parker H Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Sakurai, Yumiko; Qiu, Yongzhi; Ahn, Byungwook; Myers, David R.; Tran, Reginald; Fay, Meredith E.; Lam, Wilbur A.] Georgia Inst Technol, Inst Elect & Nanotechnol, Atlanta, GA 30332 USA. [Fitch-Tewfik, Jennifer L.; Flaumenhaft, Robert] Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA. [Fitch-Tewfik, Jennifer L.; Flaumenhaft, Robert] Harvard Univ, Sch Med, Boston, MA USA. [Michelson, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Childrens Hosp, Ctr Platelet Res Studies,Div Hematol Oncol,Boston, Boston, MA 02115 USA. RP Lam, WA (reprint author), Emory Univ, Sch Med, 2015 Uppergate Dr NE 448, Atlanta, GA 30322 USA. EM wilbur.lam@emory.edu FU NSF CAREER [1150235]; National Institutes of Health National Heart, Lung, and Blood Institute [U54 HL112309, R01 HL121264] FX This study was supported by NSF CAREER Award 1150235 and National Institutes of Health National Heart, Lung, and Blood Institute grants U54 HL112309 and R01 HL121264 (W.A.L.). NR 39 TC 7 Z9 7 U1 0 U2 5 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 JUL 23 PY 2015 VL 126 IS 4 BP 531 EP 538 DI 10.1182/blood-2014-11-607614 PG 8 WC Hematology SC Hematology GA CO0UP UT WOS:000358869300019 PM 25964667 ER PT J AU Kondo, A Shahpasand, K Mannix, R Qiu, JH Moncaster, J Chen, CH Yao, YD Lin, YM Driver, JA Sun, Y Wei, S Luo, ML Albayram, O Huang, PY Rotenberg, A Ryo, A Goldstein, LE Pascual-Leone, A McKee, AC Meehan, W Zhou, XZ Lu, KP AF Kondo, Asami Shahpasand, Koorosh Mannix, Rebekah Qiu, Jianhua Moncaster, Juliet Chen, Chun-Hau Yao, Yandan Lin, Yu-Min Driver, Jane A. Sun, Yan Wei, Shuo Luo, Man-Li Albayram, Onder Huang, Pengyu Rotenberg, Alexander Ryo, Akihide Goldstein, Lee E. Pascual-Leone, Alvaro McKee, Ann C. Meehan, William Zhou, Xiao Zhen Lu, Kun Ping TI Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy SO NATURE LA English DT Article ID PROLYL ISOMERASE PIN1; CHRONIC TRAUMATIC ENCEPHALOPATHY; ALZHEIMERS-DISEASE; HEAD-INJURY; PATHOLOGY; PROTEIN; IMMUNOTHERAPY; MODEL; ONSET; TRANSMISSION AB Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. C1 [Kondo, Asami; Shahpasand, Koorosh; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Driver, Jane A.; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Translat Therapeut, Dept Med,Med Sch, Boston, MA 02215 USA. [Kondo, Asami; Shahpasand, Koorosh; Chen, Chun-Hau; Yao, Yandan; Lin, Yu-Min; Wei, Shuo; Luo, Man-Li; Albayram, Onder; Huang, Pengyu; Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Res Inst, Sch Med, Boston, MA 02215 USA. [Mannix, Rebekah; Qiu, Jianhua] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Emergency Med, Boston, MA 02115 USA. [Moncaster, Juliet; Goldstein, Lee E.; McKee, Ann C.] Boston Univ, Sch Med, Alzheimers Dis Ctr, CTE Program, Boston, MA 02118 USA. [Driver, Jane A.] Harvard Univ, Sch Med, Geriatr Res Educ & Clin Ctr, VA Boston Healthcare Syst, Boston, MA 02130 USA. [Sun, Yan; Rotenberg, Alexander] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurol, Boston, MA 02115 USA. [Ryo, Akihide] Yokohama City Univ, Dept Microbiol, Sch Med, Yokohama, Kanagawa 2360004, Japan. [Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Meehan, William] Harvard Univ, Sch Med, Childrens Hosp Boston, Micheli Ctr Sports Injury Prevent, Boston, MA 02115 USA. RP Lu, KP (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Div Translat Therapeut, Dept Med,Med Sch, Boston, MA 02215 USA. EM xzhou@bidmc.harvard.edu; klu@bidmc.harvard.edu OI Moncaster, Juliet/0000-0002-7849-4325 FU NIH [S10RR017927, T32HD040128, UO1NS086659-01, P30AG13846, R01AG029385, R01CA167677, R01HL111430, R01AG046319]; NIA; VA Career Development Award; Susan G. Komen postdoctoral fellowship; Boston Children's Hospital Pilot Grant Award; NFLPA; VA; Sports Legacy Institute; Andlinger Foundation; NFL; WWE; Alzheimer's Association [DVT-14-322623]; BIDMC FX We thank T. Hunter and M. Zeidel for advice; S. Hagen for Microscopy Facility (NIH grantS10RR017927) and P. Davies for tauopathy antibodies. C.-H.C., Y.-M.L., J.A.D. and S.W. are recipients of NIA-funded T32 Translational Research in Aging Training Grant, National Science Council Postdoctoral Fellowship from Taiwan, a VA Career Development Award, and Susan G. Komen postdoctoral fellowship, respectively. R.M. is supported by Boston Children's Hospital Pilot Grant Award and NIH training grant T32HD040128, and A.P.-L. and W.M. by NFLPA. The CTE and blast samples used are supported by grants from NIH (UO1NS086659-01, P30AG13846), VA, Sports Legacy Institute, Andlinger Foundation, NFL and WWE. The work is supported by NIH grants R01AG029385, R01CA167677, R01HL111430 and R01AG046319, and Alzheimer's Association grant DVT-14-322623 to K.P.L. and BIDMC and NFLPA pilot grants to K.P.L. and X.Z.Z. NR 50 TC 47 Z9 49 U1 12 U2 38 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 JUL 23 PY 2015 VL 523 IS 7561 BP 431 EP U118 DI 10.1038/nature14658 PG 26 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN4DD UT WOS:000358378900030 PM 26176913 ER PT J AU Joshi, PK Esko, T Mattsson, H Eklund, N Gandin, I Nutile, T Jackson, AU Schurmann, C Smith, AV Zhang, WH Okada, Y Stancakova, A Faul, JD Zhao, W Bartz, TM Concas, MP Franceschini, N Enroth, S Vitart, V Trompet, S Guo, XQ Chasman, DI O'Connel, JR Corre, T Nongmaithem, SS Chen, Y Mangino, M Ruggiero, D Michela, T Farmaki, AE Kacprowski, T Bjonnes, A van der Spek, A Wu, Y Giri, AK Yanek, LR Wang, LH Hofer, E Rietveld, CA McLeod, O Cornelis, MC Pattaro, C Verweij, N Baumbach, C Abdellaoui, A Warren, HR Vuckovic, D Mei, H Bouchard, C Perry, JRB Cappellani, S Mirza, SS Benton, MC Broeckel, U Medland, SE Lind, P Malerba, G Drong, A Yengo, L Bielak, LF Zhi, DG van der Most, PJ Shriner, D Magi, R Hemani, G Karaderi, T Wang, ZM Liu, T Demuth, I Zhao, JH Meng, WH Lataniotis, L van der Laan, SW Bradfield, JP Wood, AR Bonnefond, A Ahluwalia, TS Hall, L Salvi, E Yazar, S Carstensen, L de Haan, HG Abney, M Afzal, U Allison, MA Amin, N Asselbergs, FW Bakker, SJL Barr, RG Baumeister, SE Benjamin, DJ Bergmann, S Boerwinkle, E Bottinger, EP Campbell, A Chakravarti, A Chan, YL Chanock, SJ Chen, C Chen, YDI Collins, FS Connell, J Correa, A Cupples, LA Smith, GD Davies, G Dorr, M Ehret, G Ellis, SB Feenstra, B Feitosa, MF Ford, I Fox, CS Frayling, TM Friedrich, N Geller, F Scotland, G Gillham-Nasenya, I Gottesman, O Graff, M Grodstein, F Gu, C Haley, C Hammond, CJ Harris, SE Harris, TB Hastie, ND Heard-Costa, NL Heikkila, K Hocking, LJ Homuth, G Hottenga, JJ Huang, JY Huffman, JE Hysi, PG Ikram, MA Ingelsson, E Joensuu, A Johansson, A Jousilahti, P Jukema, JW Kahonen, M Kamatani, Y Kanoni, S Kerr, SM Khan, NM Koellinger, P Koistinen, HA Kooner, MK Kubo, M Kuusisto, J Lahti, J Launer, LJ Lea, RA Lehne, B Lehtimaki, T Liewald, DCM Lind, L Loh, M Lokki, ML London, SJ Loomis, SJ Loukola, A Lu, YC Lumley, T Lundqvist, A Mannisto, S Marques-Vidal, P Masciullo, C Matchan, A Mathias, RA Matsuda, K Meigs, JB Meisinger, C Meitinger, T Menni, C Mentch, FD Mihailov, E Milani, L Montasser, ME Montgomery, G Morrison, A Myers, RH Nadukuru, R Navarro, P Nelis, M Nieminen, MS Nolte, IM O'Connor, GT Ogunniyi, A Padmanabhan, S Palmas, WR Pankow, JS Patarcic, I Pavani, F Peyser, PA Pietilainen, K Poulter, N Prokopenko, I Ralhan, S Redmond, P Rich, SS Rissanen, H Robino, A Rose, LM Rose, R Sala, C Salako, B Salomaa, V Sarin, AP Saxena, R Schmidt, H Scott, LJ Scott, WR Sennblad, B Seshadri, S Sever, P Shrestha, S Smith, BH Smith, JA Soranzo, N Sotoodehnia, N Southam, L Stanton, AV Stathopoulou, MG Strauch, K Strawbridge, RJ Suderman, MJ Tandon, N Tang, ST Taylor, KD Tayo, BO Toglhofer, AM Tomaszewski, M Tsernikova, N Tuomilehto, J Uitterlinden, AG Vaidya, D Vlieg, AV van Setten, J Vasankari, T Vedantam, S Vlachopoulou, E Vozzi, D Vuoksimaa, E Waldenberger, M Ware, EB Wentworth-Shields, W Whitfield, JB Wild, S Willemsen, G Yajnik, CS Yao, J Zaza, G Zhu, XF Salem, RM Melbye, M Bisgaard, H Samani, NJ Cusi, D Mackey, DA Cooper, RS Froguel, P Pasterkamp, G Grant, SFA Hakonarson, H Ferrucci, L Scott, RA Morris, AD Palmer, CNA Dedoussis, G Deloukas, P Bertram, L Lindenberger, U Berndt, SI Lindgren, CM Timpson, NJ Tonjes, A Munroe, PB Sorensen, TIA Rotimi, CN Arnett, DK Oldehinkel, AJ Kardia, SLR Balkau, B Gambaro, G Morris, AP Eriksson, JG Wright, MJ Martin, NG Hunt, SC Starr, JM Deary, IJ Griffiths, LR Tiemeier, H Pirastu, N Kaprio, J Wareham, NJ Peerusse, L Wilson, JG Girotto, G Caulfield, MJ Raitakari, O Boomsma, DI Gieger, C van der Harst, P Hicks, AA Kraft, P Sinisalo, J Knekt, P Johannesson, M Magnusson, PKE Hamsten, A Schmidt, R Borecki, IB Vartiainen, E Becker, DM Bharadwaj, D Mohlke, KL Boehnke, M van Duijn, CM Sanghera, DK Teumer, A Zeggini, E Metspalu, A Gasparini, P Ulivi, S Ober, C Toniolo, D Rudan, I Porteous, DJ Ciullo, M Spector, TD Hayward, C Dupuis, J Loos, RJF Wright, AF Chandak, GR Vollenweider, P Shuldiner, AR Ridker, PM Rotter, JI Sattar, N Gyllensten, U North, KE Pirastu, M Psaty, BM Weir, DR Laakso, M Gudnason, V Takahashi, A Chambers, JC Kooner, JS Strachan, DP Campbell, H Hirschhorn, JN Perola, M Polasek, O Wilson, JF AF Joshi, Peter K. Esko, Tonu Mattsson, Hannele Eklund, Niina Gandin, Ilaria Nutile, Teresa Jackson, Anne U. Schurmann, Claudia Smith, Albert V. Zhang, Weihua Okada, Yukinori Stancakova, Alena Faul, Jessica D. Zhao, Wei Bartz, Traci M. Concas, Maria Pina Franceschini, Nora Enroth, Stefan Vitart, Veronique Trompet, Stella Guo, Xiuqing Chasman, Daniel I. O'Connel, Jeffrey R. Corre, Tanguy Nongmaithem, Suraj S. Chen, Yuning Mangino, Massimo Ruggiero, Daniela Traglia, Michela Farmaki, Aliki-Eleni Kacprowski, Tim Bjonnes, Andrew van der Spek, Ashley Wu, Ying Giri, Anil K. Yanek, Lisa R. Wang, Lihua Hofer, Edith Rietveld, Cornelius A. McLeod, Olga Cornelis, Marilyn C. Pattaro, Cristian Verweij, Niek Baumbach, Clemens Abdellaoui, Abdel Warren, Helen R. Vuckovic, Dragana Mei, Hao Bouchard, Claude Perry, John R. B. Cappellani, Stefania Mirza, Saira S. Benton, Miles C. Broeckel, Ulrich Medland, Sarah E. Lind, PenelopeA. Malerba, Giovanni Drong, Alexander Yengo, Loic Bielak, Lawrence F. Zhi, Degui van der Most, Peter J. Shriner, Daniel Maegi, Reedik Hemani, Gibran Karaderi, Tugce Wang, Zhaoming Liu, Tian Demuth, Ilja Zhao, Jing Hua Meng, Weihua Lataniotis, Lazaros van der Laan, Sander W. Bradfield, Jonathan P. Wood, Andrew R. Bonnefond, Amelie Ahluwalia, Tarunveer S. Hall, LeanneM. Salvi, Erika Yazar, Seyhan Carstensen, Lisbeth de Haan, Hugoline G. Abney, Mark Afzal, Uzma Allison, Matthew A. Amin, Najaf Asselbergs, Folkert W. Bakker, Stephan J. L. Barr, R. Graham Baumeister, Sebastian E. Benjamin, Daniel J. Bergmann, Sven Boerwinkle, Eric Bottinger, Erwin P. Campbell, Archie Chakravarti, Aravinda Chan, Yingleong Chanock, Stephen J. Chen, Constance Chen, Y. -D. Ida Collins, Francis S. Connell, John Correa, Adolfo Cupples, L. Adrienne Smith, George Davey Davies, Gail Doerr, Marcus Ehret, Georg Ellis, Stephen B. Feenstra, Bjarke Feitosa, Mary F. Ford, Ian Fox, Caroline S. Frayling, Timothy M. Friedrich, Nele Geller, Frank Scotland, Generation Gillham-Nasenya, Irina Gottesman, Omri Graff, Misa Grodstein, Francine Gu, Charles Haley, Chris Hammond, Christopher J. Harris, Sarah E. Harris, Tamara B. Hastie, Nicholas D. Heard-Costa, Nancy L. Heikkila, Kauko Hocking, Lynne J. Homuth, Georg Hottenga, Jouke-Jan Huang, Jinyan Huffman, Jennifer E. Hysi, Pirro G. Ikram, M. Arfan Ingelsson, Erik Joensuu, Anni Johansson, Asa Jousilahti, Pekka Jukema, J. Wouter Kahonen, Mika Kamatani, Yoichiro Kanoni, Stavroula Kerr, Shona M. Khan, Nazir M. Koellinger, Philipp Koistinen, Heikki A. Kooner, Manraj K. Kubo, Michiaki Kuusisto, Johanna Lahti, Jari Launer, Lenore J. Lea, Rodney A. Lehne, Benjamin Lehtimaki, Terho Liewald, David C. M. Lind, Lars Loh, Marie Lokki, Marja-Liisa London, Stephanie J. Loomis, Stephanie J. Loukola, Anu Lu, Yingchang Lumley, Thomas Lundqvist, Annamari Mannisto, Satu Marques-Vidal, Pedro Masciullo, Corrado Matchan, Angela Mathias, Rasika A. Matsuda, Koichi Meigs, James B. Meisinger, Christa Meitinger, Thomas Menni, Cristina Mentch, Frank D. Mihailov, Evelin Milani, Lili Montasser, May E. Montgomery, GrantW. Morrison, Alanna Myers, Richard H. Nadukuru, Rajiv Navarro, Pau Nelis, Mari Nieminen, Markku S. Nolte, Ilja M. O'Connor, George T. Ogunniyi, Adesola Padmanabhan, Sandosh Palmas, Walter R. Pankow, James S. Patarcic, Inga Pavani, Francesca Peyser, Patricia A. Pietilainen, Kirsi Poulter, Neil Prokopenko, Inga Ralhan, Sarju Redmond, Paul Rich, Stephen S. Rissanen, Harri Robino, Antonietta Rose, Lynda M. Rose, Richard Sala, Cinzia Salako, Babatunde Salomaa, Veikko Sarin, Antti-Pekka Saxena, Richa Schmidt, Helena Scott, Laura J. Scott, William R. Sennblad, Bengt Seshadri, Sudha Sever, Peter Shrestha, Smeeta Smith, Blair H. Smith, Jennifer A. Soranzo, Nicole Sotoodehnia, Nona Southam, Lorraine Stanton, Alice V. Stathopoulou, Maria G. Strauch, Konstantin Strawbridge, Rona J. Suderman, Matthew J. Tandon, Nikhil Tang, Sian-Tsun Taylor, Kent D. Tayo, Bamidele O. Toeglhofer, Anna Maria Tomaszewski, Maciej Tsernikova, Natalia Tuomilehto, Jaakko Uitterlinden, Andre G. Vaidya, Dhananjay Vlieg, Astrid van Hylckama van Setten, Jessica Vasankari, Tuula Vedantam, Sailaja Vlachopoulou, Efthymia Vozzi, Diego Vuoksimaa, Eero Waldenberger, Melanie Ware, Erin B. Wentworth-Shields, William Whitfield, John B. Wild, Sarah Willemsen, Gonneke Yajnik, Chittaranjan S. Yao, Jie Zaza, Gianluigi Zhu, Xiaofeng Salem, Rany M. Melbye, Mads Bisgaard, Hans Samani, Nilesh J. Cusi, Daniele Mackey, David A. Cooper, Richard S. Froguel, Philippe Pasterkamp, Gerard Grant, Struan F. A. Hakonarson, Hakon Ferrucci, Luigi Scott, Robert A. Morris, Andrew D. Palmer, Colin N. A. Dedoussis, George Deloukas, Panos Bertram, Lars Lindenberger, Ulman Berndt, Sonja I. Lindgren, Cecilia M. Timpson, Nicholas J. Toenjes, Anke Munroe, Patricia B. Sorensen, Thorkild I. A. Rotimi, Charles N. Arnett, Donna K. Oldehinkel, Albertine J. Kardia, Sharon L. R. Balkau, Beverley Gambaro, Giovanni Morris, Andrew P. Eriksson, Johan G. Wright, Margie J. Martin, Nicholas G. Hunt, Steven C. Starr, John M. Deary, Ian J. Griffiths, Lyn R. Tiemeier, Henning Pirastu, Nicola Kaprio, Jaakko Wareham, Nicholas J. Perusse, Louis Wilson, James G. Girotto, Giorgia Caulfield, Mark J. Raitakari, Olli Boomsma, Dorret I. Gieger, Christian van der Harst, Pim Hicks, Andrew A. Kraft, Peter Sinisalo, Juha Knekt, Paul Johannesson, Magnus Magnusson, Patrik K. E. Hamsten, Anders Schmidt, Reinhold Borecki, Ingrid B. Vartiainen, Erkki Becker, Diane M. Bharadwaj, Dwaipayan Mohlke, Karen L. Boehnke, Michael van Duijn, Cornelia M. Sanghera, Dharambir K. Teumer, Alexander Zeggini, Eleftheria Metspalu, Andres Gasparini, Paolo Ulivi, Sheila Ober, Carole Toniolo, Daniela Rudan, Igor Porteous, David J. Ciullo, Marina Spector, Tim D. Hayward, Caroline Dupuis, Josee Loos, Ruth J. F. Wright, Alan F. Chandak, Giriraj R. Vollenweider, Peter Shuldiner, Alan R. Ridker, Paul M. Rotter, Jerome I. Sattar, Naveed Gyllensten, Ulf North, Kari E. Pirastu, Mario Psaty, Bruce M. Weir, David R. Laakso, Markku Gudnason, Vilmundur Takahashi, Atsushi Chambers, John C. Kooner, Jaspal S. Strachan, David P. Campbell, Harry Hirschhorn, Joel N. Perola, Markus Polasek, Ozren Wilson, James F. CA BioBank Japan Project TI Directional dominance on stature and cognition in diverse human populations SO NATURE LA English DT Article ID GENETIC-VARIANTS; INBREEDING DEPRESSION; ASSOCIATION ANALYSIS; QUANTITATIVE TRAITS; BLOOD-PRESSURE; INTELLIGENCE; HOMOZYGOSITY; ARCHITECTURE; PATHWAYS; DISEASE AB Homozygosity has long been associated with rare, often devastating, Mendelian disorders(1), and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness(2). However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power(3,4). Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples(5,6), no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection(7), this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been. C1 [Joshi, Peter K.; Rudan, Igor; Campbell, Harry; Polasek, Ozren; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh EH8 9AG, Midlothian, Scotland. [Esko, Tonu; Maegi, Reedik; Mihailov, Evelin; Milani, Lili; Nelis, Mari; Tsernikova, Natalia; Morris, Andrew P.; Metspalu, Andres; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Esko, Tonu; Chan, Yingleong; Vedantam, Sailaja; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Cambridge, MA 02141 USA. [Esko, Tonu; Chan, Yingleong; Vedantam, Sailaja; Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Cambridge, MA 02141 USA. [Esko, Tonu; Chan, Yingleong; Vedantam, Sailaja; Salem, Rany M.; Lindgren, Cecilia M.; Hirschhorn, Joel N.] Cambridge Ctr 7, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02242 USA. [Esko, Tonu; Chan, Yingleong; Vedantam, Sailaja; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Mattsson, Hannele; Eklund, Niina; Joensuu, Anni; Sarin, Antti-Pekka; Perola, Markus] Natl Inst Hlth & Welf, Unit Publ Hlth Genom, FI-00251 Helsinki, Finland. [Mattsson, Hannele; Joensuu, Anni; Pietilainen, Kirsi; Sarin, Antti-Pekka; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland. [Gandin, Ilaria; Vuckovic, Dragana; Pirastu, Nicola; Girotto, Giorgia] Univ Trieste, Dept Med Sci, I-34149 Trieste, Italy. [Nutile, Teresa; Ruggiero, Daniela; Ciullo, Marina] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80131 Naples, Italy. [Jackson, Anne U.; Scott, Laura J.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Jackson, Anne U.; Scott, Laura J.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Schurmann, Claudia; Bottinger, Erwin P.; Ellis, Stephen B.; Gottesman, Omri; Lu, Yingchang; Nadukuru, Rajiv; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schurmann, Claudia; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Zhang, Weihua; Afzal, Uzma; Lehne, Benjamin; Loh, Marie; Scott, William R.; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Zhang, Weihua; Afzal, Uzma; Kooner, Manraj K.; Scott, William R.; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Dept Cardiol, Southall UB1 3HW, Middx, England. [Okada, Yukinori] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Bunkyo Ku, Tokyo 1138510, Japan. [Okada, Yukinori; Kamatani, Yoichiro; Takahashi, Atsushi; BioBank Japan Project] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Stancakova, Alena] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48104 USA. [Zhao, Wei; Bielak, Lawrence F.; Peyser, Patricia A.; Smith, Jennifer A.; Ware, Erin B.; Kardia, Sharon L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Bartz, Traci M.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Concas, Maria Pina; Pirastu, Mario] CNR, Inst Populat Genet, I-07100 Sassari, Italy. [Franceschini, Nora; Graff, Misa; North, Kari E.] Univ N Carolina, Epidemiol, Chapel Hill, NC 27599 USA. [Enroth, Stefan; Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol Genet & Pathol, Biomed Ctr, SciLifeLab Uppsala, SE-75108 Uppsala, Sweden. [Vitart, Veronique; Haley, Chris; Hastie, Nicholas D.; Huffman, Jennifer E.; Kerr, Shona M.; Navarro, Pau; Hayward, Caroline; Wright, Alan F.; Wilson, James F.] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Trompet, Stella] Leiden Univ, Dept Gerontol & Geriatr, Med Ctr, NL-2300 RC Leiden, Netherlands. [Guo, Xiuqing; Chen, Y. -D. Ida; Taylor, Kent D.; Yao, Jie; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Gen & Populat Sci, Torrance, CA 90502 USA. [Guo, Xiuqing; Chen, Y. -D. Ida; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Harvard Univ, Brigham & Womens Hosp, Div Prevent Med, Sch Med, Boston, MA 02215 USA. [O'Connel, Jeffrey R.; Montasser, May E.; Shuldiner, Alan R.] Univ Maryland, Div Endocrinol Diabet & Nutr, Sch Med, Baltimore, MD 21201 USA. [O'Connel, Jeffrey R.; Montasser, May E.; Shuldiner, Alan R.] Univ Maryland, Program Personalised & Genom Med, Dept Med, Sch Med, Baltimore, MD 21201 USA. [Corre, Tanguy; Bergmann, Sven] Univ Lausanne, Dept Med Genet, CH-1005 Lausanne, Switzerland. [Corre, Tanguy; Bergmann, Sven] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Nongmaithem, Suraj S.; Shrestha, Smeeta; Chandak, Giriraj R.] CSIR Ctr Cellular & Mol Biol, Genom Res Complex Dis GRC Grp, Hyderabad 500007, Andhra Pradesh, India. [Chen, Yuning; Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Mangino, Massimo; Gillham-Nasenya, Irina; Hammond, Christopher J.; Hysi, Pirro G.; Menni, Cristina; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Mangino, Massimo] Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London SE1 7EH, England. [Traglia, Michela; Masciullo, Corrado; Sala, Cinzia; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Farmaki, Aliki-Eleni; Dedoussis, George] Harokopio Univ Athens, Dept Nutr & Dietet, Athens 17671, Greece. [Kacprowski, Tim; Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Bjonnes, Andrew; Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [van der Spek, Ashley; Mirza, Saira S.; Amin, Najaf; Ikram, M. Arfan; Uitterlinden, Andre G.; Tiemeier, Henning; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Giri, Anil K.; Khan, Nazir M.; Bharadwaj, Dwaipayan] CSIR Inst Genom & Integrat Biol, Genom & Mol Med, New Delhi 110025, India. [Yanek, Lisa R.; Mathias, Rasika A.; Vaidya, Dhananjay; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program,Div Gen Internal Med, Baltimore, MD 21287 USA. [Wang, Lihua; Feitosa, Mary F.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63108 USA. [Hofer, Edith; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria. [Rietveld, Cornelius A.; Koellinger, Philipp] Erasmus Univ, Erasmus Sch Econ, NL-3000 DR Rotterdam, Netherlands. [McLeod, Olga; Sennblad, Bengt; Strawbridge, Rona J.; Hamsten, Anders] Karolinska Univ Hosp, Atherosclerosis Res Unit, Dept Med Solna, Karolinska Inst, S-17176 Stockholm, Sweden. [Cornelis, Marilyn C.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Cornelis, Marilyn C.; Grodstein, Francine] Harvard Univ, Sch Publ Hlth, Nutr, Boston, MA 02215 USA. [Pattaro, Cristian; Pavani, Francesca; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Baumbach, Clemens; Waldenberger, Melanie; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Baumbach, Clemens; Meisinger, Christa; Waldenberger, Melanie; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Baumbach, Clemens; Strauch, Konstantin; Gieger, Christian] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany. [Abdellaoui, Abdel; Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Warren, Helen R.; Munroe, Patricia B.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England. [Warren, Helen R.; Munroe, Patricia B.; Caulfield, Mark J.] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Mei, Hao; Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Bouchard, Claude] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Perry, John R. B.; Zhao, Jing Hua; Scott, Robert A.; Wareham, Nicholas J.] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Cappellani, Stefania; Robino, Antonietta; Vozzi, Diego; Pirastu, Nicola; Gasparini, Paolo; Ulivi, Sheila] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, I-34137 Trieste, Italy. [Benton, Miles C.; Lea, Rodney A.; Griffiths, Lyn R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Broeckel, Ulrich] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Medland, Sarah E.; Lind, PenelopeA.] QIMR Berghofer Med Res Inst, Quantitat Genet, Brisbane, Qld 4006, Australia. [Malerba, Giovanni] Univ Verona, Dipartimento Sci Vita & Riprod, I-37134 Verona, Italy. [Drong, Alexander; Karaderi, Tugce; Ingelsson, Erik; Southam, Lorraine; Lindgren, Cecilia M.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Yengo, Loic; Bonnefond, Amelie; Froguel, Philippe] Univ Lille 2, EGID, CNRS, UMR 199, F-59000 Lille, France. [Zhi, Degui] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [van der Most, Peter J.; Nolte, Ilja M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Shriner, Daniel; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Hemani, Gibran; Smith, George Davey; Suderman, Matthew J.; Timpson, Nicholas J.; Sorensen, Thorkild I. A.] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Wang, Zhaoming; Chanock, Stephen J.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Wang, Zhaoming] SAIC Frederick Inc, Canc Genom Res Lab, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Liu, Tian; Lindenberger, Ulman] Max Planck Inst Human Dev, Ctr Lifespan Psychol, D-14195 Berlin, Germany. [Liu, Tian; Bertram, Lars] Max Planck Inst Mol Genet, Vertebrate Genom, D-14195 Berlin, Germany. [Demuth, Ilja] Charite, Charite Res Grp Geriatr, D-13347 Berlin, Germany. [Demuth, Ilja] Charite, Inst Med & Human Genet, D-13353 Berlin, Germany. [Meng, Weihua] Univ Dundee, Div Populat Hlth Sci, Med Res Inst, Ninewells Hosp & Sch Med, Dundee DD2 4BF, Scotland. [Lataniotis, Lazaros; Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [van der Laan, Sander W.; van Setten, Jessica; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Heart & Lungs, Expt Cardiol, NL-3584 CX Utrecht, Netherlands. [Bradfield, Jonathan P.; Mentch, Frank D.; Grant, Struan F. A.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Wood, Andrew R.; Frayling, Timothy M.] Univ Exeter, Genet Complex Traits, Sch Med, Royal Devon & Exeter Hosp, Exeter EX2 5DW, Devon, England. [Ahluwalia, Tarunveer S.; Bisgaard, Hans] Univ Copenhagen, COPSAC, Prospect Studies Asthma Childhood, Herlev & Gentofte Hosp, DK-2820 Copenhagen, Denmark. [Ahluwalia, Tarunveer S.; Sorensen, Thorkild I. A.] Univ Copenhagen, Sect Metab Genet, Fac Hlth & Med Sci, Novo Nordisk Ctr Basic Metab Res, DK-2100 Copenhagen, Denmark. [Hall, LeanneM.; Tomaszewski, Maciej; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Salvi, Erika; Cusi, Daniele] Univ Milan, Dept Hlth Sci, I-20142 Milan, Italy. [Yazar, Seyhan; Mackey, David A.] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Carstensen, Lisbeth; Feenstra, Bjarke; Geller, Frank; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [de Haan, Hugoline G.; Vlieg, Astrid van Hylckama] Leiden Univ, Med Ctr, Clin Epidemiol, NL-2300 RC Leiden, Netherlands. [Abney, Mark; Wentworth-Shields, William; Ober, Carole] Univ Chicago, Dept HumanGenet, Chicago, IL 60637 USA. [Allison, Matthew A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, NL-3584 CX Utrecht, Netherlands. [Asselbergs, Folkert W.; van der Harst, Pim] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth, Inst Cardiovasc Sci, London WC1E 6BT, England. [Bakker, Stephan J. L.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands. [Barr, R. Graham; Palmas, Walter R.] Columbia Univ, Dept Med, New York, NY 10032 USA. [Baumeister, Sebastian E.; Teumer, Alexander] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Benjamin, Daniel J.] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Benjamin, Daniel J.] Univ So Calif, Dept Econ, Los Angeles, CA 90089 USA. [Benjamin, Daniel J.] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA. [Boerwinkle, Eric; Morrison, Alanna] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Campbell, Archie; Scotland, Generation; Harris, Sarah E.; Porteous, David J.] Univ Edinburgh, Western Gen Hosp, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Chakravarti, Aravinda; Ehret, Georg] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA. [Chen, Constance; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Connell, John] Ninewells Hosp & Med Sch, Coll Med Dent & Nursing, Dundee DD1 9SY, Scotland. [Cupples, L. Adrienne; Fox, Caroline S.; Heard-Costa, Nancy L.; O'Connor, George T.; Seshadri, Sudha; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Davies, Gail; Redmond, Paul; Deary, Ian J.] Univ Edinburgh, Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Davies, Gail; Harris, Sarah E.; Liewald, David C. M.; Starr, John M.; Deary, Ian J.; Porteous, David J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany. [Ehret, Georg] Univ Hosp Geneva, Cardiol, CH-1211 Geneva, Switzerland. [Ford, Ian] Univ Glasgow, Robertson Ctr, Glasgow G12 8QQ, Lanark, Scotland. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Friedrich, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Gu, Charles] Washington Univ, Div Biostat, St Louis, MO 63110 USA. [Haley, Chris] Univ Edinburgh, Roslin Inst, Edinburgh EH25 9RG, Midlothian, Scotland. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Heard-Costa, Nancy L.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Heikkila, Kauko; Loukola, Anu; Vuoksimaa, Eero; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, FI-00014 Helsinki, Finland. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen AB25 2ZD, Scotland. [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Hematol, State Key Lab Med Genom,Rui Jin Hosp, Shanghai 200025, Peoples R China. [Ikram, M. Arfan] Erasmus MC, Dept Radiol, NL-3000 CA Rotterdam, Netherlands. [Ingelsson, Erik] Uppsala Univ, Mol Epidemiol & Sci Life Lab, Dept Med Sci, SE-17121 Uppsala, Sweden. [Johansson, Asa] Uppsala Univ, Uppsala Clin Res Ctr, SE-75237 Uppsala, Sweden. [Jousilahti, Pekka; Mannisto, Satu; Salomaa, Veikko; Eriksson, Johan G.; Vartiainen, Erkki] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol C5 P, NL-2300 RC Leiden, Netherlands. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, FI-33521 Tampere, Finland. [Kahonen, Mika] Tampere Univ Hosp, FI-33521 Tampere, Finland. [Koistinen, Heikki A.; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, FI-00271 Helsinki, Finland. [Koistinen, Heikki A.; Pietilainen, Kirsi] Univ Helsinki, Cent Hosp, Div Endocrinol, Dept Med, FI-00029 Helsinki, Finland. [Koistinen, Heikki A.] Biomedicum 2U, Minerva Fdn Inst Med Res, FI-00290 Helsinki, Finland. [Kubo, Michiaki] Lab Genotyping Dev RCfIMS, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Laakso, Markku] Univ Eastern Finland, Dept Med, FI-70210 Kuopio, Finland. [Laakso, Markku] Kuopio Univ Hosp, FI-70210 Kuopio, Finland. [Kuusisto, Johanna; Lahti, Jari] Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland. [Lahti, Jari] Univ Helsinki, Folkhalsan Reasearch Ctr, FI-00014 Helsinki, Finland. [Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Lind, Lars] Univ Hosp, Dept Med Sci, S-75185 Uppsala, Sweden. [Lokki, Marja-Liisa; Vlachopoulou, Efthymia] Univ Helsinki, Haartman Inst, Transplantat Lab, FI-00014 Helsinki, Finland. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Loomis, Stephanie J.] Massachusetts Eye & Ear, Ophthalmol, Boston, MA 02114 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1142, New Zealand. [Lundqvist, Annamari; Rissanen, Harri; Knekt, Paul] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, FI-00271 Helsinki, Finland. [Marques-Vidal, Pedro; Vollenweider, Peter] Univ Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Matchan, Angela; Soranzo, Nicole; Southam, Lorraine; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Human Genet, Cambridge CB10 1HH, England. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21224 USA. [Matsuda, Koichi] Univ Tokyo, Lab Mol Med, Ctr Human Genome, Inst Med Sci,Minato Ku, Tokyo 1088639, Japan. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Meitinger, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Klinikum Rechts Isar, D-81675 Munich, Germany. [Montgomery, GrantW.] QIMR Berghofer Med Res Inst, Mol Epidemiol, Brisbane, Qld 4006, Australia. [Myers, Richard H.] Boston Univ, Sch Med, Genome Sci Inst, Boston, MA 02118 USA. [Nieminen, Markku S.; Sinisalo, Juha] Univ Helsinki, Cent Hosp, HUCH Heart & Lung Ctr, FI-00029 Helsinki, Finland. [O'Connor, George T.] Boston Univ, Sch Med, Pulm Ctr, Boston, MA 02118 USA. [O'Connor, George T.] Boston Univ, Dept Med, Boston, MA 02118 USA. [Ogunniyi, Adesola; Salako, Babatunde] Univ Ibadan, Dept Med, Ibadan, Nigeria. [Padmanabhan, Sandosh] Univ Glasgow, ICAMS, Glasgow G12 8TA, Lanark, Scotland. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Patarcic, Inga; Polasek, Ozren] Univ Split, Ctr Global Hlth, Split 21000, Croatia. [Patarcic, Inga; Polasek, Ozren] Univ Split, Dept Publ Hlth, Sch Med, Split 21000, Croatia. [Pietilainen, Kirsi] Univ Helsinki, Obes Res Unit, Res Programs Unit, Diabet & Obes, FI-00014 Helsinki, Finland. [Poulter, Neil; Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London W2 1LA, England. [Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London SW7 2AZ, England. [Ralhan, Sarju] Hero DMC Heart Inst, Dept Cardiol & Cardio Thorac Surg, Civil Lines, Ludhiana 141001, Punjab, India. [Rich, Stephen S.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Rose, Richard] Indiana Univ Bloomington, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. [Schmidt, Helena; Toeglhofer, Anna Maria] Med Univ Graz, Inst Mol Biol & Biochem, A-8010 Graz, Austria. [Sennblad, Bengt] Karolinska Inst, Sci Life Lab, SE-17121 Stockholm, Sweden. [Smith, Blair H.] Univ Dundee, Dundee DD2 4DB, Scotland. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Stanton, Alice V.] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin 2, Ireland. [Stathopoulou, Maria G.] UMR INSERM U1122, F-54000 Nancy, France. [Stathopoulou, Maria G.] Univ Lorraine, INSERM, IGE PCV Interact Geneenvironm Physiopathol Cardio, F-54000 Nancy, France. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Tandon, Nikhil] All India Inst Med Sci, Dept Endocrinol, New Delhi 110029, India. ImpColl London, Natl Heart & Lung Inst, London W12 0NN, England. [Tang, Sian-Tsun; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA. [Tomaszewski, Maciej; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Tsernikova, Natalia; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Res Grp, Jeddah 21589, Saudi Arabia. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Vaidya, Dhananjay] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Vasankari, Tuula] Finnish Lung Hlth Assoc, FI-00250 Helsinki, Finland. [Whitfield, John B.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4006, Australia. [Yajnik, Chittaranjan S.] KEM Hosp & Res Ctr, Diabet Unit, Pune 411011, Maharashtra, India. [Zaza, Gianluigi] Univ Verona, Dept Med, Renal Unit, I-37124 Verona, Italy. [Zhu, Xiaofeng] CaseWestern Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Melbye, Mads] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Morris, Andrew D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH16 4UX, Midlothian, Scotland. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Sch Med, Med Res Inst, Ctr Pharmacogenet & Pharmacogen, Dundee DD1 9SY, Scotland. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Bertram, Lars] Univ London Imperial Coll Sci Technol & Med, Fac Med, London W6 8RP, England. [Toenjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Copenhagen, Denmark. [Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Balkau, Beverley] INSERM, Epidemiol Diabet Obes & Chron Kidney Dis Lifecour, CESP Ctr Res Epidemiol & Populat Hlth, U1018, F-94807 Villejuif, France. [Gambaro, Giovanni] Univ Cattolica Sacro Cuore, Dipartimento Sci Med, I-00168 Rome, Italy. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00014 Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, FI-65130 Vaasa, Finland. [Eriksson, Johan G.] Univ Helsinki, Folkhalsan Reasearch Ctr, FI-00014 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FI-00290 Helsinki, Finland. [Wright, Margie J.] QIMR Berghofer Med Res Inst, Neuroimaging Genet, Brisbane, Qld 4006, Australia. [Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Salt Lake City, UT 84117 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Tiemeier, Henning] Erasmus MC, Dept Psychiat, NL-3000 CA Rotterdam, Netherlands. [Kaprio, Jaakko] Natl Inst Hlth & Welf THL, FI-00271 Helsinki, Finland. [Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ 2300, Canada. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Raitakari, Olli] Univ Turku, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, FI-20521 Turku, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20521 Turku, Finland. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet & Biostat, St Louis, MO 63108 USA. [Becker, Diane M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73104 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pharmaceut Sci, Oklahoma City, OK 73104 USA. [Gasparini, Paolo] Sidra Med & Res Ctr, Doha, Qatar. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Chandak, Giriraj R.] Genome Inst Singapore, Singapore 138672, Singapore. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Sattar, Naveed] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Chambers, John C.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Healthcare NHS Trust, London W2 1NY, England. [Strachan, David P.] Univ London, Populat Hlth Res Inst, London SW17 0RE, England. [Ahluwalia, Tarunveer S.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Loh, Marie] ASTAR, Translat Lab Genet Med TLGM, Singapore 138648, Singapore. [Wild, Sarah] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Bertram, Lars] Med Univ Lubeck, Inst Neurogenet, D-23562 Lubeck, Germany. [Bertram, Lars] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany. [Bharadwaj, Dwaipayan] Jawaharlal Nehru Univ, Sch Biotechnol, New Delhi 110067, India. RP Joshi, PK (reprint author), Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. RI Padmanabhan, Sandosh/S-3963-2016; Bisgaard, Hans/N-4761-2016; van Hylckama Vlieg, Astrid/A-3323-2017; Verweij, Niek/A-4499-2017; Magnusson, Patrik/C-4458-2017; Yengo, Loic/D-2692-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Colaus, PsyColaus/K-6607-2013; Bertram, Lars/K-3889-2015; Stathopoulou, Maria/H-7324-2016; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; Kubo, Michiaki/N-7947-2015; ruggiero, daniela/K-5638-2016; Schurmann, Claudia/L-1204-2016; Deloukas, Panos/B-2922-2013; Mackey, David/H-5340-2014; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Kacprowski, Tim/K-8650-2013; Kamatani, Yoichiro/N-5513-2015; Montgomery, Grant/B-7148-2008; Waldenberger, Melanie/B-5355-2014; Johannesson, Magnus/E-9680-2011; Fox, Laura /C-6249-2016; Gudnason, Vilmundur/K-6885-2015; Enroth, Stefan/C-7396-2009; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Palmer, Colin/C-7053-2008; Meitinger, Thomas/O-1318-2015; Marques-Vidal, Pedro/C-9449-2009; Wright, Margaret/A-4560-2016; OI Zeggini, Eleftheria/0000-0003-4238-659X; Verweij, Niek/0000-0002-4303-7685; Meisinger, Christa/0000-0002-9026-6544; Benton, Miles/0000-0003-3442-965X; Salvi, Erika/0000-0002-2724-2291; vozzi, diego/0000-0002-2902-8184; Girotto, Giorgia/0000-0003-4507-6589; Timpson, Nicholas/0000-0002-7141-9189; Navarro, Pau/0000-0001-5576-8584; Allison, Matthew/0000-0003-0777-8272; Strawbridge, Rona/0000-0001-8506-3585; Eriksson, Johan/0000-0002-2516-2060; Smith, Blair/0000-0002-5362-9430; Zaza, Gianluigi/0000-0002-6004-6196; Kaprio, Jaakko/0000-0002-3716-2455; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Kerr, Shona/0000-0002-4137-1495; Medland, Sarah/0000-0003-1382-380X; Padmanabhan, Sandosh/0000-0003-3869-5808; Gieger, Christian/0000-0001-6986-9554; NUTILE, TERESA/0000-0001-7062-8352; Loukola, Anu-Maria/0000-0003-0542-5967; van der Laan, Sander W./0000-0001-6888-1404; Soranzo, Nicole/0000-0003-1095-3852; Koistinen, Heikki/0000-0001-7870-070X; Bisgaard, Hans/0000-0003-4131-7592; Yengo, Loic/0000-0002-4272-9305; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Malerba, Giovanni/0000-0001-8705-8560; Menni, Cristina/0000-0001-9790-0571; Bertram, Lars/0000-0002-0108-124X; Stathopoulou, Maria/0000-0003-4376-2083; Smith, Albert/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; Schurmann, Claudia/0000-0003-4158-9192; Deloukas, Panos/0000-0001-9251-070X; Mackey, David/0000-0001-7914-4709; mangino, massimo/0000-0002-2167-7470; Kacprowski, Tim/0000-0002-5393-2413; Montgomery, Grant/0000-0002-4140-8139; Waldenberger, Melanie/0000-0003-0583-5093; Johannesson, Magnus/0000-0001-8759-6393; Gudnason, Vilmundur/0000-0001-5696-0084; Enroth, Stefan/0000-0002-5056-9137; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Palmer, Colin/0000-0002-6415-6560; Marques-Vidal, Pedro/0000-0002-4548-8500; Wright, Margaret/0000-0001-7133-4970; Johansson, Asa/0000-0002-2915-4498; Pankow, James/0000-0001-7076-483X; Griffiths, Lyn/0000-0002-6774-5475; Ware, Erin/0000-0003-4731-8158; Sinisalo, Juha/0000-0002-0169-5137; Lahti, Jari/0000-0002-4310-5297; Vuckovic, Dragana/0000-0001-9343-6142; London, Stephanie/0000-0003-4911-5290 FU UK Medical Research Council (MRC); MRC Human Genetics Unit "QTL in Health and Disease" programme FX This paper is the work of the ROHgen consortium. We thank the participants in all ROHgen studies; cohort-specific acknowledgements are detailed in Supplementary Table 6. This work was funded by a UK Medical Research Council (MRC) PhD studentship to P.K.J.; and J.F.W. and O.P. acknowledge support from the MRC Human Genetics Unit "QTL in Health and Disease" programme. We thank W. G. Hill for discussions and comments on the manuscript and K. Lindsay for administrative assistance. NR 44 TC 25 Z9 25 U1 23 U2 90 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 JUL 23 PY 2015 VL 523 IS 7561 BP 459 EP U176 DI 10.1038/nature14618 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN4DD UT WOS:000358378900036 PM 26131930 ER PT J AU Li, PL Lahvic, JL Binder, V Pugach, EK Riley, EB Tamplin, OJ Panigrahy, D Bowman, TV Barrett, FG Heffner, GC McKinney-Freeman, S Schlaeger, TM Daley, GQ Zeldin, DC Zon, LI AF Li, Pulin Lahvic, Jamie L. Binder, Vera Pugach, Emily K. Riley, Elizabeth B. Tamplin, Owen J. Panigrahy, Dipak Bowman, Teresa V. Barrett, Francesca G. Heffner, Garrett C. McKinney-Freeman, Shannon Schlaeger, Thorsten M. Daley, George Q. Zeldin, Darryl C. Zon, Leonard I. TI Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment SO NATURE LA English DT Article ID STEM-CELLS; AORTIC ENDOTHELIUM; RNA-SEQ; ZEBRAFISH; MIGRATION; RUNX1; TRANSPLANTATION; IDENTIFICATION; REGENERATION; TRANSITION AB Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids(1,2) that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3) K) pathway, specifically PI(3) K gamma. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation. C1 [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA. [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Haematol Oncol, Boston, MA 02115 USA. [Li, Pulin; Lahvic, Jamie L.; Binder, Vera; Pugach, Emily K.; Riley, Elizabeth B.; Tamplin, Owen J.; Bowman, Teresa V.; Barrett, Francesca G.; Heffner, Garrett C.; Schlaeger, Thorsten M.; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Pulin; Zon, Leonard I.] Harvard Univ, Chem Biol Program, Cambridge, MA 02138 USA. [Binder, Vera] Univ Munich, Dr von Hauner Childrens Hosp, Dept Hematol & Oncol, D-80337 Munich, Germany. [Panigrahy, Dipak] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02115 USA. [McKinney-Freeman, Shannon] St Jude Childrens Res Hosp, Dept Haematol, Memphis, TN 38105 USA. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zon, LI (reprint author), Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu RI Binder, Vera/N-2078-2015 FU NIH [P50-NS40828, P30-HD18655]; HHMI; National Institutes of Health (NIH) [R01 HL04880, P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, 1R01HL097794-04]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025034]; National Cancer Institute [ROCA148633-01A5]; DFG; Care-for-Rare Foundation FX We thank C. R. Lee, M. L. Edin and N. Gray for providing reagents; Y. Zhou, A. Dibiase, S. Yang, S. Datta, P. Manos, R. Mathieu and M. Ammerman for technical assistance; H. Huang for providing graphic illustration; R. M. White, T.E. North and C. Mosimann for discussion. Microarray studies were performed by the Molecular Genetics Core Facility at Boston Children's Hospital, supported by NIH-P50-NS40828 and NIH-P30-HD18655. S. Li in Y. Zhang's laboratory at the Longwood HHMI joint core facility helped with RNA-seq. L.I.Z. and G.Q.D. are Howard Hughes Medical Institute (HHMI) investigators. This work was supported by HHMI and National Institutes of Health (NIH) grants R01 HL04880, P015PO1HL32262-32, 5P30 DK49216, 5R01 DK53298, 5U01 HL10001-05, R24 DK092760, and 1R01HL097794-04 (to L.I.Z.). This work was also funded, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034 to D.C.Z.), the National Cancer Institute grant ROCA148633-01A5 (D.P.), and DFG and Care-for-Rare Foundation (V.B.). NR 38 TC 25 Z9 26 U1 0 U2 12 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 JUL 23 PY 2015 VL 523 IS 7561 BP 468 EP U203 DI 10.1038/nature14569 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN4DD UT WOS:000358378900038 PM 26201599 ER PT J AU Kleinstiver, BP Prew, MS Tsai, SQ Topkar, VV Nguyen, NT Zheng, ZL Gonzales, APW Li, ZY Peterson, RT Yeh, JRJ Aryee, MJ Joung, JK AF Kleinstiver, Benjamin P. Prew, Michelle S. Tsai, Shengdar Q. Topkar, Ved V. Nguyen, Nhu T. Zheng, Zongli Gonzales, Andrew P. W. Li, Zhuyun Peterson, Randall T. Yeh, Jing-Ruey Joanna Aryee, Martin J. Joung, J. Keith TI Engineered CRISPR-Cas9 nucleases with altered PAM specificities SO NATURE LA English DT Article ID CAS SYSTEMS; STREPTOCOCCUS-THERMOPHILUS; DIRECTED EVOLUTION; HUMAN-CELLS; DUAL-RNA; ENDONUCLEASE; RECOGNITION; DIVERSITY; CLEAVAGE; IMMUNITY AB Although CRISPR-Cas9 nucleases are widely used for genome editing(1,2), the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM)(3-6). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis(7). In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGAPAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities. C1 [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Prew, Michelle S.; Tsai, Shengdar Q.; Topkar, Ved V.; Nguyen, Nhu T.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Zheng, Zongli; Aryee, Martin J.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zheng, Zongli] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Gonzales, Andrew P. W.; Li, Zhuyun; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Gonzales, Andrew P. W.; Peterson, Randall T.] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. [Gonzales, Andrew P. W.; Peterson, Randall T.] Broad Inst, Cambridge, MA 02142 USA. [Yeh, Jing-Ruey Joanna] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Aryee, Martin J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. EM jjoung@mgh.harvard.edu RI Li, Zhuyun/L-4792-2016; Zheng, Zongli/B-2917-2011 OI Zheng, Zongli/0000-0003-4849-4903 FU National Institutes of Health (NIH) [DP1 GM105378]; NIH [R01 GM107427, R01 GM088040]; Jim and Ann Orr Research Scholar Award; National Sciences and Engineering Research Council of Canada FX We thank D. Edgell for providing the bacterial strain and plasmids related to the bacterial selection; J. Angstman and V. Pattanayak for discussion and comments on the manuscript. This work was supported by a National Institutes of Health (NIH) Director's Pioneer Award (DP1 GM105378) and NIH R01 GM107427 to J.K.J., NIH R01 GM088040 to J.K.J. and R.T.P., The Jim and Ann Orr Research Scholar Award (to J.K.J.), and a National Sciences and Engineering Research Council of Canada Postdoctoral Fellowship (to B.P.K.). NR 36 TC 191 Z9 208 U1 29 U2 153 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 JUL 23 PY 2015 VL 523 IS 7561 BP 481 EP U249 DI 10.1038/nature14592 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN4DD UT WOS:000358378900041 PM 26098369 ER PT J AU Gautam, V D'Avanzo, C Berezovska, O Tanzi, RE Kovacs, DM AF Gautam, Vivek D'Avanzo, Carla Berezovska, Oksana Tanzi, Rudolph E. Kovacs, Dora M. TI Synaptotagmins interact with APP and promote A beta generation SO MOLECULAR NEURODEGENERATION LA English DT Article DE Alzheimer's disease; APP; BACE1; A beta; APP-interacting proteins; Synaptotagmin; Synaptic vesicles; Proteomics ID AMYLOID PRECURSOR PROTEIN; PAIRED HELICAL FILAMENTS; ACTIVE GAMMA-SECRETASE; ALZHEIMERS-DISEASE; PC12 CELLS; MICE LACKING; IN-VIVO; TRANSGENIC MICE; RELEASE; BRAIN AB Background: Accumulation of the beta-amyloid peptide (A beta) is a major pathological hallmark of Alzheimer's disease (AD). Recent studies have shown that synaptic A beta toxicity may directly impair synaptic function. However, proteins regulating A beta generation at the synapse have not been characterized. Here, we sought to identify synaptic proteins that interact with the extracellular domain of APP and regulate A beta generation. Results: Affinity purification-coupled mass spectrometry identified members of the Synaptotagmin (Syt) family as novel interacting proteins with the APP ectodomain in mouse brains. Syt-1, -2 and -9 interacted with APP in cells and in mouse brains in vivo. Using a GST pull-down approach, we have further demonstrated that the Syt interaction site lies in the 108 amino acids linker region between the E1 and KPI domains of APP. Stable overexpression of Syt-1 or Syt-9 with APP in CHO and rat pheochromocytoma cells (PC12) significantly increased APP-CTF and sAPP levels, with a 2 to 3 fold increase in secreted A beta levels in PC12 cells. Moreover, using a stable knockdown approach to reduce the expression of endogenous Syt-1 in PC12 cells, we have observed a similar to 50 % reduction in secreted A beta generation. APP processing also decreased in these cells, shown by lower CTF levels. Lentiviral-mediated knock down of endogenous Syt-1 in mouse primary neurons also led to a significant reduction in both A beta 40 and A beta 42 generation. As secreted sAPP beta levels were significantly reduced in PC12 cells lacking Syt-1 expression, our results suggest that Syt-1 regulates A beta generation by modulating BACE1-mediated cleavage of APP. Conclusion: Altogether, our data identify the synaptic vesicle proteins Syt-1 and 9 as novel APP-interacting proteins that promote A beta generation and thus may play an important role in the pathogenesis of AD. C1 [Gautam, Vivek; D'Avanzo, Carla; Tanzi, Rudolph E.; Kovacs, Dora M.] Harvard Univ, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp,Med Sch, Charlestown, MA 02129 USA. [Berezovska, Oksana] Harvard Univ, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP Kovacs, DM (reprint author), Harvard Univ, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp,Med Sch, Charlestown, MA 02129 USA. EM dora_kovacs@hms.harvard.edu FU NIH/NIA FX We would like to thank Dr. Dennis Selkoe's Lab and Dr. Ting Yang for their help with the A beta measurements. We are also very thankful to Dr. Amy Harkins (St. Louis University, St. Louis, Missouri) for providing us WT and Syt-1 KD PC12 cells. This work is supported by grants from the NIH/NIA to DMK. NR 67 TC 6 Z9 6 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JUL 23 PY 2015 VL 10 AR 31 DI 10.1186/s13024-015-0028-5 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CN3TT UT WOS:000358350300001 PM 26202512 ER PT J AU Burstein, HJ Morrow, M AF Burstein, Harold J. Morrow, Monica TI Nodal Irradiation after Breast-Cancer Surgery in the Era of Effective Adjuvant Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID POSITIVE LYMPH-NODES; SENTINEL NODE; POSTMASTECTOMY RADIOTHERAPY; RECURRENCE; METAANALYSIS; MASTECTOMY; TRIAL; WOMEN; RISK C1 [Burstein, Harold J.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Morrow, Monica] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA. RP Burstein, HJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. NR 15 TC 13 Z9 13 U1 1 U2 5 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 JUL 23 PY 2015 VL 373 IS 4 BP 379 EP 381 DI 10.1056/NEJMe1503608 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CN3NL UT WOS:000358333500013 PM 26200984 ER PT J AU DeFronzo, RA Ferrannini, E Groop, L Henry, RR Herman, WH Holst, JJ Hu, FB Kahn, CR Raz, I Shulman, GI Simonson, DC Testa, MA Weiss, R AF DeFronzo, Ralph A. Ferrannini, Ele Groop, Leif Henry, Robert R. Herman, William H. Holst, Jens Juul Hu, Frank B. Kahn, C. Ronald Raz, Itamar Shulman, Gerald I. Simonson, Donald C. Testa, Marcia A. Weiss, Ram TI Type 2 diabetes mellitus SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID BETA-CELL FUNCTION; IMPAIRED GLUCOSE-TOLERANCE; HEPATIC INSULIN-RESISTANCE; ENDOPLASMIC-RETICULUM STRESS; RANDOMIZED CONTROLLED-TRIAL; LIFE-STYLE INTERVENTIONS; FATTY LIVER-DISEASE; 10-YEAR FOLLOW-UP; QUALITY-OF-LIFE; DIPEPTIDYL PEPTIDASE-4 INHIBITORS AB Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic beta-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, C1 [DeFronzo, Ralph A.] Univ Texas Hlth Sci Ctr, South Texas Vet Hlth Care Syst, Dept Med, Diabet Div, 701 S Zarzamoro, San Antonio, TX 78207 USA. [DeFronzo, Ralph A.] Texas Diabet Inst, San Antonio, TX 78207 USA. [Ferrannini, Ele] CNR Inst Clin Physiol, Pisa, Italy. [Groop, Leif] Lund Univ, Ctr Diabet, Dept Clin Sci Malmoe Diabet & Endocrinol, Lund, Sweden. [Henry, Robert R.] Univ Calif San Diego, VA San Diego Healthcare Syst, Ctr Metab Res, Sect Diabet Endocrinol & Metab, San Diego, CA USA. [Herman, William H.] Univ Michigan, Ann Arbor, MI USA. [Holst, Jens Juul] Univ Copenhagen, Copenhagen, Denmark. [Hu, Frank B.] Harvard Med Sch, Brigham & Womens Hosp, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hu, Frank B.] Harvard Med Sch, Brigham & Womens Hosp, Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank B.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Kahn, C. Ronald] Harvard Med Sch, Boston, MA USA. [Kahn, C. Ronald] Joslin Diabet Ctr, Boston, MA USA. [Raz, Itamar] Hadassah Hebrew Univ Hosp, Div Internal Med, Diabet Unit, Jerusalem, Israel. [Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT USA. [Simonson, Donald C.] Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. [Testa, Marcia A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Weiss, Ram] Hebrew Univ Jerusalem, Braun Sch Publ Hlth, Dept Human Metab & Nutr, Jerusalem, Israel. RP DeFronzo, RA (reprint author), Univ Texas Hlth Sci Ctr, South Texas Vet Hlth Care Syst, Dept Med, Diabet Div, 701 S Zarzamoro, San Antonio, TX 78207 USA. EM defronzo@uthscsa.edu FU South Texas Veterans Healthcare System; National Institutes of Health [R01DK24092, DK58845, P30 DK46200, R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659, R24 DK085610, P30 DK036836]; Novo Nordisk Foundation for Basic Metabolic Research; University of Copenhagen; DVA-Merit Review grant; VA San Diego Healthcare System; National Institute for Diabetes and Digestive and Kidney Disease [P30DK092926]; Swedish Research Council [2010-3490, 2008-6589]; European Council [GA269045]; Italian Ministry of University Research [MIUR 2010329EKE]; Patient-Centered Outcomes Research Institute (PCORI) Program Award [CE1304-6756]; NovoNordisk Foundation FX The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010-3490 and 2008-6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance. NR 321 TC 8 Z9 8 U1 7 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD JUL 23 PY 2015 VL 1 AR 15019 DI 10.1038/nrdp.2015.19 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA DT2KZ UT WOS:000381310500001 PM 27189025 ER PT J AU Sweigard, JH Matsumoto, H Smith, KE Kim, LA Paschalis, EI Okonuki, Y Castillejos, A Kataoka, K Hasegawa, E Yanai, R Husain, D Lambris, JD Vavvas, D Miller, JW Connor, KM AF Sweigard, J. Harry Matsumoto, Hidetaka Smith, Kaylee E. Kim, Leo A. Paschalis, Eleftherios I. Okonuki, Yoko Castillejos, Alexandra Kataoka, Keiko Hasegawa, Eiichi Yanai, Ryoji Husain, Deeba Lambris, John D. Vavvas, Demetrios Miller, Joan W. Connor, Kip M. TI Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID DECAY-ACCELERATING FACTOR; HUMAN ENDOTHELIAL-CELLS; REPERFUSION INJURY; PROLIFERATIVE VITREORETINOPATHY; OXYGEN SUPPLEMENTATION; MACULAR DEGENERATION; REGULATORY PROTEINS; PROTEOMIC ANALYSIS; MULLER CELLS; 2 PARTS AB Degeneration of photoreceptors is a primary cause of vision loss worldwide, making the underlying mechanisms surrounding photoreceptor cell death critical to developing new treatment strategies. Retinal detachment, characterized by the separation of photoreceptors from the underlying retinal pigment epithelium, is a sight-threatening event that can happen in a number of retinal diseases. The detached photoreceptors undergo apoptosis and programmed necrosis. Given that photoreceptors are nondividing cells, their loss leads to irreversible visual impairment even after successful retinal reattachment surgery. To better understand the underlying disease mechanisms, we analyzed innate immune system regulators in the vitreous of human patients with retinal detachment and correlated the results with findings in a mouse model of retinal detachment. We identified the alternative complement pathway as promoting early photoreceptor cell death during retinal detachment. Photoreceptors down-regulate membrane-bound inhibitors of complement, allowing for selective targeting by the alternative complement pathway. When photoreceptors in the detached retina were removed from the primary source of oxygen and nutrients (choroidal vascular bed), the retina became hypoxic, leading to an up-regulation of complement factor B, a key mediator of the alternative pathway. Inhibition of the alternative complement pathway in knockout mice or through pharmacological means ameliorated photoreceptor cell death during retinal detachment. Our current study begins to outline the mechanism by which the alternative complement pathway facilitates photoreceptor cell death in the damaged retina. C1 [Sweigard, J. Harry; Matsumoto, Hidetaka; Smith, Kaylee E.; Okonuki, Yoko; Castillejos, Alexandra; Kataoka, Keiko; Hasegawa, Eiichi; Yanai, Ryoji; Husain, Deeba; Vavvas, Demetrios; Miller, Joan W.; Connor, Kip M.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Kim, Leo A.; Paschalis, Eleftherios I.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Lambris, John D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Connor, KM (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Angiogenesis Lab,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM kip_connor@meei.harvard.edu RI Kataoka, Keiko/B-2806-2016; OI Kataoka, Keiko/0000-0002-8795-6536; Connor, Kip/0000-0002-2048-9080 FU NIH [R01EY022084-01/S1, EY020633-02, R21EY023079, 5K12EY016335, T32EY007145, P30EY014104]; Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; March of Dimes Foundation [5-FY09-535]; Research to Prevent Blindness (RPB); RPB Physician-Scientist Award; Massachusetts Lions Eye Research Fund Inc; Yeatts Family Foundation; Loeffler Family fund; Macula Society Research grant; Japan Eye Bank Association FX This study was supported by NIH grants R01EY022084-01/S1 (K.M.C.), EY020633-02 (J.D.L.), R21EY023079 (D.V.), 5K12EY016335 (L.A.K.), T32EY007145 (J.H.S.), and P30EY014104; Howe Laboratory endowment of the Massachusetts Eye and Ear Infirmary; March of Dimes Foundation grant no. 5-FY09-535; Research to Prevent Blindness (RPB) Special Research Scholar Award (K.M.C.), RPB Physician-Scientist Award (D.V.), and unrestricted grant (J.W.M.); Massachusetts Lions Eye Research Fund Inc.; Yeatts Family Foundation (D.V.); The Loeffler Family fund; 2013 Macula Society Research grant (D.V.); and an award from the Japan Eye Bank Association (R.Y.). NR 60 TC 2 Z9 2 U1 3 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 22 PY 2015 VL 7 IS 297 AR 297ra116 DI 10.1126/scitranslmed.aab1482 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CN9AT UT WOS:000358738700008 PM 26203084 ER PT J AU Taylor, MJ Robinson, EB Happe, F Bolton, P Freeman, D Ronald, A AF Taylor, Mark J. Robinson, Elise B. Happe, Francesca Bolton, Patrick Freeman, Daniel Ronald, Angelica TI A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence SO MOLECULAR AUTISM LA English DT Article DE Autism; Psychotic experiences; Twin study; Genetics; Comorbidity ID POPULATION-BASED TWIN; SPECTRUM DISORDER; SCHIZOPHRENIA SPECTRUM; PSYCHIATRIC-DISORDERS; GENERAL-POPULATION; RISK-FACTORS; CHILDREN; SYMPTOMS; ASPERGER; INTERVIEW AB Background: This twin study investigated whether autistic traits during childhood were associated with adolescent psychotic experiences. Methods: Data were collected from a community sample of approximately 5000 twin pairs, which included 32 individuals with diagnosed autism spectrum conditions (ASC). Parents rated autistic traits in the twins at four points between ages 8-16 years. Positive, negative, and cognitive psychotic experiences were assessed at age 16 years using self-and parent-report scales. Longitudinal twin analyses tested the associations between these measures. Results: Autistic traits correlated weakly or nonsignificantly with positive psychotic experiences (paranoia, hallucinations, and grandiosity), and modestly with cognitive psychotic experiences (cognitive disorganisation). Higher correlations were observed for parent-rated negative symptoms and self-reported anhedonia, although the proportion of variance in both accounted for by autistic traits was low (10 and 31 %, respectively). The majority of the genetic influences on negative symptoms and anhedonia were independent of autistic traits. Additionally, individuals with ASC displayed significantly more negative symptoms, anhedonia, and cognitive disorganisation than controls. Conclusions: Autistic traits do not appear to be strongly associated with psychotic experiences in adolescence; associations were also largely restricted to negative symptoms. Of note, the degree to which the genetic and environmental causes of autistic traits influenced psychotic experiences was limited. These findings thus support a phenotypic and etiological distinction between autistic traits and psychotic experiences. C1 [Taylor, Mark J.; Ronald, Angelica] Univ London, Ctr Brain & Cognit Dev, Dept Psychol Sci, London, England. [Robinson, Elise B.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.] Harvard Univ, Sch Med, Boston, MA USA. [Robinson, Elise B.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Robinson, Elise B.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Happe, Francesca] Kings Coll London, MRC, Social Genet & Dev Psychiat Ctr, Inst Psychiat Psychol & Neurosci, London WC2R 2LS, England. [Bolton, Patrick] Kings Coll London, Dept Child Psychiat, London WC2R 2LS, England. [Bolton, Patrick] Kings Coll London, MRC, SGDP Ctr, Inst Psychiat Psychol & Neurosci, London WC2R 2LS, England. [Freeman, Daniel] Univ Oxford, Dept Psychiat, Oxford, England. RP Ronald, A (reprint author), Univ London, Ctr Brain & Cognit Dev, Dept Psychol Sci, London, England. EM a.ronald@bbk.ac.uk RI Freeman, Daniel/C-6851-2009; Bolton, Patrick/E-8501-2010; Ronald, Angelica/C-7812-2009; Taylor, Mark/D-4853-2017; OI Freeman, Daniel/0000-0002-2541-2197; Bolton, Patrick/0000-0002-5270-6262; Ronald, Angelica/0000-0002-9576-2176; Taylor, Mark/0000-0001-5161-4182; Robinson, Elise/0000-0003-2314-2792; Happe, Francesca/0000-0001-9226-4000 FU Medical Research Council [G100559, G0500870, G0901245, G0500079]; NIHR Senior Investigator Award; South London and Maudsley Hospital Biomedical Research Centre in Mental Health; MRC Senior Clinical Fellowship FX We thank the TEDS participants and team, including Andrew McMillan, Francesca Lewis, Louise Webster, Neil Harvey, Rachel Ogden, Peter McGuffin, Robert Plomin, Emma Colvert (all King's College London), and the Social Relationships Study team. This research was funded by the Medical Research Council [G100559 to Angelica Ronald; G0500870 to Francesca Happe and Patrick Bolton; G0901245, and previously G0500079, to Robert Plomin]. Patrick Bolton was supported by a NIHR Senior Investigator Award and the South London and Maudsley Hospital Biomedical Research Centre in Mental Health. Daniel Freeman is supported by an MRC Senior Clinical Fellowship and is a member of the Wellcome Trust Oxford Sleep and Circadian Neuroscience Institute (SCNi). NR 52 TC 1 Z9 1 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD JUL 22 PY 2015 VL 6 DI 10.1186/s13229-015-0037-9 PG 11 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA CN1SG UT WOS:000358199800001 PM 26199714 ER PT J AU Peters, C Rabkin, SD AF Peters, Cole Rabkin, Samuel D. TI Designing herpes viruses as oncolytics SO MOLECULAR THERAPY-ONCOLYTICS LA English DT Review ID BACTERIAL ARTIFICIAL CHROMOSOME; ENHANCES ANTITUMOR EFFICACY; METASTATIC OVARIAN-CANCER; MUTANT EXPRESSING ICP34.5; SQUAMOUS-CELL CARCINOMA; TYPE-1 US11 PROTEIN; BEARING TUMOR-CELLS; HIGH-GRADE GLIOMA; SIMPLEX-VIRUS; RIBONUCLEOTIDE REDUCTASE AB Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional-or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be "armed" with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity. C1 [Peters, Cole; Rabkin, Samuel D.] Harvard Med Sch, Program Virol, Boston, MA 02215 USA. [Peters, Cole; Rabkin, Samuel D.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02215 USA. [Peters, Cole; Rabkin, Samuel D.] Harvard Med Sch, Boston, MA 02215 USA. RP Rabkin, SD (reprint author), Harvard Med Sch, Program Virol, Boston, MA 02215 USA.; Rabkin, SD (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02215 USA.; Rabkin, SD (reprint author), Harvard Med Sch, Boston, MA 02215 USA. EM rabkin@mgh.harvard.edu FU National Institutes of Health [R01CA160762, R01NS032677, R01CA102139]; Thomas A. Pappas Chair in Neurosciences FX The authors would like to thank the members of the Brain Tumor Research Center who have contributed to our research. Our studies have been supported in part by grants from the National Institutes of Health (R01CA160762, R01NS032677, and R01CA102139) and the Thomas A. Pappas Chair in Neurosciences. NR 184 TC 10 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2372-7705 J9 Mol Ther-Oncolytics JI Mol. Ther.-Oncolytics PD JUL 22 PY 2015 VL 2 AR UNSP 15010 DI 10.1038/mto.2015.10 PG 14 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA EE2SB UT WOS:000389433400001 ER PT J AU Rees, E Kirov, G Walters, JT Richards, AL Howrigan, D Kavanagh, DH Pocklington, AJ Fromer, M Ruderfer, DM Georgieva, L Carrera, N Gormley, P Palta, P Williams, H Dwyer, S Johnson, JS Roussos, P Barker, DD Banks, E Milanova, V Rose, SA Chambert, K Mahajan, M Scolnick, EM Moran, JL Tsuang, MT Glatt, SJ Chen, WJ Hwu, HG Neale, BM Palotie, A Sklar, P Purcell, SM McCarroll, SA Holmans, P Owen, MJ O'Donovan, MC AF Rees, E. Kirov, G. Walters, J. T. Richards, A. L. Howrigan, D. Kavanagh, D. H. Pocklington, A. J. Fromer, M. Ruderfer, D. M. Georgieva, L. Carrera, N. Gormley, P. Palta, P. Williams, H. Dwyer, S. Johnson, J. S. Roussos, P. Barker, D. D. Banks, E. Milanova, V. Rose, S. A. Chambert, K. Mahajan, M. Scolnick, E. M. Moran, J. L. Tsuang, M. T. Glatt, S. J. Chen, W. J. Hwu, H-G Neale, B. M. Palotie, A. Sklar, P. Purcell, S. M. McCarroll, S. A. Holmans, P. Owen, M. J. O'Donovan, M. C. CA Taiwanese Trios Exome Sequencing C TI Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID DE-NOVO MUTATIONS; GENOME-WIDE ASSOCIATION; INTELLECTUAL DISABILITY; VARIANTS; CONSANGUINITY; HOMOZYGOSITY; SPECTRUM; AUTISM; RISK; LOCI AB Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF <= 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 x 10(-4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF <= 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios. C1 [Rees, E.; Kirov, G.; Walters, J. T.; Richards, A. L.; Pocklington, A. J.; Georgieva, L.; Carrera, N.; Holmans, P.; O'Donovan, M. C.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Med Res Council Ctr Neuropsychiat Genet & Gen, Cardiff, Wales. [Howrigan, D.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Howrigan, D.] Harvard Univ, Sch Med, Boston, MA USA. [Kavanagh, D. H.; Fromer, M.; Ruderfer, D. M.; Johnson, J. S.; Roussos, P.; Rose, S. A.; Mahajan, M.; Sklar, P.; Purcell, S. M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Psychiat, Div Psychiat Gen, New York, NY 10029 USA. [Fromer, M.; Barker, D. D.; Chambert, K.; Scolnick, E. M.; Moran, J. L.; Neale, B. M.; Purcell, S. M.; McCarroll, S. A.] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Gormley, P.; Banks, E.; Palotie, A.; McCarroll, S. A.] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA. Harvard Univ, Cambridge, MA 02138 USA. [Palta, P.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Williams, H.] UCL, Fac Populat Hlth Sci, Inst Child Hlth, ICH Genet & Genom Med Program,GOSgene, London, England. [Dwyer, S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Mol Genet & Gen, London, England. [Milanova, V.] Med Univ, Dept Psychiat, Sofia, Bulgaria. [Tsuang, M. T.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Tsuang, M. T.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Tsuang, M. T.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Tsuang, M. T.] Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. [Glatt, S. J.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, PsychGENe Lab, Syracuse, NY 13210 USA. [Chen, W. J.; Hwu, H-G] Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Hwu, H-G] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Dept Psychiat, Taipei 10764, Taiwan. [McCarroll, S. A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Owen, M. J.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Neurosci & Mental Hlth Res Inst, Med Res Council Ctr Neuropsychiat Genet & Gen, Cardiff CF10 3AX, S Glam, Wales. RP O'Donovan, MC (reprint author), Cardiff Univ, Inst Psychol Med & Clin Neurosci, Med Res Council Ctr Neuropsychiat Genet & Gen, Cardiff, Wales. EM owenmj@cf.ac.uk; ODonovanMC@cf.ac.uk RI Ruderfer, Douglas/M-5795-2016; Roussos, Panos/J-7090-2013; OI Palta, Priit/0000-0001-9320-7008; Ruderfer, Douglas/0000-0002-2365-386X; Roussos, Panos/0000-0002-4640-6239; Glatt, Stephen/0000-0002-0360-7567; Gormley, Padhraig/0000-0002-8908-6968; Moran, Jennifer/0000-0002-5664-4716; Walters, James/0000-0002-6980-4053; Holmans, Peter/0000-0003-0870-9412 FU Medical Research Council Centre Grants [G0800509]; Medical Research Council Program Grants [G0801418]; European Community [HEALTH-F2-2010-241909]; Friedman Brain Institute; Institute for Genomics and Multiscale Biology; National Institutes of Health [R01HG005827, R01MH099126, R01MH071681]; Fidelity Foundations; Sylvan Herman Foundation; Wellcome Trust [WT089062, WT098051]; European Commission [261123]; NIH/NHGRI [U54HG003067]; NIMH [R01 MH085521, R01 MH085560]; Gerber Foundation; Sidney R. Baer, Jr. Foundation; NARSAD: The Brain and Behavior Research Foundation; Stanley Center for Psychiatric Research FX Work in Cardiff was supported by Medical Research Council Centre (G0800509) and Program Grants (G0801418) and the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)). Work at the Icahn School of Medicine at Mount Sinai was supported by the Friedman Brain Institute, the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing) and National Institutes of Health grants R01HG005827 (SMP), R01MH099126 (SMP) and R01MH071681 (PS). Work at the Broad Institute was funded by Fidelity Foundations, the Sylvan Herman Foundation, philanthropic gifts from Kent and Liz Dauten, Ted and Vada Stanley and an anonymous donor to the Stanley Center for Psychiatric Research. Work at the Wellcome Trust Sanger Institute was supported by The Wellcome Trust (grant numbers WT089062 and WT098051) and also by the European Commission FP7 project gEUVADIS no. 261123 (PP). Work on the Taiwanese trios was supported by NIH/NHGRI grant U54HG003067 (Eric S Lander, Principal Investigator (PI)), NIMH grants R01 MH085521 (SJG, PI) and R01 MH085560 (MTT, PI), a grant from the Gerber Foundation (SJG, PI), a grant from the Sidney R. Baer, Jr. Foundation (SJG, PI) grants from NARSAD: The Brain and Behavior Research Foundation (SJG and MTT, PIs) and the Stanley Center for Psychiatric Research. NR 40 TC 3 Z9 3 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUL 21 PY 2015 VL 5 DI 10.1038/tp.2015.99 PG 6 WC Psychiatry SC Psychiatry GA DA2XO UT WOS:000367660700003 PM 26196440 ER PT J AU Schwartz, CE Kunwar, PS Hirshfeld-Becker, DR Henin, A Vangel, MG Rauch, SL Biederman, J Rosenbaum, JF AF Schwartz, C. E. Kunwar, P. S. Hirshfeld-Becker, D. R. Henin, A. Vangel, M. G. Rauch, S. L. Biederman, J. Rosenbaum, J. F. TI Behavioral inhibition in childhood predicts smaller hippocampal volume in adolescent offspring of parents with panic disorder SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PRESCHOOL-AGED CHILDREN; EARLY-LIFE STRESS; ANXIOUS TEMPERAMENT; SOCIAL ANXIETY; PSYCHIATRIC-DISORDERS; EARLY INTERVENTION; PREFRONTAL CORTEX; MIDDLE CHILDHOOD; GENE-EXPRESSION AB Behavioral inhibition ( BI) is a genetically influenced behavioral profile seen in 15-20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI - based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation. C1 [Schwartz, C. E.; Kunwar, P. S.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neurosci Program, Dev Neuroimaging Lab, Boston, MA 02114 USA. [Schwartz, C. E.; Hirshfeld-Becker, D. R.; Henin, A.; Rauch, S. L.; Biederman, J.; Rosenbaum, J. F.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Schwartz, C. E.; Vangel, M. G.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Hirshfeld-Becker, D. R.; Henin, A.; Biederman, J.; Rosenbaum, J. F.] Massachusetts Gen Hosp, Dept Psychiat, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. [Rauch, S. L.] McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. RP Schwartz, CE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neurosci Program, Bldg 149-2627, Boston, MA 02114 USA. EM carl_schwartz@hms.harvard.edu FU National Institutes of Mental Health [R01MH074848]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health [P41EB015896]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University FX We thank the families and children who have participated in the study over 16 years. This study was supported by the National Institutes of Mental Health R01MH074848 (CES, SLR, JFR, JB). This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. 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 health care 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 health care centers or the National Institutes of Health. NR 84 TC 1 Z9 1 U1 5 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUL 21 PY 2015 VL 5 DI 10.1038/tp.2015.95 PG 6 WC Psychiatry SC Psychiatry GA DA2XO UT WOS:000367660700001 PM 26196438 ER PT J AU Bot, A Brewer, JE Eshhar, Z Frankel, SR Hickman, E Jungbluth, AA Morgan, R Peretz, Y Radvanyi, L Ramos, CA Robbins, PF Wucherpfennig, KW AF Bot, Adrian Brewer, Joanna E. Eshhar, Zelig Frankel, Stanley R. Hickman, Emma Jungbluth, Achim A. Morgan, Richard Peretz, Yoav Radvanyi, Laszlo Ramos, Carlos A. Robbins, Paul F. Wucherpfennig, Kai W. TI Target discovery for T cell therapy: next steps to advance Immunotherapies SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Immunotherapy; Adoptive T cell therapy; Chimeric antigen receptors; T cell receptors; Tumor infiltrating lymphocytes; Targets; Adoptive T cell therapy; Antibodies; Vaccines AB Investigators from academia and industry gathered on August 14, 2014, in Boston at the Inaugural ImVacS conference entitled "Target Discovery for T Cell Therapy: Next Step to Advance Immunotherapies". Novel targets, discovery strategies and enabling technologies were presented and discussed. C1 [Bot, Adrian] Kite Pharma Inc, Translat Med, Santa Monica, CA 90404 USA. [Brewer, Joanna E.] Adaptimmune Ltd, Cellular Biol, Abingdon, Oxon, England. [Eshhar, Zelig] Weizmann Inst Sci, Immunol, IL-76100 Rehovot, Israel. [Frankel, Stanley R.] Amgen Inc, Oncol Early Dev, Therapeut Area Head, Thousand Oaks, CA USA. [Hickman, Emma] Immunocore, Target Validat, Abingdon, Oxon, England. [Jungbluth, Achim A.] Mem Sloan Kettering Canc Ctr, Immunohistochem, Pathol, New York, NY 10021 USA. [Morgan, Richard] Bluebird Bio, Immunotherapy, Boston, MA USA. [Peretz, Yoav] Caprion, ImmuneCarta, Immunol, Montreal, PQ, Canada. [Radvanyi, Laszlo] Lion Biotechnol, Woodland Hills, CA USA. [Ramos, Carlos A.] Baylor Coll Med, Hematol Oncol Sect, Med, Houston, TX 77030 USA. [Robbins, Paul F.] NCI, DNA Sequencing Core, Surg Branch, Bethesda, MD 20892 USA. [Robbins, Paul F.] NCI, FACS Core, Surg Branch, Bethesda, MD 20892 USA. [Robbins, Paul F.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Canc Immunol & AIDS, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Bot, A (reprint author), Kite Pharma Inc, Translat Med, 2225 Colorado Ave, Santa Monica, CA 90404 USA. EM abot@kitepharma.com NR 0 TC 0 Z9 0 U1 1 U2 2 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 JUL 21 PY 2015 VL 3 AR 31 DI 10.1186/s40425-015-0061-5 PG 5 WC Oncology SC Oncology GA CU7TJ UT WOS:000363744200002 ER PT J AU Dzierzewski, JM Song, Y Fung, CH Rodriguez, JC Jouldjian, S Alessi, CA Breen, EC Irwin, MR Martin, JL AF Dzierzewski, Joseph M. Song, Yeonsu Fung, Constance H. Rodriguez, Juan C. Jouldjian, Stella Alessi, Cathy A. Breen, Elizabeth C. Irwin, Michael R. Martin, Jennifer L. TI Self-reported sleep duration mitigates the association between inflammation and cognitive functioning in hospitalized older men SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE sleep duration; inflammation; cognition; hospitalization; older adults ID ILLNESS RATING-SCALE; C-REACTIVE PROTEIN; AGING POPULATION; ADULTS; DECLINE; WOMEN; INTERLEUKIN-6; PERFORMANCE; VALIDATION; CYTOKINE AB Examination of predictors of late-life cognitive functioning is particularly salient in at-risk older adults, such as those who have been recently hospitalized. Sleep and inflammation are independently related to late-life cognitive functioning. The potential role of sleep as a moderator of the relationship between inflammation and global cognitive functioning has not been adequately addressed. We examined the relationship between self-reported sleep duration, inflammatory markers, and general cognitive functioning in hospitalized older men. Older men (n = 135; Mean age = 72.9 +/- 9.7 years) were recruited from inpatient rehabilitation units at a VA Medical Center to participate in a cross-sectional study of sleep. Participants completed the Mini-Mental State Examination and Pittsburgh Sleep Quality Index, and underwent an 8 a.m. blood draw to measure inflammatory markers [i.e., C-reactive protein (CRP), tumor necrosis factor alpha (TNFot), soluble intercellular adhesion molecule-1 (5ICAM-1), and interleukin-6 (IL-6)]. Hierarchical regression analyses (controlling for age, education, race, depression, pain, health comorbidity, and BMI) revealed that higher levels of CRP and sICAM are associated with higher global cognitive functioning in older men with sleep duration >6h (beta = -0.19, beta = -0.18, p's < 0.05, respectively), but not in those with short sleep durations (p's > 0.05). In elderly hospitalized men, sleep duration moderates the association between inflammation and cognitive functioning. These findings have implications for the clinical care of older men within medical settings. C1 [Dzierzewski, Joseph M.; Song, Yeonsu; Fung, Constance H.; Rodriguez, Juan C.; Jouldjian, Stella; Alessi, Cathy A.; Martin, Jennifer L.] VA Greater Los Angeles Healthcare Syst, Educ & Clin Ctr, Geriatr Res, Los Angeles, CA USA. [Dzierzewski, Joseph M.; Fung, Constance H.; Rodriguez, Juan C.; Alessi, Cathy A.; Breen, Elizabeth C.; Irwin, Michael R.; Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Breen, Elizabeth C.; Irwin, Michael R.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA 90024 USA. RP Dzierzewski, JM (reprint author), VA Greater Los Angeles Healthcare Syst, Educ & Clin Ctr, Geriatr Res, 16111 Plummer St 11E, North Hills, CA 91343 USA. EM joseph.dzierzewski@va.gov RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU National Institute on Aging [K23AG028452, K23AG045937]; UCLA Claude D. Pepper Older Americans Independence Center [NIA 5P30 AG028748]; National Center for Advancing Translational Sciences UCLA CTSI [UL1TR000124]; VA Health Services Research Development [IIR 04-321-3]; VA Advanced Geriatrics Fellowship Program; Beeson Career Development in Aging research award program; NIA; AFAR; John A. Hartford Foundation; Atlantic Philanthropies; VA Greater Los Angeles Healthcare System Geriatric Research, Education, and Clinical Center FX This work was supported by the National Institute on Aging (K23AG028452, K23AG045937), UCLA Claude D. Pepper Older Americans Independence Center (NIA 5P30 AG028748), National Center for Advancing Translational Sciences UCLA CTSI (UL1TR000124), VA Health Services Research & Development (IIR 04-321-3), VA Advanced Geriatrics Fellowship Program, the Beeson Career Development in Aging research award program (supported by NIA, AFAR, the John A. Hartford Foundation, and the Atlantic Philanthropies), and VA Greater Los Angeles Healthcare System Geriatric Research, Education, and Clinical Center. The authors would like to thank Mr. Sergio Martinez, Ms. Terry Vandenberg, and Ms. Karen Josephson, and the laboratory staff of the Inflammatory Biology Core of the UCLA Older Americans Independence Center and the Cousins Center for Psychoneuroimmunology, for their assistance with the project. NR 34 TC 0 Z9 0 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 21 PY 2015 VL 6 AR 1004 DI 10.3389/fpsyg.2015.01004 PG 8 WC Psychology, Multidisciplinary SC Psychology GA CN9VE UT WOS:000358797300002 PM 26257670 ER PT J AU Zhang, N Liang, HY Farese, RV Li, J Musi, N Hussey, SE AF Zhang, Ning Liang, Hanyu Farese, Robert V. Li, Ji Musi, Nicolas Hussey, Sophie E. TI Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats SO PLOS ONE LA English DT Article ID TOLL-LIKE RECEPTOR-4; ADIPOSE-TISSUE; ENDOTOXIN ANTAGONIST; SEVERE SEPSIS; TAK-242; OBESITY; ACID; MICE; MUTATION; INFLAMMATION AB Aims To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline-but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced similar to 30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. C1 [Zhang, Ning; Liang, Hanyu; Li, Ji; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Liang, Hanyu; Li, Ji; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Liang, Hanyu; Musi, Nicolas] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Farese, Robert V.; Hussey, Sophie E.] Univ S Florida, Dept Internal Med, Tampa, FL 33620 USA. [Farese, Robert V.; Hussey, Sophie E.] James A Haley Vet Adm Med Ctr, Tampa, FL 33612 USA. RP Musi, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. EM musi@uthscsa.edu; sophiehussey@icloud.com FU NIH [1F32DK095565-01A1, RO1-DK80157, RO1-DK089229]; American Diabetes Association FX This work was supported by grants from the NIH (1F32DK095565-01A1) to S. Hussey, and the NIH (RO1-DK80157 and RO1-DK089229) and American Diabetes Association to N. Musi. NR 37 TC 3 Z9 3 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2015 VL 10 IS 7 AR e0132575 DI 10.1371/journal.pone.0132575 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN6LZ UT WOS:000358547600040 PM 26196892 ER PT J AU Jones, BE Sauer, B Jones, MM Campo, J Damal, K He, T Ying, J Greene, T Goetz, MB Neuhauser, MM Hicks, LA Samore, MH AF Jones, Barbara Ellen Sauer, Brian Jones, Makoto M. Campo, Jose Damal, Kavitha He, Tao Ying, Jian Greene, Tom Goetz, Matthew Bidwell Neuhauser, Melinda M. Hicks, Lauri A. Samore, Matthew H. TI Variation in Outpatient Antibiotic Prescribing for Acute Respiratory Infections in the Veteran Population A Cross-sectional Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID UNITED-STATES; TRACT INFECTIONS; DISEASES SOCIETY; ACUTE BRONCHITIS; AMBULATORY-CARE; ADULTS; AMERICA; TRENDS; RATES AB Background: Despite efforts to reduce antibiotic prescribing for acute respiratory infections (ARIs), information on factors that drive prescribing is limited. Objective: To examine trends in antibiotic prescribing in the Veterans Affairs population over an 8-year period and to identify patient, provider, and setting sources of variation. Design: Retrospective, cross-sectional study. Setting: All emergency departments and primary and urgent care clinics in the Veterans Affairs health system. Participants: All patient visits between 2005 and 2012 with primary diagnoses of ARIs that typically had low proportions of bacterial infection. Patients with infections or comorbid conditions that indicated antibiotic use were excluded. Measurements: Overall antibiotic prescription; macrolide prescription; and patient, provider, and setting characteristics extracted from the electronic health record. Results: The proportion of 1 million visits with ARI diagnoses that resulted in antibiotic prescriptions increased from 67.5% in 2005 to 69.2% in 2012 (P < 0.001). The proportion of macrolide antibiotics prescribed increased from 36.8% to 47.0% (P < 0.001). Antibiotic prescribing was highest for sinusitis (adjusted proportion, 86%) and bronchitis (85%) and varied little according to fever, age, setting, or comorbid conditions. Substantial variation was identified in prescribing at the provider level: The 10% of providers who prescribed the most antibiotics did so during at least 95% of their ARI visits, and the 10% who prescribed the least did so during 40% or fewer of their ARI visits. Limitation: Some clinical data that may have influenced the prescribing decision were missing. Conclusion: Veterans with ARIs commonly receive antibiotics, regardless of patient, provider, or setting characteristics. Macrolide use has increased, and substantial variation was identified in antibiotic prescribing at the provider level. C1 Vet Affairs Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. Univ Utah, Salt Lake City, UT 84112 USA. Vet Affairs Kansas City Hlth Care Syst, Kansas City, MO USA. Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. US Dept Vet Affairs, Hines, IL USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Jones, BE (reprint author), George E Wahlen Dept Vet Affairs Med Ctr, Decision Enhancement & Analyt Sci Ctr, 500 Foothill Blvd,Mail Code 182, Salt Lake City, UT 84148 USA. EM barbara.jones@hsc.utah.edu OI Goetz, Matthew/0000-0003-4542-992X FU U.S. Department of Veterans Affairs, Centers for Disease Control and Prevention FX U.S. Department of Veterans Affairs, Centers for Disease Control and Prevention. NR 32 TC 7 Z9 8 U1 0 U2 5 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 JUL 21 PY 2015 VL 163 IS 2 BP 73 EP + DI 10.7326/M14-1933 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA CN4NS UT WOS:000358407500014 PM 26192562 ER PT J AU Agenor, M Peitzmeier, S Gordon, AR Haneuse, S Potter, JE Austin, SB AF Agenor, Madina Peitzmeier, Sarah Gordon, Allegra R. Haneuse, Sebastien Potter, Jennifer E. Austin, S. Bryn TI Sexual Orientation Identity Disparities in Awareness and Initiation of the Human Papillomavirus Vaccine Among US Women and Girls A National Survey SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID GENITAL HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; LESBIAN HEALTH; BISEXUAL WOMEN; SAME-SEX; TRANSMITTED INFECTIONS; HETEROSEXUAL WOMEN; HPV VACCINATION; ADULTS; RISK AB Background: Lesbians and bisexual women are at risk for human papillomavirus (HPV) infection from female and male sexual partners. Objective: To examine the association between sexual orientation identity and HPV vaccination among U.S. women and girls. Design: Cross-sectional, using 2006-2010 National Survey of Family Growth data. Setting: U.S.civilian noninstitutionalized population. Participants: The 2006-2010 National Survey of Family Growth used stratified cluster sampling to establish a national probability sample of 12 279 U.S. women and girls aged 15 to 44 years. Analyses were restricted to 3253 women and girls aged 15 to 25 years who were asked about HPV vaccination. Measurements: Multivariable logistic regression was used to obtain prevalence estimates of HPV vaccine awareness and initiation adjusted for sociodemographic and health care factors for each sexual orientation identity group. Results: Among U.S. women and girls aged 15 to 25 years, 84.4% reported having heard of the HPV vaccine; of these, 28.5% had initiated HPV vaccination. The adjusted prevalence of vaccine awareness was similar among heterosexual, bisexual, and lesbian respondents. After adjustment for covariates, 8.5% (P = 0.007) of lesbians and 33.2% (P = 0.33) of bisexual women and girls who had heard of the vaccine had initiated vaccination compared with 28.4% of their heterosexual counterparts. Limitation: Self-reported, cross-sectional data, and findings may not be generalizable to periods after 2006 to 2010 or all U. S. lesbians aged 15 to 25 years (because of the small sample size for this group). Conclusion: Adolescent and young adult lesbians may be less likely to initiate HPV vaccination than their heterosexual counterparts. Programs should facilitate access to HPV vaccination services among young lesbians. C1 Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Fenway Hlth,Beth Israel Deaconess Med Ctr,Med Sch, Boston, MA 02115 USA. Boston Childrens Hosp, Boston, MA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Agenor, M (reprint author), Harvard Univ, Dept Social & Behav Sci, TH Chan Sch Publ Hlth, Kresge Bldg,7th Floor,677 Huntington Ave, Boston, MA 02115 USA. EM magenor@mail.harvard.edu FU National Cancer Institute FX National Cancer Institute. NR 66 TC 10 Z9 10 U1 2 U2 5 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 JUL 21 PY 2015 VL 163 IS 2 BP 99 EP + DI 10.7326/M14-2108 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CN4NS UT WOS:000358407500017 PM 25961737 ER PT J AU Uno, H Wittes, J Fu, HD Solomon, SD Claggett, B Tian, L Cai, TX Pfeffer, MA Evans, SR Wei, LJ AF Uno, Hajime Wittes, Janet Fu, Haoda Solomon, Scott D. Claggett, Brian Tian, Lu Cai, Tianxi Pfeffer, Marc A. Evans, Scott R. Wei, Lee-Jen TI Alternatives to Hazard Ratios for Comparing the Efficacy or Safety of Therapies in Noninferiority Studies SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID 2 SURVIVAL FUNCTIONS; NON-INFERIORITY; PROPORTIONAL HAZARDS; DIFFERENCE; REGRESSION; TRIALS; TIME; LIFE AB A noninferiority study is often used to investigate whether a treatment's efficacy or safety profile is acceptable compared with an alternative therapy regarding the time to a clinical event. The empirical quantification of the treatment difference for such a study is routinely based on the hazard ratio (HR) estimate. The HR, which is not a relative risk, may be difficult to interpret clinically, especially when the underlying proportional hazards assumption is violated. The precision of the HR estimate depends primarily on the number of observed events but not directly on exposure times or sample size of the study population. If the event rate is low, the study may require an impractically large number of events to ensure that the prespecified noninferiority criterion for the HR is attainable. This article discusses deficiencies in the current approach for the design and analysis of a noninferiority study. Alternative procedures are provided, which do not depend on any model assumption, to compare 2 treatments. For a noninferiority safety study, the patients' exposure times are more clinically important than the observed number of events. If the patients' exposure times are long enough to evaluate safety reliably, then these alternative procedures can effectively provide clinically interpretable evidence on safety, even with relatively few observed events. These procedures are illustrated with data from 2 studies. One explores the cardiovascular safety of a pain medicine; the second examines the cardiovascular safety of a new treatment for diabetes. These alternative strategies to evaluate safety or efficacy of an intervention lead to more meaningful interpretations of the analysis results than the conventional strategy that uses the HR estimate. C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Boston, MA 02115 USA. Stat Collaborat, Washington, DC 20036 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. RP Wei, LJ (reprint author), Harvard Univ, Dept Biostat, Sch Publ Hlth, 655 Huntington Ave, Boston, MA 02115 USA. EM wei@hsph.harvardedu FU National Institute of Health [UM1AI104681] FX Partially supported by the National Institute of Health (grant UM1AI104681 [Dr. Evans]) and contracts. NR 27 TC 14 Z9 14 U1 1 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 JUL 21 PY 2015 VL 163 IS 2 BP 127 EP + DI 10.7326/M14-1741 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CN4NS UT WOS:000358407500020 PM 26054047 ER PT J AU Matiello, M Zimmerman, E Caplan, D Cohen, AB AF Matiello, Marcelo Zimmerman, Eli Caplan, David Cohen, Adam B. TI Reversible cursive agraphia SO NEUROLOGY LA English DT Editorial Material C1 [Matiello, Marcelo; Zimmerman, Eli; Caplan, David; Cohen, Adam B.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Matiello, M (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM mmatiello@partners.org NR 3 TC 0 Z9 0 U1 3 U2 6 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 JUL 21 PY 2015 VL 85 IS 3 BP 295 EP 296 DI 10.1212/WNL.0000000000001754 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CN1GV UT WOS:000358167500010 PM 26195237 ER PT J AU Simon, TG Butt, AA AF Simon, Tracey G. Butt, Adeel A. TI Lipid dysregulation in hepatitis C virus, and impact of statin therapy upon clinical outcomes SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Hepatitis C virus; Lipid profiles; Cholesterol; Statin; Fibrosis; Cirrhosis ID DENSITY-LIPOPROTEIN RECEPTOR; FATTY LIVER-DISEASE; B TYPE-I; TRIGLYCERIDE TRANSFER PROTEIN; LOVASTATIN-INDUCED APOPTOSIS; CORE PROTEIN; HEPATOCELLULAR-CARCINOMA; CHOLESTEROL-SYNTHESIS; PNPLA3 POLYMORPHISM; DRUG-INTERACTIONS AB The hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide. Every aspect of the HCV life cycle is closely tied to human lipid metabolism. The virus circulates as a lipid-rich particle, utilizing lipoprotein cell receptors to gain entry into the hepatocyte. It has also been shown to upregulate lipid biosynthesis and impair lipid degradation, resulting in significant intracellular lipid accumulation and circulating hypocholesterolemia. Patients with chronic hepatitis C (CHC) are at increased risk of hepatic steatosis, fibrosis, and cardiovascular disease including accelerated atherosclerosis. HMG CoA Reductase inhibitors, or statins, have been shown to play an important role in the modulation of hepatic steatosis and fibrosis, and recent attention has focused upon their potential therapeutic role in CHC. This article reviews the hepatitis C viral life cycle as it impacts host lipoproteins and lipid metabolism. It then describes the pathogenesis of HCV-related hepatic steatosis, hypocholesterolemia and atherosclerosis, and finally describes the promising anti-viral and anti-fibrotic effects of statins, for the treatment of CHC. C1 [Simon, Tracey G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Simon, Tracey G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha 3050, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha 3050, Qatar. RP Butt, AA (reprint author), Univ Pittsburgh, Sch Med, 3601 Fifth Ave,Suite 3A, Pittsburgh, PA 15213 USA. EM aabutt@pitt.edu OI Butt, Adeel/0000-0002-1118-1826 NR 132 TC 3 Z9 3 U1 1 U2 9 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 21 PY 2015 VL 21 IS 27 BP 8293 EP 8303 DI 10.3748/wjg.v21.i27.8293 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CN2CS UT WOS:000358228600009 PM 26217081 ER PT J AU Itani, KMF AF Itani, Kamal M. F. TI Care Bundles and Prevention of Surgical Site Infection in Colorectal Surgery SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material AB IMPORTANCE Surgical site infections (SSIs) in colorectal surgery are associated with increased morbidity and health care costs. OBJECTIVE To determine the effect of a preventive SSI bundle (hereafter bundle) on SSI rates and costs in colorectal surgery. DESIGN Retrospective study of institutional clinical and cost data. The study period was January 1, 2008, to December 31, 2012, and outcomes were assessed and compared before and after implementation of the bundle on July 1, 2011. SETTING AND PARTICIPANTS Academic tertiary referral center among 559 patients who underwent major elective colorectal surgery. MAIN OUTCOMES AND MEASURES The primary outcome was the rate of superficial SSIs before and after implementation of the bundle. Secondary outcomes included deep SSIs, organ-space SSIs, wound disruption, postoperative sepsis, length of stay, 30-day readmission, and variable direct costs of the index admission. RESULTS Of 559 patients in the study, 346 (61.9%) and 213 (38.1%) underwent their operation before and after implementation of the bundle, respectively. Groups were matched on their propensity to be treated with the bundle to account for significant differences in the preimplementation and postimplementation characteristics. Comparison of the matched groups revealed that implementation of the bundle was associated with reduced superficial SSIs (19.3% vs 5.7%, P < .001) and postoperative sepsis (8.5% vs 2.4%, P = .009). No significant difference was observed in deep SSIs, organ-space SSIs, wound disruption, length of stay, 30-day readmission, or variable direct costs between the matched groups. However, in a subgroup analysis of the postbundle period, superficial SSI occurrence was associated with a 35.5% increase in variable direct costs ($13 253 vs $9779, P = .001) and a 71.7% increase in lengthof stay (7.9 vs 4.6days, P < .001). CONCLUSIONS AND RELEVANCE The preventive SSI bundle was associated with a substantial reduction in SSIs after colorectal surgery. The increased costs associated with SSIs support that the bundle represents an effective approach to reduce health care costs. C1 VA Boston Healthcare Syst, West Roxbury, MA USA. Boston Univ, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Itani, KMF (reprint author), VA Boston Healthcare Syst 112A, 1400 VFWPkwy, West Roxbury, MA 02132 USA. EM kitani@va.gov NR 8 TC 5 Z9 6 U1 1 U2 4 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 JUL 21 PY 2015 VL 314 IS 3 BP 289 EP 290 DI 10.1001/jamasurg.2014.346 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CN2CM UT WOS:000358228000023 PM 26197189 ER PT J AU Nan, HM Hsu, L Chan, AT AF Nan, Hongmei Hsu, Li Chan, Andrew T. TI Single-Gene Genotyping and Personalized Preventive Care Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Nan, Hongmei] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA. [Hsu, Li] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, GRJ 825C, Boston, MA 02114 USA. EM achan@mgh.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 1 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 JUL 21 PY 2015 VL 314 IS 3 BP 298 EP 298 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CN2CM UT WOS:000358228000027 PM 26197193 ER PT J AU Van Dort, CJ Brown, EN AF Van Dort, Christa J. Brown, Emery N. TI Reply to Grace: Role of cholinergic neurons in rapid eye movement (REM) sleep control SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Van Dort, Christa J.; Brown, Emery N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Van Dort, Christa J.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Van Dort, CJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM vandortc@mit.edu; enb@neurostat.mit.edu NR 4 TC 2 Z9 2 U1 0 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 JUL 21 PY 2015 VL 112 IS 29 BP E3756 EP E3756 DI 10.1073/pnas.1506854112 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN2BJ UT WOS:000358225100004 PM 26124152 ER PT J AU Ding, AP Gao, YM Liu, HK Caracappa, PF Long, DJ Bolch, WE Liu, B Xu, XG AF Ding, Aiping Gao, Yiming Liu, Haikuan Caracappa, Peter F. Long, Daniel J. Bolch, Wesley E. Liu, Bob Xu, X. George TI VirtualDose: a software for reporting organ doses from CT for adult and pediatric patients SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE CT dosimetry; dose reporting; software as a service (SaaS) ID MONTE-CARLO SIMULATIONS; FEMALE COMPUTATIONAL PHANTOMS; COMPUTED-TOMOGRAPHY; MULTIDETECTOR CT; RADIATION-EXPOSURE; ANTHROPOMORPHIC PHANTOMS; PHOTON IRRADIATION; PREGNANT PATIENTS; MDCT; OPTIMIZATION AB This paper describes the development and testing of VirtualDose-a software for reporting organ doses for adult and pediatric patients who undergo x-ray computed tomography (CT) examinations. The software is based on a comprehensive database of organ doses derived from Monte Carlo (MC) simulations involving a library of 25 anatomically realistic phantoms that represent patients of different ages, body sizes, body masses, and pregnant stages. Models of GE Lightspeed Pro 16 and Siemens SOMATOM Sensation 16 scanners were carefully validated for use in MC dose calculations. The software framework is designed with the 'software as a service (SaaS)' delivery concept under which multiple clients can access the web-based interface simultaneously from any computer without having to install software locally. The RESTful web service API also allows a third-party picture archiving and communication system software package to seamlessly integrate with VirtualDose's functions. Software testing showed that VirtualDose was compatible with numerous operating systems including Windows, Linux, Apple OS X, and mobile and portable devices. The organ doses from VirtualDose were compared against those reported by CT-Expo and ImPACT-two dosimetry tools that were based on the stylized pediatric and adult patient models that were known to be anatomically simple. The organ doses reported by VirtualDose differed from those reported by CT-Expo and ImPACT by as much as 300% in some of the patient models. These results confirm the conclusion from past studies that differences in anatomical realism offered by stylized and voxel phantoms have caused significant discrepancies in CT dose estimations. C1 [Ding, Aiping; Gao, Yiming; Liu, Haikuan; Caracappa, Peter F.; Xu, X. George] Rensselaer Polytech Inst, Nucl Engn Program, Troy, NY 12180 USA. [Liu, Haikuan] Fudan Univ, Inst Radiat Med, Shanghai 200032, Peoples R China. [Long, Daniel J.; Bolch, Wesley E.] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA. [Liu, Bob] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Ding, AP (reprint author), Rensselaer Polytech Inst, Nucl Engn Program, Troy, NY 12180 USA. EM xug2@rpi.edu OI Liu, Haikuan/0000-0002-2781-2637 FU STTR grant from the national institute of biomedical imaging and bioengineering (NIBIB) [1R42EB010404]; national cancer institute (NCI) [R01CA116743]; national library of medicine (NLM) [R01LM009362, R01LM009362-03S1]; NIBIB [R01EB00267] FX The development of VirtualDose (www.virtul-dose.com) as a commercial software was supported by an STTR grant to Virtual Phantoms, Inc. (www.virtualphantoms.com) from the national institute of biomedical imaging and bioengineering (NIBIB) (1R42EB010404). Patient phantoms used in VirtualDose were developed previously by grants to Rensselaer Polytechnic Institute from the national cancer institute (NCI) (R01CA116743) and the national library of medicine (NLM) (R01LM009362; R01LM009362-03S1) and a grant to the University of Florida from NIBIB (R01EB00267). NR 72 TC 5 Z9 7 U1 1 U2 13 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2015 VL 60 IS 14 BP 5601 EP 5625 DI 10.1088/0031-9155/60/14/5601 PG 25 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CM3YD UT WOS:000357620400017 PM 26134511 ER PT J AU Gottschalk, B Cascio, EW Daartz, J Wagner, MS AF Gottschalk, Bernard Cascio, Ethan W. Daartz, Juliane Wagner, Miles S. TI On the nuclear halo of a proton pencil beam stopping in water SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton; pencil beam; nuclear halo ID LOW-DOSE ENVELOPE; SPOT PROFILES; SCATTERING AB The dose distribution of a proton beam stopping in water has components due to basic physics and may have others from beam contamination. We propose the concise terms core for the primary beam, halo (see Pedroni et al 2005 Phys. Med. Biol. 50 541-61) for the low dose region from charged secondaries, aura for the low dose region from neutrals, and spray for beam contamination. We have measured the dose distribution in a water tank at 177 MeV under conditions where spray, therefore radial asymmetry, is negligible. We used an ADCL calibrated thimble chamber and a Faraday cup calibrated integral beam monitor so as to obtain immediately the absolute dose per proton. We took depth scans at fixed distances from the beam centroid rather than radial scans at fixed depths. That minimizes the signal range for each scan and better reveals the structure of the core and halo. Transitions from core to halo to aura are already discernible in the raw data. The halo has components attributable to coherent and incoherent nuclear reactions. Due to elastic and inelastic scattering by the nuclear force, the Bragg peak persists to radii larger than can be accounted for by Moliere single scattering. The radius of the incoherent component, a dose bump around midrange, agrees with the kinematics of knockout reactions. We have fitted the data in two ways. The first is algebraic or model dependent (MD) as far as possible, and has 25 parameters. The second, using 2D cubic spline regression, is model independent. Optimal parameterization for treatment planning will probably be a hybrid of the two, and will of course require measurements at several incident energies. The MD fit to the core term resembles that of the PSI group (Pedroni et al 2005), which has been widely emulated. However, we replace their T(w), a mass stopping power which mixes electromagnetic (EM) and nuclear effects, with one that is purely EM, arguing that protons that do not undergo hard single scatters continue to lose energy according to the Beth-Bloch formula. If that is correct, it is no longer necessary to measure T(w), and the dominant role played by the 'Bragg peak chamber' vanishes. For mathematical and other details we will refer to Gottschalk et al (2014, arXiv: 1409.1938v1), a long technical report of this project. C1 [Gottschalk, Bernard] Harvard Univ, Lab Particle Phys & Cosmol, Cambridge, MA 02138 USA. [Cascio, Ethan W.; Daartz, Juliane] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Wagner, Miles S.] Mevion Med Syst Inc, Littleton, MA 01460 USA. RP Gottschalk, B (reprint author), Harvard Univ, Lab Particle Phys & Cosmol, 18 Hammond St, Cambridge, MA 02138 USA. EM bgottsch@fas.harvard.edu FU Harvard University; Physics Department; Laboratory for Particle Physics and Cosmology FX BG thanks Harvard University, the Physics Department, and the Laboratory for Particle Physics and Cosmology for their continuing support. We thank Drs. Grevillot, Pedroni, Sawakuchi and Zhu for communication regarding their work, and the referees for helpful comments. NR 35 TC 11 Z9 11 U1 1 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2015 VL 60 IS 14 BP 5627 EP 5654 DI 10.1088/0031-9155/60/14/5627 PG 28 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CM3YD UT WOS:000357620400018 PM 26146956 ER PT J AU Sineshaw, HM Freedman, RA Ward, EM Flanders, WD Jemal, A AF Sineshaw, Helmneh M. Freedman, Rachel A. Ward, Elizabeth M. Flanders, W. Dana Jemal, Ahmedin TI Black/White Disparities in Receipt of Treatment and Survival Among Men With Early-Stage Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT SYSTEMIC THERAPY; RACIAL DISPARITIES; UNITED-STATES; OLDER WOMEN; SOCIOECONOMIC-FACTORS; DATA-BASE; POPULATION; CARE; MORTALITY; CARCINOMA AB Purpose To examine the extent of black/white disparities in receipt of treatment and survival for early-stage breast cancer in men age 18 to 64 and 65 years. Patients and Methods We identified 725 non-Hispanic black (black) and 5,247 non-Hispanic white (white) men diagnosed with early-stage breast cancer from 2004 to 2011 in the National Cancer Data Base. We used multivariable logistic regression and calculated standardized risk ratios to predict receipt of treatment and a proportional hazards model to estimate overall hazard ratios (HRs) in black versus white men age 18 to 64 and 65 years, separately. Results Receipt of treatment was remarkably similar between blacks and whites in both age groups. Black and white older men had lower receipt of chemotherapy (39.2% and 42.0%, respectively) compared with younger patients (76.7% and 79.3%, respectively). Younger black men had a 76% higher risk of death than younger white men after adjustment for clinical factors only (HR, 1.76; 95% CI, 1.11 to 2.78), but this difference significantly diminished after subsequent adjustment for insurance and income (HR, 1.37; 95% CI, 0.83 to 2.24). In those age 65 years, the excess risk of death in blacks versus whites was nonsignificant and not affected by adjustment for covariates. Conclusion The excess risk of death in black versus white men diagnosed with early-stage breast cancer was largely confined to those age 18 to 64 years and became nonsignificant after adjustment for differences in insurance and income. These findings suggest the importance of improving access to care in reducing racial disparities in male breast cancer mortality. (C) 2015 by American Society of Clinical Oncology C1 [Sineshaw, Helmneh M.; Ward, Elizabeth M.; Flanders, W. Dana; Jemal, Ahmedin] Amer Canc Soc, Atlanta, GA 30303 USA. [Flanders, W. Dana] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Freedman, Rachel A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sineshaw, HM (reprint author), Amer Canc Soc, 250 Williams St NW, Atlanta, GA 30303 USA. EM helmneh.sineshaw@cancer.org NR 56 TC 4 Z9 4 U1 4 U2 5 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 JUL 20 PY 2015 VL 33 IS 21 BP 2337 EP U21 DI 10.1200/JCO.2014.60.5584 PG 10 WC Oncology SC Oncology GA CR9DR UT WOS:000361653900004 PM 25940726 ER PT J AU Sparano, JA Zhao, FM Martino, S Ligibel, JA Perez, EA Saphner, T Wolff, AC Sledge, GW Wood, WC Davidson, NE AF Sparano, Joseph A. Zhao, Fengmin Martino, Silvana Ligibel, Jennifer A. Perez, Edith A. Saphner, Tom Wolff, Antonio C. Sledge, George W., Jr. Wood, William C. Davidson, Nancy E. TI Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT CHEMOTHERAPY; RACIAL DISPARITIES; RANDOMIZED-TRIALS; WEEKLY PACLITAXEL; AMERICAN-SOCIETY; SURVIVAL; WOMEN; TAMOXIFEN; OBESITY; DIAGNOSIS AB Purpose To determine long-term outcomes in a clinical trial evaluating the role of taxane type and schedule in operable breast cancer and evaluate the impact of obesity and black race on outcome. Patients and Methods A total of 4,954 eligible women with stage II to III breast cancer treated with four cycles of doxorubicin plus cyclophosphamide were randomly assigned to receive paclitaxel or docetaxel every 3 weeks for four doses or weekly for 12 doses using a 2 x 2 factorial design. The primary end point was disease-free survival (DFS). Results are expressed as hazard ratios (HRs) from Cox proportional hazards models. All P values are two sided. Results When compared with the standard every-3-week paclitaxel arm, after a median follow-up of 12.1 years, DFS significantly improved and overall survival (OS) marginally improved only for the weekly paclitaxel (HR, 0.84; P = .011 and HR, 0.87; P = .09, respectively) and every-3-week docetaxel arms (HR, 0.79; P = .001 and HR, 0.86; P = .054, respectively). Weekly paclitaxel improved DFS and OS (HR, 0.69; P = .010 and HR, 0.69; P = .019, respectively) in triple-negative breast cancer. For hormone receptor-positive, human epidermal growth factor receptor 2-nonoverexpressing disease, no experimental arm improved OS, and black race and obesity were associated with increased risk of breast cancer recurrence and death. Conclusion Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in triple-negative disease. Further research is required to understand why obesity and race influence clinical outcome in hormone receptor-positive disease. (C) 2015 by American Society of Clinical Oncology C1 [Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Zhao, Fengmin; Ligibel, Jennifer A.] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Martino, Silvana] John Wayne Canc Inst, Santa Monica, CA USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Saphner, Tom] Lombardi Canc Ctr, Two Rivers, WI USA. [Wolff, Antonio C.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Sledge, George W., Jr.] Indiana Univ Sch Med, Simon Canc Ctr, Indianapolis, IN 46202 USA. [Wood, William C.] Emory Univ, Winship Canc Ctr, Atlanta, GA 30322 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Univ Pittsburgh, Med Ctr, Ctr Canc, Pittsburgh, PA USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Weiler Div, 1625 East Chester Rd, Bronx, NY 10461 USA. EM jsparano@montefiore.org OI Wolff, Antonio/0000-0003-3734-1063 FU Public Health Service Grants from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services [CA180794, CA180820, CA189859, CA180888, CA180821, CA180867, CA180790, CA190140, CA180802, CA180795, CA180816, CA180864, CA180844] FX Supported in part by Public Health Service Grants No. CA180794, CA180820, CA189859, CA180888, CA180821, CA180867, CA180867, CA180790, CA190140, CA180802, CA180795, CA180816, CA180864, and CA180844 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 46 TC 19 Z9 21 U1 2 U2 5 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 JUL 20 PY 2015 VL 33 IS 21 BP 2353 EP U44 DI 10.1200/JCO.2015.60.9271 PG 11 WC Oncology SC Oncology GA CR9DR UT WOS:000361653900006 PM 26077235 ER PT J AU Rugo, HS Barry, WT Moreno-Aspitia, A Lyss, AP Cirrincione, C Leung, E Mayer, EL Naughton, M Toppmeyer, D Carey, LA Perez, EA Hudis, C Winer, EP AF Rugo, Hope S. Barry, William T. Moreno-Aspitia, Alvaro Lyss, Alan P. Cirrincione, Constance Leung, Eleanor Mayer, Erica L. Naughton, Michael Toppmeyer, Deborah Carey, Lisa A. Perez, Edith A. Hudis, Clifford Winer, Eric P. TI Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EPOTHILONE-B ANALOG; PLUS BEVACIZUMAB; CLINICAL-TRIAL; THERAPY; BMS-247550; SURVIVAL; TAXANES; ANTHRACYCLINE; ONCOLOGY; TRENDS AB Purpose We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. Patients and Methods Eligible patients were age 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m(2) (arm A), nab-paclitaxel 150 mg/m(2) (arm B), or ixabepilone 16 mg/m(2) (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. Results In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. Conclusion In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting. (C) 2015 by American Society of Clinical Oncology C1 [Rugo, Hope S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Barry, William T.] Dana Farber Canc Inst, Alliance Stat & Data Ctr, Boston, MA 02115 USA. [Mayer, Erica L.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moreno-Aspitia, Alvaro; Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Lyss, Alan P.] Heartland Canc Res Community Clin Oncol Program, St Louis, MO USA. [Lyss, Alan P.] Michael Naughton Washington Univ, Sch Med, St Louis, MO USA. [Lyss, Alan P.] Duke Univ, Alliance Stat & Data Ctr, Constance Cirrincione & Eleanor Leung, Durham, NC 27706 USA. [Carey, Lisa A.] Univ N Carolina, Chapel Hill, NC USA. [Toppmeyer, Deborah] Canc Inst New Jersey, New Brunswick, NJ USA. [Hudis, Clifford] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Rugo, HS (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. EM hrugo@medicine.ucsf.edu FU National Cancer Institute [CA31946, CA25224, CA21115]; Alliance Statistics and Data Center [CA33601]; Breast Cancer Research Foundation [86809-454967] FX Supported in part by Grants No. CA31946 from the National Cancer Institute (Alliance for Clinical Trials in Oncology for Cancer and Leukemia Group B 40502 trial), CA33601 from the Alliance Statistics and Data Center, CA25224 (North Central Cancer Treatment Group) and CA21115 (Eastern Cooperative Oncology Group) from the National Cancer Institute, and 86809-454967 from the Breast Cancer Research Foundation (H.S.R.). NR 33 TC 27 Z9 27 U1 0 U2 7 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 JUL 20 PY 2015 VL 33 IS 21 BP 2361 EP U57 DI 10.1200/JCO.2014.59.5298 PG 13 WC Oncology SC Oncology GA CR9DR UT WOS:000361653900007 PM 26056183 ER PT J AU Flaherty, KT Manola, JB Pins, M McDermott, DF Atkins, MB Dutcher, JJ George, DJ Margolin, KA DiPaola, RS AF Flaherty, Keith T. Manola, Judith B. Pins, Michael McDermott, David F. Atkins, Michael B. Dutcher, Janice J. George, Daniel J. Margolin, Kim A. DiPaola, Robert S. TI BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell CarcinomaA Trial of the ECOG-ACRIN Cancer Research Group (E2804) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DOUBLE-BLIND; INTERFERON-ALPHA; SUNITINIB; PAZOPANIB; BIOMARKERS; EVEROLIMUS; TOXICITY; SURVIVAL; EFFICACY; TUMORS AB Purpose On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade. Patients and Methods A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point. Results Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms. Conclusion The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy. (C) 2015 by American Society of Clinical Oncology C1 [Flaherty, Keith T.] Univ Penn, Philadelphia, PA 19104 USA. [Manola, Judith B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McDermott, David F.; Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pins, Michael] Advocate Lutheran Gen Hosp, Park Ridge, IL USA. [Dutcher, Janice J.] Montefiore Med Ctr, Bronx, NY 10467 USA. [George, Daniel J.] Duke Univ, Med Ctr, Durham, NC USA. [Margolin, Kim A.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [DiPaola, Robert S.] Canc Inst New Jersey Hamilton, New Brunswick, NJ USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org FU Public Health Service Grants from the National Cancer Institute, National Institutes of Health [CA180820, CA180794, CA180867, CA32102, CA20319, CA180888, CA47577, CA31946]; US Department of Health and Human Services FX Coordinated by the Eastern Cooperative Oncology Group (ECOG) -American College of Radiology Imaging Network Cancer Research Group (co-chairs Robert L. Comis, MD, and Mitchell D. Schnall, MD, PhD) and supported in part by Public Health Service Grants No. CA180820, CA180794, CA180867, CA32102, CA20319, CA180888, CA47577, and CA31946 from the National Cancer Institute, National Institutes of Health, and the US Department of Health and Human Services. Biospecimens were provided by the ECOG Pathology Coordinating Office and Reference Laboratory. NR 33 TC 17 Z9 18 U1 1 U2 5 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 JUL 20 PY 2015 VL 33 IS 21 BP 2384 EP U88 DI 10.1200/JCO.2015.60.9727 PG 11 WC Oncology SC Oncology GA CR9DR UT WOS:000361653900010 PM 26077237 ER PT J AU Ross, JD Cullen, DK Harris, JP LaPlaca, MC DeWeerth, SP AF Ross, James D. Cullen, D. Kacy Harris, James P. LaPlaca, Michelle C. DeWeerth, Stephen P. TI A three-dimensional image processing program for accurate, rapid, and semi-automated segmentation of neuronal somata with dense neurite outgrowth SO FRONTIERS IN NEUROANATOMY LA English DT Article DE image processing; segmentation; fluorescent microscopy; confocal; neural constructs ID HISTOPATHOLOGICAL IMAGES; ALGORITHM; MICROSCOPY; CYTOMETRY; TISSUE; DEFORMATION; STACKS; NUCLEI; CORTEX; MODEL AB Three-dimensional (3-D) image analysis techniques provide a powerful means to rapidly and accurately assess complex morphological and functional interactions between neural cells. Current software-based identification methods of neural cells generally fall into two applications: (1) segmentation of cell nuclei in high-density constructs or (2) tracing of cell neurites in single cell investigations. We have developed novel methodologies to permit the systematic identification of populations of neuronal somata possessing rich morphological detail and dense neurite arborization throughout thick tissue or 3-D in vitro constructs. The image analysis incorporates several novel automated features for the discrimination of neurites and somata by initially classifying features in 2-D and merging these classifications into 3-D objects; the 3-D reconstructions automatically identify and adjust for over and under segmentation errors. Additionally, the platform provides for software-assisted error corrections to further minimize error. These features attain very accurate cell boundary identifications to handle a wide range of morphological complexities. We validated these tools using confocal z-stacks from thick 3-D neural constructs where neuronal somata had varying degrees of neurite arborization and complexity, achieving an accuracy of >95%. We demonstrated the robustness of these algorithms in a more complex arena through the automated segmentation of neural cells in ex vivo brain slices. These novel methods surpass previous techniques by improving the robustness and accuracy by: (1) the ability to process neurites and somata, (2) bidirectional segmentation correction, and (3) validation via software-assisted user input. This 3-D image analysis platform provides valuable tools for the unbiased analysis of neural tissue or tissue surrogates within a 3D context, appropriate for the study of multi-dimensional cell-cell and cell-extracellular matrix interactions. C1 [Ross, James D.; LaPlaca, Michelle C.; DeWeerth, Stephen P.] Georgia Inst Technol Emory, Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Ross, James D.; DeWeerth, Stephen P.] Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. [Cullen, D. Kacy; Harris, James P.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Cullen, D. Kacy; Harris, James P.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP DeWeerth, SP (reprint author), Georgia Inst Technol Emory, Sch Elect & Comp Engn, Coulter Dept Biomed Engn, 313 Ferst Dr, Atlanta, GA 30332 USA. EM steve.deweerth@ece.gatech.edu FU National Institutes of Health [EB00786-01, T32-N5043126] FX The authors gratefully acknowledge Mr. Chintan Patel for his valuable feedback on the software and for his help generating the test image database. Additionally, the authors wish to thank Dr. Oskar Skrinjar and Mr. Edgar Brown for their insightful discussions on image processing and algorithm implementation. The National Institutes of Health supported this research through a Bioengineering Research Partnership (award no. EB00786-01) and an Institutional Training Grant (award no. T32-N5043126). The custom Matlab code presented here is available upon request. NR 34 TC 2 Z9 2 U1 5 U2 7 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 JUL 20 PY 2015 VL 9 AR 87 DI 10.3389/fnana.2015.00087 PG 15 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CQ2LE UT WOS:000360431000001 PM 26257609 ER PT J AU Copen, WA Morais, LT Wu, O Schwamm, LH Schaefer, PW Gonzalez, RG Yoo, AJ AF Copen, William A. Morais, Livia T. Wu, Ona Schwamm, Lee H. Schaefer, Pamela W. Gonzalez, R. Gilberto Yoo, Albert J. TI In Acute Stroke, Can CT Perfusion-Derived Cerebral Blood Volume Maps Substitute for Diffusion-Weighted Imaging in Identifying the Ischemic Core? SO PLOS ONE LA English DT Article ID ACUTE HEMISPHERIC STROKE; COMPUTED-TOMOGRAPHY; HYPERACUTE STROKE; INFARCT CORE; MRI; BRAIN; FLOW; REPERFUSION; THRESHOLDS; THROMBOLYSIS AB Background and Purpose In the treatment of patients with suspected acute ischemic stroke, increasing evidence suggests the importance of measuring the volume of the irreversibly injured "ischemic core." The gold standard method for doing this in the clinical setting is diffusion-weighted magnetic resonance imaging (DWI), but many authors suggest that maps of regional cerebral blood volume (CBV) derived from computed tomography perfusion imaging (CTP) can substitute for DWI. We sought to determine whether DWI and CTP-derived CBV maps are equivalent in measuring core volume. Methods 58 patients with suspected stroke underwent CTP and DWI within 6 hours of symptom onset. We measured low-CBV lesion volumes using three methods: "objective absolute," i.e. the volume of tissue with CBV below each of six published absolute thresholds (0.9-2.5 mL/100 g), "objective relative," whose six thresholds (51%-60%) were fractions of mean contralateral CBV, and "subjective," in which two radiologists (R1, R2) outlined lesions subjectively. We assessed the sensitivity and specificity of each method, threshold, and radiologist in detecting infarction, and the degree to which each over-or underestimated the DWI core volume. Additionally, in the subset of 32 patients for whom follow-up CT or MRI was available, we measured the proportion of CBV- or DWI-defined core lesions that exceeded the follow-up infarct volume, and the maximum amount by which this occurred. Results DWI was positive in 72% (42/58) of patients. CBV maps' sensitivity/specificity in identifying DWI-positive patients were 100%/0% for both objective methods with all thresholds, 43%/94% for R1, and 83%/44% for R2. Mean core overestimation was 156-699 mL for objective absolute thresholds, and 127-200 mL for objective relative thresholds. For R1 and R2, respectively, mean +/- SD subjective overestimation were -11 +/- 26 mL and -11 +/- 23 mL, but subjective volumes differed from DWI volumes by up to 117 and 124 mL in individual patients. Inter-rater agreement regarding the presence of infarction on CBV maps was poor (kappa = 0.21). Core lesions defined by the six objective absolute CBV thresholds exceeded followup infarct volumes for 81%-100% of patients, by up to 430-1002 mL. Core estimates produced by objective relative thresholds exceeded follow-up volumes in 91% of patients, by up to 210-280 mL. Subjective lesions defined by R1 and R2 exceeded follow-up volumes in 18% and 26% of cases, by up to 71 and 15 mL, respectively. Only 1 of 23 DWI lesions (4%) exceeded final infarct volume, by 3 mL. Conclusion CTP-derived CBV maps cannot reliably substitute for DWI in measuring core volume, or even establish which patients have DWI lesions. C1 [Copen, William A.; Morais, Livia T.; Wu, Ona; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Yoo, Albert J.] Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02115 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Copen, William A.; Wu, Ona; Schwamm, Lee H.; Schaefer, Pamela W.; Gonzalez, R. Gilberto; Yoo, Albert J.] Harvard Univ, Sch Med, Boston, MA USA. RP Copen, WA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02115 USA. EM wcopen@partners.org FU National Institutes of Health [R01NS059775] FX This work was supported by National Institutes of Health grant R01NS059775 to OW and WAC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 2 U1 2 U2 8 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 JUL 20 PY 2015 VL 10 IS 7 AR e0133566 DI 10.1371/journal.pone.0133566 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN6LN UT WOS:000358546400103 PM 26193486 ER PT J AU Shiwaku, Y Neff, L Nagano, K Takeyama, KI de Bruijn, J Dard, M Gori, F Baron, R AF Shiwaku, Yukari Neff, Lynn Nagano, Kenichi Takeyama, Ken-Ichi de Bruijn, Joost Dard, Michel Gori, Francesca Baron, Roland TI The Crosstalk between Osteoclasts and Osteoblasts Is Dependent upon the Composition and Structure of Biphasic Calcium Phosphates SO PLOS ONE LA English DT Article ID BETA-TRICALCIUM PHOSPHATE; BONE-FORMATION; SPHINGOSINE 1-PHOSPHATE; SEALING ZONE; RESORPTION; HYDROXYAPATITE; DIFFERENTIATION; ACTIVATION; TISSUE; CELLS AB Biphasic calcium phosphates (BCPs), consisting of hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP), exhibit good biocompatibility and osteoconductivity, maintaining a balance between resorption of the biomaterial and formation of new bone. We tested whether the chemical composition and/or the microstructure of BCPs affect osteoclasts (OCs) differentiation and/or their ability to crosstalk with osteoblasts (OBs). To this aim, OCs were cultured on BCPs with HA content of 5, 20 or 60% and their differentiation and activity were assessed. We found that OC differentiation is partially impaired by increased HA content, but not by the presence of micropores within BCP scaffolds, as indicated by TRAP staining and gene profile expression. We then investigated whether the biomaterial-induced changes in OC differentiation also affect their ability to crosstalk with OBs and regulate OB function. We found that BCPs with low percentage of HA favored the expression of positive coupling factors, including sphingosine-kinase 1 (SPHK1) and collagen triple helix repeat containing 1 (Cthrc1). In turn, the increase of these secreted coupling factors promotes OB differentiation and function. All together our studies suggest that the chemical composition of biomaterials affects not only the differentiation and activity of OCs but also their potential to locally regulate bone formation. C1 [Shiwaku, Yukari; Neff, Lynn; Nagano, Kenichi; Takeyama, Ken-Ichi; Gori, Francesca; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Baron, Roland] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Endocrine Unit, Boston, MA USA. [de Bruijn, Joost] Xpand Biotechnol BV, Bilthoven, Netherlands. [Dard, Michel] NYU, Coll Dent, Dept Periodontol & Implant Dent, New York, NY 10003 USA. RP Baron, R (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. EM Roland_Baron@hsdm.harvard.edu FU Straumann FX This work was supported by Straumann in the form of research support for Dr. Baron's laboratory at Harvard. NR 48 TC 6 Z9 6 U1 5 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 20 PY 2015 VL 10 IS 7 AR e0132903 DI 10.1371/journal.pone.0132903 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN6LN UT WOS:000358546400042 PM 26193362 ER PT J AU Tarhini, AA Lin, Y Zahoor, H Shuai, YL Butterfield, LH Ringquist, S Gogas, H Sander, C Lee, S Agarwala, SS Kirwood, JM AF Tarhini, Ahmad A. Lin, Yan Zahoor, Haris Shuai, Yongli Butterfield, Lisa H. Ringquist, Steven Gogas, Helen Sander, Cindy Lee, Sandra Agarwala, Sanjiv S. Kirwood, John M. TI Pro-Inflammatory Cytokines Predict RelapseFree Survival after One Month of Interferon-a but Not Observation in Intermediate Risk Melanoma Patients SO PLOS ONE LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; METASTATIC MALIGNANT-MELANOMA; ANGIOGENESIS IN-VIVO; INTERLEUKIN-2 RECEPTORS; ADJUVANT INTERFERON; SERUM INTERLEUKIN-6; CUTANEOUS MELANOMA; IL-2 RECEPTORS; CELL CARCINOMA; III MELANOMA AB Background E1697 was a phase III trial of adjuvant interferon (IFN)-alpha 2b for one month (Arm B) versus observation (Arm A) in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS) in Arm A and Arm B among 268 patients with banked biospecimens. Methods ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs) and microsatellites were tested for by polymerase chain reaction (PCR). Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV) was used to avoid over-fitting of the data. Results In the multi-marker modeling analysis conducted in Arm B, one month serum IL2R alpha, IL-12p40 and IFNa levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2R alpha and IFN alpha were the most stable (selected in all the cross validation cycles). The risk score (linear combination of the 3 markers) separated the RFS curves of low and high risk groups well (p = 0.05). This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy). Conclusions Early on-treatment proinflammatory serum markers (IL2R alpha, IL-12p40, IFN alpha) significantly predict RFS in our cohort of patients treated with adjuvant IFN-alpha 2b and warrant further study. C1 [Tarhini, Ahmad A.; Zahoor, Haris; Butterfield, Lisa H.; Ringquist, Steven; Sander, Cindy; Kirwood, John M.] Univ Pittsburgh, Pittsburgh, PA 15261 USA. [Lin, Yan; Shuai, Yongli] Univ Pittsburgh, Canc Inst Biostat Facil, Pittsburgh, PA USA. [Gogas, Helen] Hellen Cooperat Oncol Grp, Athens, Greece. [Lee, Sandra] Dana Farber Canc Inst, Boston, MA 02115 USA. [Agarwala, Sanjiv S.] St Lukes Canc Ctr, Bethlehem, PA USA. [Agarwala, Sanjiv S.] Temple Univ, Philadelphia, PA 19122 USA. RP Tarhini, AA (reprint author), Univ Pittsburgh, Pittsburgh, PA 15261 USA. EM tarhiniaa@upmc.edu FU DiaSorin Inc; Merck; Public Health Service Grants [CA180820, CA180794, CA180844]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services; National Institutes of Health [P50CA121973]; National Institutes of Health/National Cancer Institute [P30CA047904] FX This study was funded in part by DiaSorin Inc and Merck. This study was coordinated by the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180844, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. This study was supported by National Institutes of Health award P50CA121973 and in part by DiaSorin Inc. University of Pittsburgh Cancer Institute shared resources that are supported in part by National Institutes of Health/National Cancer Institute award P30CA047904 were used for this project. HLA Genotyping and PCR studies of CTLA4 and FOXP3 polymorphisms were conducted in the laboratory of Dr. Massimo Trucco at the Children's Hospital of Pittsburgh. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. DiaSorin Inc. and Merck had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. On the other hand, the study design, conduct and analysis plan were approved by ECOG-ACRIN Cancer Research Group and the National Cancer Institute and the National Institutes of Health. The final submitted manuscript was reviewed and approved for submission by ECOG-ACRIN. NR 57 TC 5 Z9 5 U1 0 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 JUL 20 PY 2015 VL 10 IS 7 AR e0132745 DI 10.1371/journal.pone.0132745 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN6LN UT WOS:000358546400037 PM 26192408 ER PT J AU Williamson, RS Hancock, KE Shinn-Cunningham, BG Polley, DB AF Williamson, Ross S. Hancock, Kenneth E. Shinn-Cunningham, Barbara G. Polley, Daniel B. TI Locomotion and Task Demands Differentially Modulate Thalamic Audiovisual Processing during Active Search SO CURRENT BIOLOGY LA English DT Article ID LATERAL GENICULATE-NUCLEUS; PRIMARY AUDITORY-CORTEX; VISUAL-CORTEX; CORTICAL REPRESENTATION; INFERIOR COLLICULUS; BEHAVIORAL STATE; RESPONSES; MECHANISMS; ATTENTION; CIRCUIT AB Active search is a ubiquitous goal-driven behavior wherein organisms purposefully investigate the sensory environment to locate a target object. During active search, brain circuits analyze a stream of sensory information from the external environment, adjusting for internal signals related to self-generated movement or "top-down" weighting of anticipated target and distractor properties. Sensory responses in the cortex can be modulated by internal state [1-9], though the extent and form of modulation arising in the cortex de novo versus an inheritance from subcortical stations is not clear [4, 8-12]. We addressed this question by simultaneously recording from auditory and visual regions of the thalamus (MG and LG, respectively) while mice used dynamic auditory or visual feedback to search for a hidden target within an annular track. Locomotion was associated with strongly suppressed responses and reduced decoding accuracy in MG but a subtle increase in LG spiking. Because stimuli in one modality provided critical information about target location while the other served as a distractor, we could also estimate the importance of task relevance in both thalamic subdivisions. In contrast to the effects of locomotion, we found that LG responses were reduced overall yet decoded stimuli more accurately when vision was behaviorally relevant, whereas task relevance had little effect on MG responses. This double dissociation between the influences of task relevance and movement in MG and LG highlights a role for extrasensory modulation in the thalamus but also suggests key differences in the organization of modulatory circuitry between the auditory and visual pathways. C1 [Williamson, Ross S.; Hancock, Kenneth E.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Williamson, Ross S.; Shinn-Cunningham, Barbara G.; Polley, Daniel B.] Boston Univ, Ctr Computat Neurosci & Neural Technol, Boston, MA 02215 USA. [Hancock, Kenneth E.; Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Williamson, RS (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM ross_williamson@meei.harvard.edu OI Polley, Daniel/0000-0002-5120-2409 FU NSF [DMS-1042134]; NIH [R21DC012894, P30DC05209, R01DC009477] FX We thank Jason Osborne (HHMI Janelia Farm) for sharing the microdrive design and Jonathon Whitton for guidance with behavioral training. This work was supported by NSF grant DMS-1042134 (R.S.W.) and NIH grants R21DC012894 (to D.B.P.), P30DC05209, and R01DC009477 (to B.G.S.-C.). NR 43 TC 5 Z9 5 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 20 PY 2015 VL 25 IS 14 BP 1885 EP 1891 DI 10.1016/j.cub.2015.05.045 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN5JM UT WOS:000358465600027 PM 26119749 ER PT J AU Dorfman, HM Buckholtz, JW AF Dorfman, Hayley M. Buckholtz, Joshua W. TI Social Behavior: A Penny for Your Shocks SO CURRENT BIOLOGY LA English DT Editorial Material ID SELF; SYSTEM AB Antisocial behavior is an enormously costly social problem, but its origins are poorly understood. A new study shows that prosocial and antisocial behaviors arise from individual differences in how we represent the value of others' pain relative to our own potential gain, rather than from variability in the capacity for effortful inhibitory control. C1 [Dorfman, Hayley M.; Buckholtz, Joshua W.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Dorfman, Hayley M.; Buckholtz, Joshua W.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Buckholtz, JW (reprint author), Harvard Univ, Dept Psychol, 52 Oxford St, Cambridge, MA 02138 USA. EM joshuabuckholtz@fas.harvard.edu NR 12 TC 0 Z9 0 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 20 PY 2015 VL 25 IS 14 BP R600 EP R601 DI 10.1016/j.cub.2015.05.036 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN5JM UT WOS:000358465600007 PM 26196484 ER PT J AU Plumlee, CR Obar, JJ Colpitts, SL Jellison, ER Haining, WN Lefrancois, L Khanna, KM AF Plumlee, Courtney R. Obar, Joshua J. Colpitts, Sara L. Jellison, Evan R. Haining, W. Nicholas Lefrancois, Leo Khanna, Kamal M. TI Early Effector CD8 T Cells Display Plasticity in Populating the Short-Lived Effector and Memory-Precursor Pools Following Bacterial or Viral Infection SO SCIENTIFIC REPORTS LA English DT Article ID SIGNAL 3; IN-VIVO; DIFFERENTIATION; EXPRESSION; RESPONSES; FATES; BET; REQUIREMENT; PATHOGEN; SUBSETS AB Naive antigen-specific CD8 T cells expand in response to infection and can be phenotypically separated into distinct effector populations, which include memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). In the days before the peak of the T cell response, a third population called early effector cells (EECs) predominate the antigen-specific response. However, the contribution of the EEC population to the CD8 T cell differentiation program during an antimicrobial immune response is not well understood. To test if EEC populations were pre-committed to either an MPEC or SLEC fate, we purified EECs from mice infected with Listeria monocytogenes (LM) or vesicular stomatitis virus (VSV), where the relative frequency of each population is known to be different at the peak of the response. Sorted EECs transferred into uninfected hosts revealed that EECs were pre-programmed to differentiate based on early signals received from the distinct infectious environments. Surprisingly, when these same EECs were transferred early into mismatched infected hosts, the transferred EECs could be diverted from their original fate. These results delineate a model of differentiation where EECs are programmed to form MPECs or SLECs, but remain susceptible to additional inflammatory stimuli that can alter their fate. C1 [Plumlee, Courtney R.; Colpitts, Sara L.; Jellison, Evan R.; Lefrancois, Leo; Khanna, Kamal M.] Univ Connecticut, Ctr Hlth, Dept Immunol, Farmington, CT USA. [Khanna, Kamal M.] Univ Connecticut, Ctr Hlth, Dept Pediat, Farmington, CT USA. [Obar, Joshua J.] Montana State Univ, Dept Immunol & Infect Dis, Bozeman, MT 59717 USA. [Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Khanna, KM (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM kkhanna@uchc.edu FU NERCE career development fellowship [U54 AI057159]; NIH [AI041576] FX We would like to thank the UCHC Flow Cytometry Core for expert assistance and Quynh-Mai Pham and Leigh Maher for exceptional technical support. This work was also supported by NERCE career development fellowship (U54 AI057159) to C.R.P. and NIH grant AI041576 to K.M.K. NR 40 TC 8 Z9 8 U1 0 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 JUL 20 PY 2015 VL 5 AR 12264 DI 10.1038/srep12264 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1BX UT WOS:000358152000001 PM 26191658 ER PT J AU Etchegaray, JP Mostoslavsky, R AF Etchegaray, Jean-Pierre Mostoslavsky, Raul TI Cell Fate by SIRT6 and TETs SO CELL CYCLE LA English DT Editorial Material ID MAMMALIAN DNA; 5-HYDROXYMETHYLCYTOSINE; 5-CARBOXYLCYTOSINE; 5-METHYLCYTOSINE C1 [Etchegaray, Jean-Pierre; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02163 USA. [Etchegaray, Jean-Pierre; Mostoslavsky, Raul] Harvard Univ, Sch Med, MGH Ctr Regenerat Med, Boston, MA USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02163 USA. EM rmostoslavsky@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD JUL 18 PY 2015 VL 14 IS 14 BP 2187 EP 2188 DI 10.1080/15384101.2015.1060768 PG 2 WC Cell Biology SC Cell Biology GA CN0TK UT WOS:000358126400004 PM 26066792 ER PT J AU Mega, JL Simon, T AF Mega, Jessica L. Simon, Tabassome TI Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments SO LANCET LA English DT Article ID ACUTE CORONARY SYNDROMES; ST-SEGMENT ELEVATION; LOW-DOSE ASPIRIN; NONVALVULAR ATRIAL-FIBRILLATION; PRASUGREL 10 MG; PHASE-II TRIAL; PLATELET REACTIVITY; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; HEALTHY-SUBJECTS AB Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies. C1 [Mega, Jessica L.] Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc Med,Sch Med, Boston, MA 02115 USA. [Simon, Tabassome] Hop St Antoine, AP HP, Dept Clin Pharmacol, F-75571 Paris, France. [Simon, Tabassome] Unite Rech Clin URCEST, Paris, France. [Simon, Tabassome] Univ Paris 06, Paris, France. [Simon, Tabassome] Natl Inst Hlth & Med Res, U 698, Inst Natl Sante & Rech Med, Paris, France. RP Mega, JL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jmega@partners.org FU Janssen Pharmaceutica; Bayer AG; Daiichi Sankyo; AstraZeneca; Eli Lilly; Bristol-Myers Squibb; Sanofi-Aventis; Boehringer Ingelheim; Portola; American Genomics; Daiichi-Sankyo; Merck Co; Novartis; Pfizer; Sanofi; Servier; Astellas FX JLM has received research grants from Janssen Pharmaceutica, Bayer AG, Daiichi Sankyo, AstraZeneca, Eli Lilly, Bristol-Myers Squibb, and Sanofi-Aventis. JLM has received personal feees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Janssen Pharmaceutica, Portola, and American Genomics. JLM has received research supplies from Accumetrics and Nanosphere. TS has received grants from AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKleine, Merck & Co, Novartis, Pfizer, Sanofi, and Servier. TS has received personal fees from AstraZeneca, Astellas, Bayer AG, Bristol-Myers Squibb, Eli Lilly, Merck & Co, and Sanofi. NR 114 TC 25 Z9 30 U1 3 U2 29 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 JUL 18 PY 2015 VL 386 IS 9990 BP 281 EP 291 DI 10.1016/S0140-6736(15)60243-4 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CN1XI UT WOS:000358213700033 PM 25777662 ER PT J AU Benson, CC McKean, D Homsy, J Kim, R Gorham, J Seidman, J Seidman, C AF Benson, Craig C. McKean, David Homsy, Jason Kim, Richard Gorham, Josh Seidman, Jon Seidman, Christine TI Identification of Novel Alternate Splicing Events in Humans With RBFOX2 Mutations and Hypoplastic Left Heart Syndrome SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Stroke-Association/American-Heart-Association Basic Cardiovascular Sciences Scientific Sessions - Pathways to Cardiovascular Therapeutics CY JUL 13-16, 2015 CL New Orleans, LA SP Amer Stroke Assoc, Amer Heart Assoc, Council Basic Cardiovascular Sci DE Alternative Splicing; Congenital Heart Disease; RNA-seq C1 [Benson, Craig C.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [McKean, David; Gorham, Josh; Seidman, Jon] Harvard Univ, Sch Med, Boston, MA USA. [Homsy, Jason] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kim, Richard] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Seidman, Christine] Brigham & Womens Hosp, 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 17 PY 2015 VL 117 SU 1 MA 46 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DJ9SI UT WOS:000374552800044 ER PT J AU Bezzerides, VJ Simonson, B Shanmugasundaram, K Phyllis, O Lynch, S Hessler, K Milan, D Rigby, A Das, S Rosenzweig, A AF Bezzerides, Vassilios J. Simonson, Bridget Shanmugasundaram, Kumaran Phyllis, Ottaviano Lynch, Stacey Hessler, Katherine Milan, David Rigby, Alan Das, Saumya Rosenzweig, Anthony TI Screening and Validation of Small Molecule Inhibitors of Serum and Glucocorticoid Regulated Kinase-1 as Novel Therapy for Cardiac Arrhythmia Disorders SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Stroke-Association/American-Heart-Association Basic Cardiovascular Sciences Scientific Sessions - Pathways to Cardiovascular Therapeutics CY JUL 13-16, 2015 CL New Orleans, LA SP Amer Stroke Assoc, Amer Heart Assoc, Council Basic Cardiovascular Sci DE SGK1; SCN5A; inhibitor C1 [Bezzerides, Vassilios J.] Boston Childrens Hosp, Div Cardiovasc, Boston, MA USA. [Simonson, Bridget; Shanmugasundaram, Kumaran; Phyllis, Ottaviano; Hessler, Katherine; Rigby, Alan; Das, Saumya; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Lynch, Stacey; Milan, David] Massachussetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 17 PY 2015 VL 117 SU 1 MA 266 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DJ9SI UT WOS:000374552800238 ER PT J AU Liu, XJ Xiao, JJ Wei, X Platt, C Xiao, CY Damilano, F Bezzerides, V Rosenzweig, A AF Liu, Xiaojun Xiao, Junjie Wei, Xin Platt, Colin Xiao, Chunyang Damilano, Federico Bezzerides, Vassilios Rosenzweig, Anthony TI An Exercise-induced MicroRNA Pathway That Protects Against Apoptosis and Pathological Cardiac Dysfunction SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Stroke-Association/American-Heart-Association Basic Cardiovascular Sciences Scientific Sessions - Pathways to Cardiovascular Therapeutics CY JUL 13-16, 2015 CL New Orleans, LA SP Amer Stroke Assoc, Amer Heart Assoc, Council Basic Cardiovascular Sci DE Exercise; miR-222; Apoptosis C1 [Liu, Xiaojun; Wei, Xin; Platt, Colin; Xiao, Chunyang; Damilano, Federico; Bezzerides, Vassilios] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Xiao, Junjie] Shanghai Univ, Shanghai, Peoples R China. Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Rosenzweig, Anthony] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 17 PY 2015 VL 117 SU 1 MA 112 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DJ9SI UT WOS:000374552800105 ER PT J AU Rhee, J Houstis, N Asara, J Liu, L Jang, C Arany, Z Rosenzweig, A AF Rhee, James Houstis, Nicholas Asara, John Liu, Laura Jang, Cholsoon Arany, Zoltan Rosenzweig, Anthony TI The Role of GAPDH in the Cardio-metabolic Response to Ischemia SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT American-Stroke-Association/American-Heart-Association Basic Cardiovascular Sciences Scientific Sessions - Pathways to Cardiovascular Therapeutics CY JUL 13-16, 2015 CL New Orleans, LA SP Amer Stroke Assoc, Amer Heart Assoc, Council Basic Cardiovascular Sci DE Glycolysis; Metabolomics; Ischemia C1 [Rhee, James; Houstis, Nicholas; Liu, Laura; Rosenzweig, Anthony] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Asara, John] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Jang, Cholsoon; Arany, Zoltan] Perelman Sch Med, 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 17 PY 2015 VL 117 SU 1 MA 386 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DJ9SI UT WOS:000374552800337 ER PT J AU Haberer, JE Bangsberg, DR Baeten, JM Curran, K Koechlin, F Amico, KR Anderson, P Mugo, N Venter, F Goicochea, P Caceres, C O'Reilly, K AF Haberer, Jessica E. Bangsberg, David R. Baeten, Jared M. Curran, Kathryn Koechlin, Florence Amico, K. Rivet Anderson, Peter Mugo, Nelly Venter, Francois Goicochea, Pedro Caceres, Carlos O'Reilly, Kevin TI Defining success with HIV pre-exposure prophylaxis: a prevention-effective adherence paradigm SO AIDS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; LESS-THAN 95-PERCENT; TRANSGENDER WOMEN; INHIBITOR THERAPY; INFECTED ADULTS; SUPPRESSION; TRIAL; MEN; TRANSMISSION; INTERMITTENT C1 [Haberer, Jessica E.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Baeten, Jared M.; Mugo, Nelly] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Baeten, Jared M.] Univ Washington, Dept Med, Seattle, WA USA. [Curran, Kathryn; Koechlin, Florence; O'Reilly, Kevin] WHO, CH-1211 Geneva, Switzerland. [Amico, K. Rivet] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Anderson, Peter] Univ Colorado, Dept Pharmaceut Sci, Denver, CO 80202 USA. [Mugo, Nelly] Kenya Govt Med Res Ctr, Clin Res Ctr, Nairobi, Kenya. [Venter, Francois] WITS Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Goicochea, Pedro] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goicochea, Pedro; Caceres, Carlos] Network Multidisciplinary Studies ARV Based HIV P, Lima, Peru. [Caceres, Carlos] Univ Peruana Cayetano Heredia, Lima, Peru. RP Haberer, JE (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM jhaberer@mgh.harvard.edu FU Bill and Melinda Gates Foundation [OPP1056051]; US National Institutes of Health [R01MH098744, R01MH095507, U01AI106499]; WHO; President's Emergency Plan for AIDS Relief FX Funding: Bill and Melinda Gates Foundation (OPP1056051), US National Institutes of Health (R01MH098744, R01MH095507, U01AI106499), WHO, and the President's Emergency Plan for AIDS Relief NR 48 TC 14 Z9 14 U1 2 U2 7 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 JUL 17 PY 2015 VL 29 IS 11 BP 1277 EP 1285 DI 10.1097/QAD.0000000000000647 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CR1UT UT WOS:000361111300001 PM 26103095 ER PT J AU Liu, EJ Makubi, A Drain, P Spiegelman, D Sando, D Li, N Chalamilla, G Sudfeld, CR Hertzmark, E Fawzi, WW AF Liu, Enju Makubi, Abel Drain, Paul Spiegelman, Donna Sando, David Li, Nan Chalamilla, Guerino Sudfeld, Christopher R. Hertzmark, Ellen Fawzi, Wafaie W. TI Tuberculosis incidence rate and risk factors among HIV-infected adults with access to antiretroviral therapy SO AIDS LA English DT Article ID VITAMIN-D STATUS; NUTRITIONAL-STATUS; SOUTH-AFRICA; MALNUTRITION; COINFECTION; COUNTRIES; TANZANIA; COHORT AB Objective: The objective of this study is to determine the incidence rate and risk factors of tuberculosis (TB) among HIV-infected adults accessing antiretroviral therapy (ART) in Tanzania. Design: A prospective observational study among HIV-infected adults attending HIV clinics in Dar es Salaam. Methods: We estimated TB incidence rates among HIV-infected patients prior to and after ART initiation. We used Cox proportional hazard regressions to determine the predictors of incident TB among HIV-infected adults enrolled in the HIV care and treatment programme. Results: We assessed 67 686 patients for a median follow-up period of 24 (interquartile range: 8-49) months; 7602 patients were diagnosed with active TB. The TB incidence rate was 7.9 [95% confidence interval (95% CI), 7.6-8.2] per 100 person-years prior to ART initiation, and 4.4 (95% CI, 4.2-4.4) per 100 person-years for patients receiving ART. In multivariate analyses, patients on ART in the first 3 months had a 57% higher risk of TB (hazard ratio: 1.57, 95% CI, 1.47-1.68) than those not on ART, but the risk significantly decreased with increasing duration of ART. Risk factors for incident TB included being male, having low BMI or middle upper arm circumference, lower CD4(+) cell count and advanced WHO disease stage. There was seasonal variation for incident TB, with higher risk observed following the rainy seasons (May, June and November). Conclusion: In TB endemic regions, HIV-infected patients initiating ART, particularly men and those with poor nutritional status, should be closely monitored for active TB at ART initiation. In addition to increasing the access to ART, interventions should be considered to improve nutritional status among HIV-infected patients. C1 [Liu, Enju; Spiegelman, Donna; Li, Nan; Sudfeld, Christopher R.; Fawzi, Wafaie W.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02120 USA. [Spiegelman, Donna; Hertzmark, Ellen; Fawzi, Wafaie W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02120 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02120 USA. [Spiegelman, Donna; Fawzi, Wafaie W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02120 USA. [Makubi, Abel] Muhimbili Univ Hlth & Allied Sci, Sch Med, Dar Es Salaam, Tanzania. [Drain, Paul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Drain, Paul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Practice Evaluat Ctr, Boston, MA USA. [Sando, David; Chalamilla, Guerino] Management & Dev Hlth, Dar Es Salaam, Tanzania. RP Liu, EJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, 1635 Tremont St,Room 108, Boston, MA 02120 USA. EM eliu@hsph.harvard.edu FU U.S. Presidents' Emergency Plan for AIDS Relief (PEPFAR) [U51HA02522]; Centers for Disease Control and Prevention [5U2GPS001966] FX The HIV care and treatment programme was supported by U.S. Presidents' Emergency Plan for AIDS Relief (PEPFAR, grant number U51HA02522), and the Centers for Disease Control and Prevention (grant number 5U2GPS001966). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. NR 37 TC 2 Z9 2 U1 0 U2 5 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 JUL 17 PY 2015 VL 29 IS 11 BP 1391 EP 1399 DI 10.1097/QAD.0000000000000705 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA CR1VC UT WOS:000361112200001 PM 26091295 ER PT J AU Han, S Lear, TB Jerome, JA Rajbhandari, S Snavely, CA Gulick, DL Gibson, KF Zou, CB Chen, BB Mallampalli, RK AF Han, SeungHye Lear, Travis B. Jerome, Jacob A. Rajbhandari, Shristi Snavely, Courtney A. Gulick, Dexter L. Gibson, Kevin F. Zou, Chunbin Chen, Bill B. Mallampalli, Rama K. TI Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NLRP3 INFLAMMASOME; ACTIVATION; DEUBIQUITINATION; MOTIF AB The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, the NALP3 inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1 beta and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1 beta in cells. Here we show that LPS increases the NALP3 protein life-span without significantly altering steady-state mRNA in human cells. LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. A unique small molecule inhibitor of FBXO3 restores FBXL2 levels, resulting in decreased NALP3 protein levels in cells and, thereby, reducing the release of IL-1 beta and IL-18 in human inflammatory cells after NALP3 activation. Our findings uncover NALP3 as a molecular target for FBXL2 and suggest that therapeutic targeting of the inflammasome may serve as a platform for preclinical intervention. C1 [Han, SeungHye; Lear, Travis B.; Jerome, Jacob A.; Rajbhandari, Shristi; Snavely, Courtney A.; Gulick, Dexter L.; Gibson, Kevin F.; Zou, Chunbin; Chen, Bill B.; Mallampalli, Rama K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol Physiol & Bioengn, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, UPMC Montefiore, Pulm Allergy & Crit Care Med, Dept Med, NW 628, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; National Institutes of Health R01 [HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453, HL116472]; Department of Veterans Affairs; Flight Attendant Medical Research Institute; American Heart Association [12SDG12040330] FX This work was performed on the basis of work supported, in part, by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was supported, in whole or in part, by National Institutes of Health R01 Grants HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453 (to R. K. M.), and HL116472 (to B. B. C.). This work was also supported by a merit review award from the Department of Veterans Affairs, the Flight Attendant Medical Research Institute, and American Heart Association Award 12SDG12040330 (to C. Z.). The authors declare that they have no conflicts of interest with the contents of this article. NR 25 TC 8 Z9 8 U1 0 U2 8 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 JUL 17 PY 2015 VL 290 IS 29 BP 18124 EP 18133 DI 10.1074/jbc.M115.645549 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN5ZB UT WOS:000358511700043 PM 26037928 ER PT J AU Chung, HJ Pellegrini, KL Chung, J Wanigasuriya, K Jayawardene, I Lee, K Lee, H Vaidya, VS Weissleder, R AF Chung, Hyun Jung Pellegrini, Kathryn L. Chung, Jaehoon Wanigasuriya, Kamani Jayawardene, Innocent Lee, Kyungheon Lee, Hakho Vaidya, Vishal S. Weissleder, Ralph TI Nanoparticle Detection of Urinary Markers for Point-of-Care Diagnosis of Kidney Injury SO PLOS ONE LA English DT Article ID CANCER-CELLS; BIOMARKERS; BACTERIA AB The high incidence of acute and chronic kidney injury due to various environmental factors such as heavy metals or chemicals has been a major problem in developing countries. However, the diagnosis of kidney injury in these areas can be more challenging due to the lack of highly sensitive and specific techniques that can be applied in point-of-care settings. To address this, we have developed a technique called 'micro-urine nanoparticle detection (mu UNPD)', that allows the detection of trace amounts of molecular markers in urine. Specifically, this technique utilizes an automated on-chip assay followed by detection with a hand-held device for the read-out. Using the mu UNPD technology, the kidney injury markers KIM-1 and Cystatin C were detected down to concentrations of 0.1 ng/ml and 20 ng/ml respectively, which meets the cut-off range required to identify patients with acute or chronic kidney injury. Thus, we show that the mu UNPD technology enables point of care and non-invasive detection of kidney injury, and has potential for applications in diagnosing kidney injury with high sensitivity in resource-limited settings. C1 [Chung, Hyun Jung; Chung, Jaehoon; Lee, Kyungheon; Lee, Hakho; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pellegrini, Kathryn L.; Vaidya, Vishal S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Renal Div,Dept Med, Boston, MA 02115 USA. [Wanigasuriya, Kamani] Univ Sri Jayewardenepura, Fac Med Sci, Dept Med, Nugegoda, Sri Lanka. [Jayawardene, Innocent] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA 02115 USA. [Jayawardene, Innocent] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Vaidya, Vishal S.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu RI Chung, Hyun Jung/J-3205-2014; OI Pellegrini, Kathryn/0000-0002-5089-5477 FU National Institute of Health [HHSN268201000044C, U54 CA151884]; National Institute of Environmental Health Sciences [ES017543] FX The work in the Weissleder laboratory was funded in parts by National Institute of Health grants HHSN268201000044C and U54 CA151884. The research in Vaidya laboratory was supported by Outstanding New Environmental Scientist Award (ES017543) from the National Institute of Environmental Health Sciences. NR 23 TC 4 Z9 4 U1 0 U2 12 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 JUL 17 PY 2015 VL 10 IS 7 AR e0133417 DI 10.1371/journal.pone.0133417 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1RV UT WOS:000358198700136 PM 26186708 ER PT J AU Nahrendorf, M Swirski, FK AF Nahrendorf, Matthias Swirski, Filip K. TI IMMUNOLOGY Neutrophil-macrophage communication in inflammation and atherosclerosis SO SCIENCE LA English DT Editorial Material C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu; fswirski@mgh.harvard.edu NR 12 TC 10 Z9 10 U1 0 U2 15 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 JUL 17 PY 2015 VL 349 IS 6245 SI SI BP 237 EP 238 DI 10.1126/science.aac7801 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1ZB UT WOS:000358218600022 PM 26185231 ER PT J AU Barouch, DH Alter, G Broge, T Linde, C Ackerman, ME Brown, EP Borducchi, EN Smith, KM Nkolola, JP Liu, JY Shields, J Parenteau, L Whitney, JB Abbink, P Ng'ang'a, DM Seaman, MS Lavine, CL Perry, JR Li, WJ Colantonio, AD Lewis, MG Chen, B Wenschuh, H Reimer, U Piatak, M Lifson, JD Handley, SA Virgin, HW Koutsoukos, M Lorin, C Voss, G Weijtens, M Pau, MG Schuitemaker, H AF Barouch, Dan H. Alter, Galit Broge, Thomas Linde, Caitlyn Ackerman, Margaret E. Brown, Eric P. Borducchi, Erica N. Smith, Kaitlin M. Nkolola, Joseph P. Liu, Jinyan Shields, Jennifer Parenteau, Lily Whitney, James B. Abbink, Peter Ng'ang'a, David M. Seaman, Michael S. Lavine, Christy L. Perry, James R. Li, Wenjun Colantonio, Arnaud D. Lewis, Mark G. Chen, Bing Wenschuh, Holger Reimer, Ulf Piatak, Michael Lifson, Jeffrey D. Handley, Scott A. Virgin, Herbert W. Koutsoukos, Marguerite Lorin, Clarisse Voss, Gerald Weijtens, Mo Pau, Maria G. Schuitemaker, Hanneke TI Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; HIGHLY PATHOGENIC SIV; HIV-1 VACCINE; HIGH-THROUGHPUT; ANTIBODIES; RESPONSES; VECTORS; BREADTH; SAMPLES; TRIAL AB Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys. C1 [Barouch, Dan H.; Brown, Eric P.; Borducchi, Erica N.; Smith, Kaitlin M.; Nkolola, Joseph P.; Liu, Jinyan; Shields, Jennifer; Parenteau, Lily; Whitney, James B.; Abbink, Peter; Ng'ang'a, David M.; Seaman, Michael S.; Lavine, Christy L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Barouch, Dan H.; Alter, Galit; Broge, Thomas; Linde, Caitlyn] MIT, Massachusetts Gen Hosp, Ragan Inst, Cambridge, MA 02139 USA. [Barouch, Dan H.; Alter, Galit; Broge, Thomas; Linde, Caitlyn] Harvard Univ, Cambridge, MA 02139 USA. [Ackerman, Margaret E.; Brown, Eric P.] Thayer Sch Engn Dartmouth, Hanover, NH 03755 USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Colantonio, Arnaud D.] New England Primate Res Ctr, Southborough, MA 01772 USA. [Lewis, Mark G.] Bioqual, Rockville, MD 20852 USA. [Chen, Bing] Childrens Hosp, Boston, MA 02115 USA. [Wenschuh, Holger; Reimer, Ulf] JPT Peptide Technol GmbH, D-12489 Berlin, Germany. [Piatak, Michael; Lifson, Jeffrey D.] Frederick Natl Lab, Leidos Biomed Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Handley, Scott A.; Virgin, Herbert W.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Koutsoukos, Marguerite; Lorin, Clarisse; Voss, Gerald] GSK Vaccines, B-1330 Rixensart, Belgium. [Weijtens, Mo; Pau, Maria G.; Schuitemaker, Hanneke] Janssen Infect Dis & Vaccines, NL-2301 Leiden, Netherlands. RP Barouch, DH (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu OI Brown, Eric/0000-0002-8438-6136 FU NIH [AI060354, AI078526, AI080289, AI084794, AI095985, AI096040, AI102660, AI102691, OD011170, HHSN261200800001E]; Bill and Melinda Gates Foundation [OPP1032817]; Ragon Institute of MGH, MIT, and Harvard FX We thank M. Pensiero, M. Marovich, M. Beck, J. Kramer, S. Westmoreland, P. Johnson, W. Wagner, J. Yalley, C. Gittens, C. Cosgrove, M. Kumar, J. Schmitz, H. Peng, J. Hendriks, D. van Manen, W. Bosche, V. Cyril, Y. Li, F. Stephens, R. Hamel, K. Kelly, and L. Dunne for generous advice, assistance, and reagents. The SIVmac239 peptides were obtained from the NIH AIDS Research and Reference Reagent Program. The data presented in this paper are tabulated in the main paper and in the supplementary materials. The authors declare no competing financial interests. D. H. B. is a named co-inventor on vector, antigen, and protein patents (PCT/EP2007/052463, PCT/US2009/060494, PCT/US2009/064999). Correspondence and requests for materials should be addressed to D. H. B. (dbarouch@bidmc.harvard.edu). Vectors, antigens, proteins, adjuvants, and viruses are subject to Material Transfer Agreements. We acknowledge support from the NIH (AI060354, AI078526, AI080289, AI084794, AI095985, AI096040, AI102660, AI102691, OD011170, and HHSN261200800001E), the Bill and Melinda Gates Foundation (OPP1032817), and the Ragon Institute of MGH, MIT, and Harvard. NR 36 TC 56 Z9 58 U1 3 U2 16 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 JUL 17 PY 2015 VL 349 IS 6245 SI SI BP 320 EP 324 DI 10.1126/science.aab3886 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1ZB UT WOS:000358218600055 PM 26138104 ER PT J AU Minajigi, A Froberg, JE Wei, CY Sunwoo, H Kesner, B Colognori, D Lessing, D Payer, B Boukhali, M Haas, W Lee, JT AF Minajigi, Anand Froberg, John E. Wei, Chunyao Sunwoo, Hongjae Kesner, Barry Colognori, David Lessing, Derek Payer, Bernhard Boukhali, Myriam Haas, Wilhelm Lee, Jeannie T. TI A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation SO SCIENCE LA English DT Article ID INACTIVE X-CHROMOSOME; HI-C REVEALS; REGULATORY ELEMENTS; GENE-EXPRESSION; DIFFERENTIAL EXPRESSION; QUANTITATIVE PROTEOMICS; DOSAGE COMPENSATION; HUMAN GENOME; CTCF; PROTEINS AB The inactive X chromosome (Xi) serves as a model to understand gene silencing on a global scale. Here, we perform "identification of direct RNA interacting proteins" (iDRiP) to isolate a comprehensive protein interactome for Xist, an RNA required for Xi silencing. We discover multiple classes of interactors-including cohesins, condensins, topoisomerases, RNA helicases, chromatin remodelers, and modifiers-that synergistically repress Xi transcription. Inhibiting two or three interactors destabilizes silencing. Although Xist attracts some interactors, it repels architectural factors. Xist evicts cohesins from the Xi and directs an Xi-specific chromosome conformation. Upon deleting Xist, the Xi acquires the cohesin-binding and chromosomal architecture of the active X. Our study unveils many layers of Xi repression and demonstrates a central role for RNA in the topological organization of mammalian chromosomes. C1 [Minajigi, Anand; Froberg, John E.; Wei, Chunyao; Sunwoo, Hongjae; Kesner, Barry; Colognori, David; Lessing, Derek; Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Minajigi, Anand; Froberg, John E.; Wei, Chunyao; Sunwoo, Hongjae; Kesner, Barry; Colognori, David; Lessing, Derek; Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Minajigi, Anand; Froberg, John E.; Wei, Chunyao; Sunwoo, Hongjae; Kesner, Barry; Colognori, David; Lessing, Derek; Payer, Bernhard; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Boukhali, Myriam; Haas, Wilhelm] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Boukhali, Myriam; Haas, Wilhelm] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu OI Payer, Bernhard/0000-0002-4694-2082 FU NIH [R01-DA-38695, R03-MH97478]; Rett Syndrome Research Trust; International Rett Syndrome Foundation; National Science Foundation; MGH Fund for Medical Discovery FX We thank S. Gygi for access to computational resources for proteomic analysis and all members of the Lee and Haas laboratories for valuable discussions. This work was supported by grants from NIH (R01-DA-38695 and R03-MH97478), the Rett Syndrome Research Trust, and the International Rett Syndrome Foundation to J.T.L.; a National Science Foundation predoctoral award to J.E.F.; and the MGH Fund for Medical Discovery to H.S. J.T.L. is an Investigator of the HHMI. J.T.L., A.M., J.E.F., C.W., and the Massachusetts General Hospital have filed patent applications (USSN 62/144,219 and 62/168,528) that relate to leveraging the Xist interactome to reactivate the Xi. The GEO accession code for data in the paper is GSE67516. RNA-seq, ChIP-seq, and HiC-seq data are deposited in GEO. NR 66 TC 46 Z9 46 U1 6 U2 29 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 JUL 17 PY 2015 VL 349 IS 6245 SI SI AR aab2276 DI 10.1126/science.aab2276 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1ZB UT WOS:000358218600044 ER PT J AU Hunt, DP Scheske, JA Dudzinski, DM Arvikar, SL AF Hunt, Daniel P. Scheske, Jonathan A. Dudzinski, David M. Arvikar, Sheila L. TI Case 22-2015: A 20-Year-Old Man with Sore Throat, Fever, Myalgias, and a Pericardial Effusion SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ONSET STILLS-DISEASE; CONSTRICTIVE PERICARDITIS; CARDIAC-TAMPONADE; ADULT; CRITERIA; CLASSIFICATION C1 [Hunt, Daniel P.; Arvikar, Sheila L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Scheske, Jonathan A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Dudzinski, David M.] Harvard Univ, Sch Med, Dept Cardiol, Boston, MA USA. [Hunt, Daniel P.; Arvikar, Sheila L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Hunt, DP (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. NR 15 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 JUL 16 PY 2015 VL 373 IS 3 BP 263 EP 271 DI 10.1056/NEJMcpc1501310 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CM8MS UT WOS:000357956200011 PM 26176384 ER PT J AU Dombret, H Seymour, JF Butrym, A Wierzbowska, A Selleslag, D Jang, JH Kumar, R Cavenagh, J Schuh, AC Candoni, A Recher, C Sandhu, I del Castillo, TB Al-Ali, HK Martinelli, G Falantes, J Noppeney, R Stone, RM Minden, MD McIntyre, H Songer, S Lucy, LM Beach, CL Dohner, H AF Dombret, Herve Seymour, John F. Butrym, Aleksandra Wierzbowska, Agnieszka Selleslag, Dominik Jang, Jun Ho Kumar, Rajat Cavenagh, James Schuh, Andre C. Candoni, Anna Recher, Christian Sandhu, Irwindeep Bernal del Castillo, Teresa Al-Ali, Haifa Kathrin Martinelli, Giovanni Falantes, Jose Noppeney, Richard Stone, Richard M. Minden, Mark D. McIntyre, Heidi Songer, Steve Lucy, Lela M. Beach, C. L. Doehner, Hartmut TI International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; RISK MYELODYSPLASTIC SYNDROMES; LOW-DOSE CYTARABINE; AGMT-STUDY GROUP; ELDERLY-PATIENTS; INTENSIVE CHEMOTHERAPY; SEQUENTIAL AZACITIDINE; SUPPORTIVE CARE; OPEN-LABEL; SURVIVAL AB This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age >= 65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR(standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1: 1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. C1 [Dombret, Herve] Univ Paris Diderot, Inst Univ Hematol, Hop St Louis, F-75010 Paris, France. [Seymour, John F.] Peter MacCallum Canc Ctr, East Melbourne, Australia. [Seymour, John F.] Univ Melbourne, Parkville, Vic 3052, Australia. [Butrym, Aleksandra] Wroclaw Med Univ, Wroclaw, Poland. [Wierzbowska, Agnieszka] Med Univ Lodz, Lodz, Poland. [Selleslag, Dominik] Algemeen Ziekenhuis St Jan, Brugge, Belgium. [Jang, Jun Ho] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Kumar, Rajat] Canc Care Manitoba, Winnipeg, MB, Canada. [Cavenagh, James] Barts Hlth Natl Hlth Serv Trust, London, England. [Schuh, Andre C.; Minden, Mark D.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Candoni, Anna] Azienda Osped Univ S Maria della Misericordia Udi, Udine, Italy. [Recher, Christian] Ctr Hosp Univ Toulouse, Toulouse, France. [Sandhu, Irwindeep] Univ Alberta Hosp, Edmonton, AB T6G 2B7, Canada. [Bernal del Castillo, Teresa] Univ Oviedo, Hosp Cent Asturias, E-33080 Oviedo, Spain. [Al-Ali, Haifa Kathrin] Univ Klinikum Leipzig, Leipzig, Germany. [Martinelli, Giovanni] Inst Hematol & Med Oncol L&A Seragnoli, Bologna, Italy. [Falantes, Jose] Hosp Univ Virgen del Rocio, Inst BioMed Sevilla, Seville, Spain. [Noppeney, Richard] Univ Klinikum Essen Klin Hamatol, Essen, Germany. [Stone, Richard M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McIntyre, Heidi; Songer, Steve; Lucy, Lela M.; Beach, C. L.] Celgene Corp, Summit, NJ USA. [Doehner, Hartmut] Univ Ulm Klinikum, Ulm, Germany. RP Dombret, H (reprint author), Univ Paris Diderot, Inst Univ Hematol, Hop St Louis, 1 Ave Claude Vellefaux, F-75010 Paris, France. EM herve.dombret@sls.aphp.fr RI IBIS, ONCOHEMATOLOGI/P-3457-2015; Wierzbowska, Agnieszka/S-9449-2016 FU Celgene Corporation FX Editorial assistance was provided by Brian Kaiser and Sheila Truten of Medical Communication Company, Inc., funded by Celgene Corporation. NR 28 TC 102 Z9 105 U1 4 U2 12 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 JUL 16 PY 2015 VL 126 IS 3 BP 291 EP 299 DI 10.1182/blood-2015-01-621664 PG 9 WC Hematology SC Hematology GA CO0UC UT WOS:000358867900005 PM 25987659 ER PT J AU Bianchi, G Richardson, PG Anderson, KC AF Bianchi, Giada Richardson, Paul G. Anderson, Kenneth C. TI Promising therapies in multiple myeloma SO BLOOD LA English DT Article ID ORAL PROTEASOME INHIBITOR; LOW-DOSE DEXAMETHASONE; OVERCOMES BORTEZOMIB RESISTANCE; HISTONE DEACETYLASE INHIBITORS; SINGLE-AGENT CARFILZOMIB; SMALL-MOLECULE INHIBITOR; IN-VIVO CYTOTOXICITY; ANTITUMOR-ACTIVITY; RANDOMIZED PHASE-2; REFRACTORY MYELOMA C1 Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancy,Dept Med Oncol,Jerome Lipp, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Mayer 557,450 Brookline Ave, Boston, MA 02215 USA. EM kenneth_anderson@dfci.harvard.edu NR 124 TC 12 Z9 12 U1 1 U2 8 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 JUL 16 PY 2015 VL 126 IS 3 BP 300 EP 310 DI 10.1182/blood-2015-03-575365 PG 11 WC Hematology SC Hematology GA CO0UC UT WOS:000358867900006 PM 26031917 ER PT J AU Jain, S Stroopinsky, D Yin, L Rosenblatt, J Alam, M Bhargava, P Clark, RA Kupper, TS Palmer, K Coll, MD Rajabi, H Pyzer, A Bar-Natan, M Luptakova, K Arnason, J Joyce, R Kufe, D Avigan, D AF Jain, Salvia Stroopinsky, Dina Yin, Li Rosenblatt, Jacalyn Alam, Maroof Bhargava, Parul Clark, Rachael A. Kupper, Thomas S. Palmer, Kristen Coll, Maxwell D. Rajabi, Hasan Pyzer, Athalia Bar-Natan, Michal Luptakova, Katarina Arnason, Jon Joyce, Robin Kufe, Donald Avigan, David TI Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA CELLS; DOWN-REGULATING TIGAR; MUC1-C ONCOPROTEIN; EXPRESSION; DEATH; PRALATREXATE; ACTIVATION; SURVIVAL; PROTEIN AB Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL. C1 [Jain, Salvia; Stroopinsky, Dina; Rosenblatt, Jacalyn; Bhargava, Parul; Palmer, Kristen; Coll, Maxwell D.; Pyzer, Athalia; Bar-Natan, Michal; Luptakova, Katarina; Arnason, Jon; Joyce, Robin; Avigan, David] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Yin, Li; Alam, Maroof; Rajabi, Hasan; Kufe, Donald] Dana Farber Canc Inst, Boston, MA 02115 USA. [Clark, Rachael A.; Kupper, Thomas S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02215 USA. RP Jain, S (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Malignant Hematol & Bone Marrow Transplantat, 330 Brookline Ave, Boston, MA 02215 USA. EM ssjain@bidmc.harvard.edu FU National Institutes of Health National Cancer Institute [P50CA100707, P50CA9368305]; Conquer Cancer Foundation; National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR063962, R01AR056720]; Damon Runyon Clinical Investigator Award; National Institutes of Health National Institute of Allergy and Infectious Diseases [R01AI097128] FX This work was supported by National Institutes of Health National Cancer Institute, MM Specialized Program of Research Excellence (grant P50CA100707); the Conquer Cancer Foundation Young Investigator Grant; National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R01AR063962 and R01AR056720) (R.A.C.); a Damon Runyon Clinical Investigator Award (R.A.C.); the National Institutes of Health National Cancer Institute, Specialized Program of Research Excellence in Skin Cancer (P50CA9368305) (T.S.K.); and National Institutes of Health National Institute of Allergy and Infectious Diseases (R01AI097128) (T.S.K. and R.A.C.). NR 24 TC 7 Z9 7 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 16 PY 2015 VL 126 IS 3 BP 354 EP 362 DI 10.1182/blood-2015-02-628149 PG 9 WC Hematology SC Hematology GA CO0UC UT WOS:000358867900012 PM 26048911 ER PT J AU Kopolovic, I Ostro, J Tsubota, H Lin, YL Cserti-Gazdewich, CM Messner, HA Keir, AK DenHollander, N Dzik, WS Callum, J AF Kopolovic, Ilana Ostro, Jackie Tsubota, Hideki Lin, Yulia Cserti-Gazdewich, Christine M. Messner, Hans A. Keir, Amy K. DenHollander, Neal Dzik, Walter S. Callum, Jeannie TI A systematic review of transfusion-associated graft-versus-host disease SO BLOOD LA English DT Review ID HLA-HOMOZYGOUS DONORS; BLOOD-TRANSFUSIONS; IRRADIATION; PRODUCTS; PATIENT; RISK; COMPONENTS; CHILDREN; THERAPY; SURGERY AB Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The clinicolaboratory features of TA-GVHD and the relative contributions of recipient and component factors remain poorly understood. We conducted a systematic review of TA-GVHD reports. The HLA relationship between donor and recipient was classified as D = 0 when no donor antigens were foreign to the recipient vs D >= 1 when >= 1 donor antigen disparity occurred. We identified 348 unique cases. Criteria for component irradiation were met in 48.9% of cases (34.5% immune-compromised, 14.4% related-donor), although nonirradiated components were transfused in the vast majority of these (97.6%). Components were typically whole blood and red cells. When reported, component storage duration was <= 10 days in 94%, and 23 (6.6%) were leukoreduced (10 bedside, 2 prestorage, and 11 unknown). Among 84 cases with HLAdata available, the category of D = 0 was present in 60 patients (71%) at either HLA class I or II loci and was more common among recipients without traditional indications for component irradiation. These data challenge the historic emphasis on host immune defects in the pathogenesis of TA-GVHD. The dominant mechanism of TA-GVHD in both immunocompetent and compromised hosts is exposure to viable donor lymphocytes not recognized as foreign by, but able to respond against, the recipient. C1 [Kopolovic, Ilana; Ostro, Jackie] Univ Toronto, Dept Med, Div Hematol, Toronto, ON, Canada. [Tsubota, Hideki] Univ Toronto, Div Cardiac Surg, Toronto, ON, Canada. [Lin, Yulia] Sunnybrook Hlth Sci Ctr, Dept Clin Pathol, Toronto, ON M4N 3M5, Canada. [Lin, Yulia; Callum, Jeannie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Cserti-Gazdewich, Christine M.] Univ Toronto, Dept Lab Med, Univ Hlth Network, Toronto, ON, Canada. [Messner, Hans A.] Univ Hlth Network, Princess Margaret Canc Ctr, Allogene Blood & Marrow Transplant Program, Toronto, ON, Canada. [Keir, Amy K.] Univ Adelaide, Robinson Inst, Adelaide, SA, Australia. [DenHollander, Neal] Univ Hlth Network, Reg Histocompatibil Lab, Toronto, ON, Canada. [Dzik, Walter S.] Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. RP Callum, J (reprint author), Sunnybrook Hlth Sci Ctr, B204,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM jeannie.callum@sunnybrook.ca NR 44 TC 13 Z9 13 U1 0 U2 5 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 JUL 16 PY 2015 VL 126 IS 3 BP 406 EP 414 DI 10.1182/blood-2015-01-620872 PG 9 WC Hematology SC Hematology GA CO0UC UT WOS:000358867900018 PM 25931584 ER PT J AU Wilcox, BJ Beckwith, JG Greenwald, RM Raukar, NP Chu, JJ McAllister, TW Flashman, LA Maerlender, AC Duhaime, AC Crisco, JJ AF Wilcox, Bethany J. Beckwith, Jonathan G. Greenwald, Richard M. Raukar, Neha P. Chu, Jeffrey J. McAllister, Thomas W. Flashman, Laura A. Maerlender, Arthur C. Duhaime, Ann-Christine Crisco, Joseph J. TI Biomechanics of head impacts associated with diagnosed concussion in female collegiate ice hockey players SO JOURNAL OF BIOMECHANICS LA English DT Article DE Impact biomechanics; Concussion; Female; Hockey ID TRAUMATIC BRAIN-INJURY; HIGH-SCHOOL FOOTBALL; EXPOSURE; ACCELERATION; SYMPTOMS; SPORTS; GENDER; GAME; SEX AB Epidemiological evidence suggests that female athletes may be at a greater risk of concussion than their male counterparts. The purpose of this study was to examine the biomechanics of head impacts associated with diagnosed concussions in a cohort of female collegiate ice hockey players. Instrumented helmets were worn by 58 female ice hockey players from 2 NCAA programs over a three year period. Kinematic measures of single impacts associated with diagnosed concussion and head impact exposure on days with and without diagnosed concussion were evaluated. Nine concussions were diagnosed. Head impact exposure was greater in frequency and magnitude on days of diagnosed concussions than on days without diagnosed concussion for individual athletes. Peak linear accelerations of head impacts associated with diagnosed concussion in this study are substantially lower than those previously reported in male athletes, while peak rotational accelerations are comparable. Further research is warranted to determine the extent to which female athletes' biomechanical tolerance to concussion injuries differs from males. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Wilcox, Bethany J.; Crisco, Joseph J.] Brown Univ, Warren Alpert Med Sch, Bioengn Lab, Dept Orthopaed, Providence, RI 02903 USA. [Wilcox, Bethany J.; Crisco, Joseph J.] Rhode Isl Hosp, Providence, RI USA. [Beckwith, Jonathan G.; Greenwald, Richard M.; Chu, Jeffrey J.] Simbex, Lebanon, NH USA. [Greenwald, Richard M.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Raukar, Neha P.] Brown Univ, Warren Alpert Med Sch, Dept Emergency Med, Providence, RI 02903 USA. [McAllister, Thomas W.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Flashman, Laura A.] Geisel Sch Med Dartmouth, Dept Psychiat, Lebanon, NH USA. [Maerlender, Arthur C.] Univ Nebraska, Ctr Brain Biol & Behav, Lincoln, NE USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Pediat Neurosurg, Boston, MA 02114 USA. RP Wilcox, BJ (reprint author), Brown Univ, Alpert Med Sch, Bioengn Lab, Dept Orthopaed, CORO West,Suite 404,1 Hoppin St, Providence, RI 02903 USA. EM Bethany_Wilcox@brown.edu FU National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences at the National Institute of Health [R01HD048638, RO1NS055020, R25GM083270, R25GM083270-S1]; National Operating Committee on Standards for Athletic Equipment (NOCSAE) FX Research reported in this publication was supported by the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute of General Medical Sciences at the National Institute of Health under award numbers R01HD048638, RO1NS055020, R25GM083270 and R25GM083270-S1 and the National Operating Committee on Standards for Athletic Equipment (NOCSAE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or NOCSAE. We gratefully acknowledge and thank the engineering team at Simbex for all of their technical support. We would like to thank Lindley Brainard and Wendy Chamberlin at Simbex for their role in data collection and clinical coordination. We would also like to thank Russell Fiore, M.Ed., A.T.C, Emily Burmeister M.S., A.T.C, and Brian Daigneault, MS, A.T.C at Brown University; Jeff Frechette, A.T.C., and Tracey Poro, A.T.C.at Dartmouth College Sports Medicine and Mary Hynes, R.N., M.P.H. at Dartmouth Medical School for their support on this project. NR 30 TC 5 Z9 5 U1 2 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 EI 1873-2380 J9 J BIOMECH JI J. Biomech. PD JUL 16 PY 2015 VL 48 IS 10 BP 2201 EP 2204 DI 10.1016/j.jbiomech.2015.04.005 PG 4 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA CN5HG UT WOS:000358459800073 PM 25913243 ER PT J AU Cacchiarelli, D Trapnell, C Ziller, MJ Soumillon, M Cesana, M Karnik, R Donaghey, J Smith, ZD Ratanasirintrawoot, S Zhang, XL Sui, SJH Wu, ZT Akopian, V Gifford, CA Doench, J Rinn, JL Daley, GQ Meissner, A Lander, ES Mikkelsen, TS AF Cacchiarelli, Davide Trapnell, Cole Ziller, Michael J. Soumillon, Magali Cesana, Marcella Karnik, Rahul Donaghey, Julie Smith, Zachary D. Ratanasirintrawoot, Sutheera Zhang, Xiaolan Sui, Shannan J. Ho Wu, Zhaoting Akopian, Veronika Gifford, Casey A. Doench, John Rinn, John L. Daley, George Q. Meissner, Alexander Lander, Eric S. Mikkelsen, Tarjei S. TI Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; HUMAN SOMATIC-CELLS; GROUND-STATE PLURIPOTENCY; IPS CELLS; FIBROBLASTS; METHYLATION; CANCER; CONVERSION; SYSTEM; GENOME AB Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here, we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered re-activation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies. C1 [Cacchiarelli, Davide; Ziller, Michael J.; Soumillon, Magali; Karnik, Rahul; Donaghey, Julie; Smith, Zachary D.; Akopian, Veronika; Gifford, Casey A.; Rinn, John L.; Meissner, Alexander; Mikkelsen, Tarjei S.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Cacchiarelli, Davide; Ziller, Michael J.; Soumillon, Magali; Karnik, Rahul; Donaghey, Julie; Smith, Zachary D.; Zhang, Xiaolan; Akopian, Veronika; Gifford, Casey A.; Doench, John; Rinn, John L.; Meissner, Alexander; Lander, Eric S.; Mikkelsen, Tarjei S.] Broad Inst, Cambridge, MA 02142 USA. [Cacchiarelli, Davide; Ziller, Michael J.; Soumillon, Magali; Cesana, Marcella; Karnik, Rahul; Donaghey, Julie; Smith, Zachary D.; Ratanasirintrawoot, Sutheera; Sui, Shannan J. Ho; Wu, Zhaoting; Akopian, Veronika; Gifford, Casey A.; Rinn, John L.; Daley, George Q.; Meissner, Alexander; Mikkelsen, Tarjei S.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Cesana, Marcella; Ratanasirintrawoot, Sutheera; Wu, Zhaoting; Daley, George Q.] Boston Childrens Hosp, Boston, MA 02115 USA. [Cesana, Marcella; Ratanasirintrawoot, Sutheera; Wu, Zhaoting; Daley, George Q.] Harvard Univ, Sch Med, Manton Ctr Orphan Dis Res, Dana Farber Canc Inst,Howard Hughes Med Inst,Dept, Boston, MA 02115 USA. [Sui, Shannan J. Ho] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Trapnell, Cole] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Mikkelsen, TS (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM tarjei@broadinstitute.org OI Karnik, Rahul/0000-0002-0400-635X; Doench, John/0000-0002-3707-9889 FU Swiss National Science Foundation postdoctoral fellowship; Harvard Stem Cell Institute; NIGMS [P01GM099117, R01GM107536] FX We are grateful to Martin Sauvageau and Alexander Tsankov for technical assistance and for helpful discussion. D.C. is a Human Frontier Science Program Fellow. C.T. is a Damon Runyon Fellow. M.C. is an EMBO and Leukemia and Lymphoma Society Fellow. M.S. was supported by a Swiss National Science Foundation postdoctoral fellowship, and D.C., M.S., S.J.H.S., and T.S.M. were supported by the Harvard Stem Cell Institute. A.M. is a New York Stem Cell Foundation, Robertson Investigator. This work was supported by grants from NIGMS to T.S.M., A.M., and J.L.R. (P01GM099117) and G.Q.D. (R01GM107536). NR 46 TC 24 Z9 24 U1 4 U2 25 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 JUL 16 PY 2015 VL 162 IS 2 BP 412 EP 424 DI 10.1016/j.cell.2015.06.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CN0EU UT WOS:000358087700020 PM 26186193 ER PT J AU Maskell, DP Renault, L Serrao, E Lesbats, P Matadeen, R Hare, S Lindemann, D Engelman, AN Costa, A Cherepanov, P AF Maskell, Daniel P. Renault, Ludovic Serrao, Erik Lesbats, Paul Matadeen, Rishi Hare, Stephen Lindemann, Dirk Engelman, Alan N. Costa, Alessandro Cherepanov, Peter TI Structural basis for retroviral integration into nucleosomes SO NATURE LA English DT Article ID PROTOTYPE FOAMY VIRUS; ELECTRON-MICROSCOPY; STRAND TRANSFER; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; SITE SELECTION; CORE PARTICLE; CELL-LINE; DNA; SEQUENCE AB Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome(1,2). How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/- 3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration. C1 [Maskell, Daniel P.; Lesbats, Paul; Cherepanov, Peter] Francis Crick Inst, Chromatin Struct & Mobile DNA, S Mimms EN6 3LD, Herts, England. [Renault, Ludovic; Costa, Alessandro] Francis Crick Inst, Clare Hall Labs, Architecture & Dynam Macromol Machines, S Mimms EN6 3LD, Herts, England. [Renault, Ludovic] Natl Inst Biol Stand & Control Microscopy & Imagi, S Mimms EN6 3QG, Herts, England. [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Matadeen, Rishi] Gorlaeus Lab, NeCEN, NL-2333 Leiden, Netherlands. [Hare, Stephen; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Med, London W2 1PG, England. [Lindemann, Dirk] Tech Univ Dresden, Inst Virol, D-01307 Dresden, Germany. RP Costa, A (reprint author), Francis Crick Inst, Clare Hall Labs, Architecture & Dynam Macromol Machines, Blanche Lane, S Mimms EN6 3LD, Herts, England. EM alessandro.costa@crick.ac.uk; peter.cherepanov@crick.ac.uk RI Cherepanov, Peter/F-6859-2010; OI Cherepanov, Peter/0000-0002-0634-538X; Renault, Ludovic/0000-0001-6464-8808; Hare, Stephen/0000-0003-2951-1595 FU European Union [305137]; US National Institute of General Medical Sciences [GM082251-06]; US National Institutes of Health [AI070042-08]; Netherlands Centre for Electron Nanoscopy (NeCEN); Nederlandse Organisatie voor Wetenschappelijk Onderzoek [175.010.2009.001]; European Union's Regional Development Fund through 'Kansen voor West' [21Z.014] FX This work was supported by the European Union FP7 HIVINNOV consortium grant 305137 (to P.C.), the US National Institute of General Medical Sciences P50 grant GM082251-06 (to P.C.) and the US National Institutes of Health R01 grant AI070042-08 (to A.N.E.). Data collection was in part funded by the Netherlands Centre for Electron Nanoscopy (NeCEN) by grants from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (project 175.010.2009.001) and by the European Union's Regional Development Fund through 'Kansen voor West' (project 21Z.014). We would like to thank L. Collinson, R. Carzaniga and Kirsty MacLellan-Gibson for EM access, R. Horton-Harpin for provision of HeLa cell pellets and assistance with tissue culture. We also thank F. Santoni, N. Sweeny and all our colleagues for helpful discussions. NR 49 TC 38 Z9 38 U1 2 U2 26 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 JUL 16 PY 2015 VL 523 IS 7560 BP 366 EP + DI 10.1038/nature14495 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM8KY UT WOS:000357950900046 PM 26061770 ER PT J AU Goodman, A AF Goodman, Annekathryn TI The Mountains Are Angry SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Goodman, Annekathryn] Massachusetts Gen Hosp, Ctr Global Hlth, Off Global Disaster Response, Boston, MA 02114 USA. [Goodman, Annekathryn] Int Med Corps, Los Angeles, CA USA. RP Goodman, A (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Off Global Disaster Response, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 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 JUL 16 PY 2015 VL 373 IS 3 BP 203 EP 205 DI 10.1056/NEJMp1506499 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CM8MS UT WOS:000357956200002 PM 26083120 ER PT J AU Salas, RN AF Salas, Renee N. TI Humanity, Teamwork, and Art in Post-Earthquake Nepal SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Salas, Renee N.] Massachusetts Gen Hosp, Dept Emergency Med, Div Wilderness Med, Boston, MA 02114 USA. [Salas, Renee N.] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. RP Salas, RN (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Wilderness Med, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 1 U2 9 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 JUL 16 PY 2015 VL 373 IS 3 BP 205 EP 207 DI 10.1056/NEJMp1506643 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CM8MS UT WOS:000357956200003 PM 26083121 ER PT J AU Steiner, ME Assmann, SF Stowell, CP AF Steiner, Marie E. Assmann, Susan F. Stowell, Christopher P. TI More on the Age of Transfused Red Cells Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID BLOOD C1 [Steiner, Marie E.] Univ Minnesota, Minneapolis, MN 55455 USA. [Assmann, Susan F.] New England Res Inst, Watertown, MA 02172 USA. [Stowell, Christopher P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Steiner, ME (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM stein083@umn.edu NR 3 TC 1 Z9 1 U1 0 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 JUL 16 PY 2015 VL 373 IS 3 BP 283 EP 284 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CM8MS UT WOS:000357956200019 PM 26176390 ER PT J AU Nishino, M Sholl, LM Hodi, FS AF Nishino, Mizuki Sholl, Lynette M. Hodi, F. Stephen TI Anti-PD-1-Related Pneumonitis during Cancer Immunotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ADVANCED MELANOMA; SAFETY; NIVOLUMAB; TRIAL C1 [Nishino, Mizuki; Sholl, Lynette M.; Hodi, F. Stephen] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. EM mizuki_nishino@dfci.harvard.edu FU NCI NIH HHS [1K23CA157631, K23 CA157631] NR 5 TC 49 Z9 49 U1 1 U2 9 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 JUL 16 PY 2015 VL 373 IS 3 BP 288 EP 290 DI 10.1056/NEJMc1505197 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CM8MS UT WOS:000357956200028 PM 26176400 ER PT J AU Weller, M Wick, W Aldape, K Brada, M Berger, M Pfister, SM Nishikawa, R Rosenthal, M Wen, PY Stupp, R Reifenberger, G AF Weller, Michael Wick, Wolfgang Aldape, Ken Brada, Michael Berger, Mitchell Pfister, Stefan M. Nishikawa, Ryo Rosenthal, Mark Wen, Patrick Y. Stupp, Roger Reifenberger, Guido TI Glioma SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID LOW-GRADE GLIOMAS; NEWLY-DIAGNOSED GLIOBLASTOMA; TERM-FOLLOW-UP; CENTRAL-NERVOUS-SYSTEM; RANDOMIZED PHASE-III; RESPONSE ASSESSMENT CRITERIA; MGMT PROMOTER METHYLATION; MAPK PATHWAY ACTIVATION; GENOME-WIDE ASSOCIATION; GIANT-CELL ASTROCYTOMA AB Gliomas are primary brain tumours that are thought to derive from neuroglial stem or progenitor cells. On the basis of their histological appearance, they have been traditionally classified as astrocytic, oligodendroglial or ependymal tumours and assigned WHO grades I-IV, which indicate different degrees of malignancy. Tremendous progress in genomic, transcriptomic and epigenetic profiling has resulted in new concepts of classifying and treating gliomas. Diffusely infiltrating gliomas in adults are now separated into three overarching tumour groups with distinct natural histories, responses to treatment and outcomes: isocitrate dehydrogenase (IDH)-mutant, 1p/19q co-deleted tumours with mostly oligodendroglial morphology that are associated with the best prognosis; IDH-mutant, 1p/19q non-co-deleted tumours with mostly astrocytic histology that are associated with intermediate outcome; and IDH wild-type, mostly higher WHO grade (III or IV) tumours that are associated with poor prognosis. Gliomas in children are molecularly distinct from those in adults, the majority being WHO grade I pilocytic astrocytomas characterized by circumscribed growth, favourable prognosis and frequent BRAF gene fusions or mutations. Ependymal tumours can be molecularly subdivided into distinct epigenetic subgroups according to location and prognosis. Although surgery, radiotherapy and alkylating agent chemotherapy are still the mainstay of treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles may ultimately improve outcome. For an illustrated summary of this Primer, visit: http://go.nature.com/TXY7Ri C1 [Weller, Michael] Univ Zurich Hosp, Dept Neurol, Frauenklin Str 26, CH-8091 Zurich, Switzerland. [Weller, Michael; Stupp, Roger] Univ Zurich Hosp, Brain Tumor Ctr, CH-8091 Zurich, Switzerland. [Weller, Michael; Stupp, Roger] Univ Zurich, CH-8091 Zurich, Switzerland. [Wick, Wolfgang] Heidelberg Univ, Neurol Clin, Heidelberg, Germany. [Wick, Wolfgang] German Canc Res Ctr, Heidelberg, Germany. [Aldape, Ken] Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. [Brada, Michael] Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England. [Brada, Michael] Univ Liverpool, Dept Radiat Oncol, Liverpool, Merseyside, England. [Brada, Michael] Clatterbridge Canc Ctr NHS Fdn Trust, Liverpool, Merseyside, England. [Berger, Mitchell] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany. [Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Haematol & Oncol, Heidelberg, Germany. [Nishikawa, Ryo] Saitama Med Univ, Dept Neurooncol & Neurosurg, Saitama, Japan. [Rosenthal, Mark] Royal Melbourne Hosp, Dept Med Oncol, Parkville, Vic 3050, Australia. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Stupp, Roger] Univ Zurich Hosp, Dept Oncol, Zurich, Switzerland. [Reifenberger, Guido] Univ Dusseldorf, Dept Neuropathol, Dusseldorf, Germany. [Reifenberger, Guido] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. RP Weller, M (reprint author), Univ Zurich Hosp, Dept Neurol, Frauenklin Str 26, CH-8091 Zurich, Switzerland. EM michael.weller@usz.ch FU MSD; Roche; Chugai; Nobelpharma; Eisai; Novocure; Merck; Merck Serono; Acceleron; Actelion; Alpinia Institute; Bayer; Isarna; PIQUR; Amgen; AngioChem; AstraZeneca; Exelixis; Genentech/Roche; GlaxoSmithKline; Novartis; Sanofi-Aventis; Vascular Biogenics; Apogenix; Boehringer Ingelheim; Eli Lilly; immatics; Pfizer FX M. Berger serves as a consultant for Ivivi Health Sciences. M. Brada served on advisory boards for Merck Serono, Roche and AbbVie. R.N. has received honoraria for lectures or advisory board participation, or sponsorship for meetings from MSD, Roche, Chugai, Nobelpharma, Eisai and Novocure. G.R. has received research grants from Roche and Merck, as well as honoraria for lectures or advisory boards from Roche and Amgen. R.S. has served on advisory boards for AbbVie, Actelion, Merck Serono, MSD, Novartis, Pfizer and Roche, and is or has been the coordinating investigator for sponsored clinical trials evaluating temozolomide (MSD), cilengitide (Merck Serono) and Tumour Treating Fields (Novocure). M.W. has received research grants from Acceleron, Actelion, Alpinia Institute, Bayer, Isarna, MSD, Merck Serono, Novocure, PIQUR and Roche, and honoraria for lectures or advisory board participation from AbbVie, Celldex, Isarna, MagForce, MSD, Merck Serono, Novartis, Novocure, Pfizer, Roche and Teva. P.Y.W. has received research grants from Amgen, AngioChem, AstraZeneca, Exelixis, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Sanofi-Aventis and Vascular Biogenics, and honoraria for lectures or advisory board participation from AbbVie, Celldex, Foundation Medicine, Genentech/Roche, Merck, Novartis, Vascular Biogenics, Midatech and Monteris. W.W. has received research grants from Apogenix, Boehringer Ingelheim, Eli Lilly, immatics, MSD and Roche, as well as honoraria for lectures or advisory board participation from MSD and Roche. W.W. is or has been the coordinating investigator for sponsored clinical trials evaluating APG101 (Apogenix), bevacizumab (Roche), galunisertib (Eli Lilly), temozolomide (MSD) and temsirolimus (Pfizer). S.M.P. and M.R. and K.A. declare no competing interests. NR 194 TC 7 Z9 8 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD JUL 16 PY 2015 VL 1 AR 15017 DI 10.1038/nrdp.2015.17 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA DT2KR UT WOS:000381309700001 PM 27188790 ER PT J AU Fisher, DE AF Fisher, David E. TI Skin pigmentation pathways and melanoma risk SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Fisher, David E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA IA21 DI 10.1158/1538-7445.MEL2014-IA21 PG 1 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700063 ER PT J AU Heppt, MV Joshua, WX Hristova, DM Wei, Z Irmler, M Berking, C Besch, R Beckers, J Rauscher, FJ Fisher, DE Herlyn, M Fukunaga-Kalabis, M AF Heppt, Markus V. Joshua, Wang X. Hristova, Denitsa M. Wei, Zhi Irmler, Martin Berking, Carola Besch, Robert Beckers, Johannes Rauscher, Frank J., III Fisher, David E. Herlyn, Meenhard Fukunaga-Kalabis, Mizuho TI MSX1-induced neural crest-like reprograming promotes melanoma progression SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Heppt, Markus V.; Joshua, Wang X.; Hristova, Denitsa M.; Rauscher, Frank J., III; Herlyn, Meenhard; Fukunaga-Kalabis, Mizuho] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Wei, Zhi] New Jersey Inst Technol, Newark, NJ 07102 USA. [Irmler, Martin; Beckers, Johannes] Helmholtz Zentrum Munchen GmbH, Inst Expt Genet, Neuherberg, Germany. [Berking, Carola; Besch, Robert] Univ Munich, Munich, Germany. [Fisher, David E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA A13 DI 10.1158/1538-7445.MEL2014-A13 PG 1 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700008 ER PT J AU Kaur, A Marchbank, K Dang, V O'Connell, M Webster, M Appleton, J Cheng, P Valiga, A Morissette, R McDonnell, N Ferrucci, L Kossenkov, A Meeth, K Bosenberg, M Tang, HY Yin, XF Wood, W Lehrmann, E Becker, K Flaherty, K Frederick, D Wargo, J Aird, K Zhang, RG Xu, XW Liu, Q Speicher, D Weeraratna, A AF Kaur, Amanpreet Marchbank, Katie Dang, Vanessa O'Connell, Michael Webster, Marie Appleton, Jessica Cheng, Phil Valiga, Alexander Morissette, Rachel McDonnell, Nazli Ferrucci, Luigi Kossenkov, Andrew Meeth, Katrina Bosenberg, Marcus Tang, Hsin-Yao Yin, Xiangfan Wood, William, III Lehrmann, Elin Becker, Kevin Flaherty, Keith Frederick, Dennie Wargo, Jennifer Aird, Katherine Zhang, Rugang Xu, Xiaowei Liu, Qin Speicher, David Weeraratna, Ashani TI Aging microenvironment modulates melanoma invasion and metastasis SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Kaur, Amanpreet; Marchbank, Katie; Dang, Vanessa; O'Connell, Michael; Webster, Marie; Appleton, Jessica; Valiga, Alexander; Kossenkov, Andrew; Tang, Hsin-Yao; Yin, Xiangfan; Aird, Katherine; Zhang, Rugang; Liu, Qin; Speicher, David; Weeraratna, Ashani] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Cheng, Phil] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Morissette, Rachel; McDonnell, Nazli; Ferrucci, Luigi; Wood, William, III; Lehrmann, Elin; Becker, Kevin] NIA, NIH, Baltimore, MD 21224 USA. [Meeth, Katrina; Bosenberg, Marcus] Yale Univ, New Haven, CT USA. [Flaherty, Keith; Frederick, Dennie; Wargo, Jennifer] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Xu, Xiaowei] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA A04 DI 10.1158/1538-7445.MEL2014-A04 PG 2 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700002 ER PT J AU Long, G Dummer, R Flaherty, K Schadendorf, D Arenberger, P Demidov, L Di Giacomo, AM Mandala, M Rangoni, G Wolter, P Yamazaki, N Ford, J Wasserman, E Weill, M Ascierto, P AF Long, Georgina Dummer, Reinhard Flaherty, Keith Schadendorf, Dirk Arenberger, Petr Demidov, Lev Di Giacomo, Anna Maria Mandala, Mario Rangoni, Giovanni Wolter, Pascal Yamazaki, Naoya Ford, James Wasserman, Ernesto Weill, Marine Ascierto, Paolo TI NEMO: A phase 3 trial of binimetinib (MEK162) versus dacarbazine in patients with advanced NRAS-mutant melanoma who are untreated or have progressed on or after immunotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Long, Georgina] Melanoma Inst Australia, Sydney, NSW, Australia. [Long, Georgina] Univ Sydney, Sydney, NSW 2006, Australia. [Dummer, Reinhard] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Flaherty, Keith] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schadendorf, Dirk] Univ Hosp Essen, Essen, Germany. [Arenberger, Petr] Charles Univ Prague, Prague, Czech Republic. [Demidov, Lev] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Di Giacomo, Anna Maria] Univ Hosp Siena, Siena, Italy. [Mandala, Mario] Papa Giovanni XXIII Hosp, Bergamo, Italy. [Rangoni, Giovanni] Spedali Civil Brescia, I-25125 Brescia, Italy. [Wolter, Pascal] Leuven Canc Inst, Leuven, Belgium. [Yamazaki, Naoya] Natl Canc Ctr, Tokyo, Japan. [Ford, James; Wasserman, Ernesto; Weill, Marine] Novartis Pharmaceut, E Hanover, NJ USA. [Ascierto, Paolo] Fdn Pascale, Ist Nazl Tumori, Naples, Italy. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA B16 DI 10.1158/1538-7445.MEL2014-B16 PG 2 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700036 ER PT J AU Pietruska, JR Luo, C Hinds, PW AF Pietruska, Jodie R. Luo, Chi Hinds, Philip W. TI Expression of BRAFV600E in melanocytes induces Schwannian differentiation in vivo SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Pietruska, Jodie R.; Hinds, Philip W.] Tufts Univ, Boston, MA 02111 USA. [Luo, Chi] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA A19 DI 10.1158/1538-7445.MEL2014-A19 PG 1 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700012 ER PT J AU Shen, CH Yuan, P Perez-Lorenzo, R Zhang, YQ Lee, SX Ou, Y Cai, L Asara, JM Cantley, LC Zheng, B AF Shen, Che-Hung Yuan, Ping Perez-Lorenzo, Rolando Zhang, Yaqing Lee, Sze Xian Ou, Yang Cai, Li Asara, John M. Cantley, Lewis C. Zheng, Bin TI Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Shen, Che-Hung; Yuan, Ping; Cai, Li; Zheng, Bin] Harvard Univ, MGH, CBRC, Boston, MA 02115 USA. [Perez-Lorenzo, Rolando; Ou, Yang] Columbia Univ, ICG, New York, NY USA. [Zhang, Yaqing] Univ Michigan, Ann Arbor, MI 48109 USA. [Lee, Sze Xian; Asara, John M.] BIDMC, Boston, MA USA. [Cantley, Lewis C.] Weill Cornell Med Coll, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA B09 DI 10.1158/1538-7445.MEL2014-B09 PG 1 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700030 ER PT J AU Zheng, B AF Zheng, Bin TI Targeting AMPK signaling in melanoma SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Melanoma - From Biology to Therapy CY SEP 20-23, 2014 CL Philadelphia, PA SP Amer Assoc Canc Res C1 [Zheng, Bin] Massachusetts Gen Hosp, Charlestown, MA USA. [Zheng, Bin] Harvard Univ, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2015 VL 75 SU 14 MA IA20 DI 10.1158/1538-7445.MEL2014-IA20 PG 1 WC Oncology SC Oncology GA DE9QK UT WOS:000370972700062 ER PT J AU Janssen, SJ Teunis, T Guitton, TG Ring, D Herndon, JH AF Janssen, Stein J. Teunis, Teun Guitton, Thierry G. Ring, David Herndon, James H. TI Orthopaedic Surgeons' View on Strategies for Improving Patient Safety SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID HEALTH-CARE; NONTEACHING HOSPITALS; SURGICAL OUTCOMES; PRESSURE ULCERS; RISK-FACTORS; CLIMATE; CULTURE; ERRORS AB Background: Many strategies have been introduced to improve safety in health care, but it is not clear that these efforts have reduced errors. This study assessed the experienced safety culture and preferred means of improving safety among orthopaedists. Methods: Members of the Science of Variation Group and Ankle Platform were invited to complete an eighty-nine-question survey. Outcomes measured were the modified Patient Safety Climate in Healthcare Organizations (PSCHO) questionnaire, which measures safety as perceived by hospital personnel, and the degree of enthusiasm expressed for seventeen means of improving safety. Results: The questionnaire was completed by 387 (92%) of the 422 participants. The rate of problematic responses, those implying a lack of safety climate, in the modified PSCHO questionnaire was 18%. In multivariable linear regression analysis, working in a non-teaching hospital (beta, 3.7; 95% confidence interval [95% CI], 1.3 to 6.2; p = 0.003), having a safety program (beta, 4.8; 95% CI, 0.74 to 8.8; p = 0.020), and male sex (beta, 3.7; 95% CI, 0.079 to 7.3; p = 0.045) were associated with higher perceived safety as measured by the PSCHO questionnaire. The majority of participants were very enthusiastic about making safety everyone's responsibility (75%), promoting better communication (80%), standardizing procedures (58%), and standardizing equipment and supplies (63%) to improve safety. Conclusions: We found a high problematic response rate concerning the perceived safety climate among surgeons, but there was a high rate of enthusiasm for means of improving safety. Knowledge of the variation in perceived safety and the enthusiasm for strategies to improve safety among surgeons can serve as a starting point for cultural change. C1 [Janssen, Stein J.; Teunis, Teun; Guitton, Thierry G.; Ring, David; Herndon, James H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand & Upper Extrem Serv,Dept Orthopaed Surg, Boston, MA 02114 USA. RP Janssen, SJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Yawkey Ctr, Hand & Upper Extrem Serv,Dept Orthopaed Surg,Sch, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM steinjanssen@gmail.com; teunteunis@gmail.com; guitton@gmail.com; dring@mgh.harvard.edu; jherndon@mgh.harvard.edu NR 37 TC 0 Z9 1 U1 1 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL 15 PY 2015 VL 97A IS 14 BP 1173 EP 1186 DI 10.2106/JBJS.N.01235 PG 14 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CY4RN UT WOS:000366396000008 PM 26178892 ER PT J AU Schwartz, AJ Nussmeier, NA Shafer, S AF Schwartz, Alan Jay Nussmeier, Nancy A. Shafer, Steven TI Experience = Education: Time for the Next Step SO A & A CASE REPORTS LA English DT Editorial Material C1 [Schwartz, Alan Jay] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. [Nussmeier, Nancy A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Shafer, Steven] Stanford Univ, Dept Anesthesia, Stanford, CA 94305 USA. RP Schwartz, AJ (reprint author), Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM schwartza@email.chop.edu 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 2325-7237 J9 A A CASE REP JI A A Case Rep. PD JUL 15 PY 2015 VL 5 IS 2 BP 15 EP 16 DI 10.1213/XAA.0000000000000199 PG 2 WC Anesthesiology SC Anesthesiology GA CQ5SL UT WOS:000360665900001 PM 26171735 ER PT J AU Brown, JR Davids, MS Rodon, J Abrisqueta, P Kasar, SN Lager, J Jiang, J Egile, C Awan, FT AF Brown, Jennifer R. Davids, Matthew S. Rodon, Jordi Abrisqueta, Pau Kasar, Siddha N. Lager, Joanne Jiang, Jason Egile, Coumaran Awan, Farrukh T. TI Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID B-CELL LYMPHOMA; ADVANCED SOLID TUMORS; PIK3CA MUTATIONS; PI3K INHIBITOR; PTEN LOSS; CANCER; RECEPTOR; P110-DELTA; IDELALISIB; SURVIVAL AB Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Patients and Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade >= 3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage >= 50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival >= 6 months. Conclusions: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. (C) 2015 AACR. C1 [Brown, Jennifer R.; Davids, Matthew S.; Kasar, Siddha N.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Rodon, Jordi; Abrisqueta, Pau] Val dHebron Univ Hosp, Barcelona, Spain. [Rodon, Jordi; Abrisqueta, Pau] Univ Autonoma Barcelona, E-08193 Barcelona, Spain. [Lager, Joanne] Sanofi Oncol, Cambridge, MA USA. [Jiang, Jason] Sanofi, Bridgewater, NJ USA. [Egile, Coumaran] Sanofi Oncol, Vitry Sur Seine, France. [Awan, Farrukh T.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Brown, JR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_brown@dfci.harvard.edu RI Awan, Farrukh/L-5642-2016 OI Awan, Farrukh/0000-0003-1813-9812 FU Sanofi; Exelixis; Leukemia Lymphoma Society; American Cancer Society; Lymphoma Research Foundation; American Society of Clinical Oncology FX This study was funded by Sanofi and Exelixis. The authors received editorial support from Paul Scutt of MediTech Media Ltd, funded by Sanofi. J.R. Brown is supported by the Leukemia Lymphoma Society and the American Cancer Society and is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. F.T. Awan is supported by a career development award from the Lymphoma Research Foundation. M.S. Davids was a Leukemia & Lymphoma Society Special Fellow in Clinical Research and has a Career Development Award from the American Society of Clinical Oncology. NR 55 TC 9 Z9 11 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2015 VL 21 IS 14 BP 3160 EP 3169 DI 10.1158/1078-0432.CCR-14-3262 PG 10 WC Oncology SC Oncology GA CO7FC UT WOS:000359324000010 PM 25840972 ER PT J AU Xu, XS Ryan, CJ Stuyckens, K Smith, MR Saad, F Griffin, TW Park, YC Yu, MK Vermeulen, A Poggesi, I Nandy, P AF Xu, Xu S. Ryan, Charles J. Stuyckens, Kim Smith, Matthew R. Saad, Fred Griffin, Thomas W. Park, Youn C. Yu, Margaret K. Vermeulen, An Poggesi, Italo Nandy, Partha TI Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID CLINICAL DRUG DEVELOPMENT; SURROGATE END-POINT; ANDROGEN RECEPTOR; WORKING GROUP; TUMOR SIZE; PHASE-II; TRIALS; PSA; CYP17; CHEMOTHERAPY AB Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapypretreated, n = 1,184) andCOU-AA-302(chemotherapy naive, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. Results: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naive and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (>= 30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR similar to 0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. Conclusions: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naive patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. (C) 2015 AACR. C1 [Xu, Xu S.; Park, Youn C.; Nandy, Partha] Janssen Res & Dev, Raritan, NJ 08869 USA. [Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Stuyckens, Kim; Vermeulen, An; Poggesi, Italo] Janssen Res & Dev, Beerse, Belgium. [Smith, Matthew R.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Saad, Fred] Univ Montreal, Montreal, PQ, Canada. [Griffin, Thomas W.; Yu, Margaret K.] Janssen Res & Dev, Los Angeles, CA USA. RP Xu, XS (reprint author), Janssen Res & Dev, US 920 Route 202, Raritan, NJ 08869 USA. EM sxu26@its.jnj.com FU Johnson & Johnson Pharmaceutical Research Development; Janssen Global Services, LLC FX The analyses and studies described in this report were funded by Johnson & Johnson Pharmaceutical Research & Development and Janssen Global Services, LLC funded the writing support. NR 43 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2015 VL 21 IS 14 BP 3170 EP 3177 DI 10.1158/1078-0432.CCR-14-1549 PG 8 WC Oncology SC Oncology GA CO7FC UT WOS:000359324000011 PM 25829400 ER PT J AU Goldberg, JM Fisher, DE Demetri, GD Neuberg, D Allsop, SA Fonseca, C Nakazaki, Y Nemer, D Raut, CP George, S Morgan, JA Wagner, AJ Freeman, GJ Ritz, J Lezcano, C Mihm, M Canning, C Hodi, FS Dranoff, G AF Goldberg, John M. Fisher, David E. Demetri, George D. Neuberg, Donna Allsop, Stephen A. Fonseca, Catia Nakazaki, Yukoh Nemer, David Raut, Chandrajit P. George, Suzanne Morgan, Jeffrey A. Wagner, Andrew J. Freeman, Gordon J. Ritz, Jerome Lezcano, Cecilia Mihm, Martin Canning, Christine Hodi, F. Stephen Dranoff, Glenn TI Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines SO CLINICAL CANCER RESEARCH LA English DT Article ID MEDIATED TUMOR DESTRUCTION; PROTEIN ML-IAP; TRANSCRIPTION FACTOR; METASTATIC MELANOMA; CANCER-IMMUNOTHERAPY; MALIGNANT-MELANOMA; ANTITUMOR IMMUNITY; GROWTH-FACTOR; GENE; INHIBITOR AB Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction. (C) 2015 AACR. C1 [Goldberg, John M.; Fisher, David E.; Wagner, Andrew J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Goldberg, John M.; Fisher, David E.; Wagner, Andrew J.] Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Goldberg, John M.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Pediat, Miami, FL 33136 USA. [Fisher, David E.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Demetri, George D.; Hodi, F. Stephen] Harvard Univ, Sch Med, Ludwig Ctr Harvard, Boston, MA USA. [Demetri, George D.; Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; George, Suzanne; Morgan, Jeffrey A.; Freeman, Gordon J.; Ritz, Jerome; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Demetri, George D.; Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; George, Suzanne; Morgan, Jeffrey A.; Freeman, Gordon J.; Ritz, Jerome; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Neuberg, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; Freeman, Gordon J.; Ritz, Jerome; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Ctr Immunooncol, Boston, MA 02215 USA. [Allsop, Stephen A.; Fonseca, Catia; Nakazaki, Yukoh; Nemer, David; Freeman, Gordon J.; Ritz, Jerome; Canning, Christine; Hodi, F. Stephen; Dranoff, Glenn] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA. [Raut, Chandrajit P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Surg Oncol, Boston, MA 02115 USA. [Raut, Chandrajit P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Lezcano, Cecilia] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mihm, Martin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 520C,450 Brookline Ave, Boston, MA 02215 USA. EM glenn_dranoff@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU NCI [P01-CA163222, U54CA163125, R01 AR043369, R01 CA111506] FX This work was supported by NCI grants P01-CA163222, U54CA163125, R01 AR043369, R01 CA111506, and philanthropic support from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.E. Fisher and G.D. Demetri), iCureASPS (to G.D. Demetri and G. Dranoff), and the Knockin' Down ASPS Committee (to G.D. Demetri and G. Dranoff). NR 52 TC 8 Z9 8 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2015 VL 21 IS 14 BP 3178 EP 3186 DI 10.1158/1078-0432.CCR-14-2932 PG 9 WC Oncology SC Oncology GA CO7FC UT WOS:000359324000012 PM 25805798 ER PT J AU Richardson, DM Medvedeva, EL Roberts, CB Linkin, DR AF Richardson, Diane M. Medvedeva, Elina L. Roberts, Christopher B. Linkin, Darren R. CA Ctr Dis Control Prevention Epictr Program TI Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccination in Community-Dwelling Veterans SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE influenza vaccines; influenza human; comparative effectiveness research; elderly ID RESPIRATORY SYNCYTIAL VIRUS; UNITED-STATES; OLDER-ADULTS; PROPENSITY SCORE; ELDERLY-PEOPLE; HOSPITALIZATIONS; VACCINES; MORTALITY; EFFICACY; SEASON AB Background. Influenza is a significant cause of morbidity and mortality in older adults. High-dose (HD) trivalent inactivated vaccine has increased immunogenicity in older adults compared with standard-dose (SD) vaccine. We assessed the relative effectiveness of HD influenza vaccination (vs SD influenza vaccination). Methods. We conducted a retrospective cohort study among patients who receive primary care at Veteran Health Administration (VHA) medical centers, and who received influenza vaccine in the 2010-2011 influenza season. The primary outcome was hospitalization for influenza or pneumonia. We also conducted an analysis in subgroups defined by age. Results. We evaluated 25 714 patients who received HD vaccine and 139 511 who received SD vaccine in 23 VHA medical centers. The rate of hospitalization for influenza or pneumonia was 0.3% in both groups in the influenza season. After accounting for patient characteristics in propensity-adjusted analyses, the risk of hospitalization for influenza or pneumonia was not significantly lower among patients receiving HD vaccine vs those receiving SD vaccine (risk ratio, 0.98; 95% confidence interval,.68-1.40). In the subgroup of patients >= 85 years of age, receiving HD (compared with SD) vaccine was associated with lower rates of hospitalization for influenza or pneumonia. Conclusions. HD vaccine was not found to be more effective than SD vaccine in protecting against hospitalization for influenza or pneumonia; however, we found a protective effect in the oldest subgroup of patients. Additional studies are needed to evaluate the effectiveness of HD vaccine. C1 [Richardson, Diane M.; Medvedeva, Elina L.; Roberts, Christopher B.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Linkin, Darren R.] Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Linkin, Darren R.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Linkin, Darren R.] Philadelphia Vet Affairs Med Ctr, Div Infect Dis, Dept Med, Philadelphia, PA USA. RP Linkin, DR (reprint author), Philadelphia VA Med Ctr, Dept Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM linkin@mail.med.upenn.edu FU Veterans Integrated Service Network 4 Competitive Pilot Project Fund; Centers for Disease Control and Prevention Epicenters Program [U54-CK000163] FX This work was supported by the Veterans Integrated Service Network 4 Competitive Pilot Project Fund. The study was also supported in part by the Centers for Disease Control and Prevention Epicenters Program (U54-CK000163 [Ebbing Lautenbach]). NR 32 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 15 PY 2015 VL 61 IS 2 BP 171 EP 176 DI 10.1093/cid/civ261 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CO7MD UT WOS:000359342500006 PM 25829001 ER PT J AU O'Brien, TD Jia, PL Xia, JF Saxena, U Jin, HL Vuong, H Kim, P Wang, QG Aryee, MJ Mino-Kenudson, M Engelman, JA Le, LP Iafrate, AJ Heist, RS Pao, W Zhao, ZM AF O'Brien, Timothy D. Jia, Peilin Xia, Junfeng Saxena, Uma Jin, Hailing Vuong, Huy Kim, Pora Wang, Qingguo Aryee, Martini J. Mino-Kenudson, Mari Engelman, Jeffrey A. Le, Long P. Iafrate, A. John Heist, Rebecca S. Pao, William Zhao, Zhongming TI Inconsistency and features of single nucleotide variants detected in whole exome sequencing versus transcriptome sequencing: A case study in lung cancer SO METHODS LA English DT Article DE Single nucleotide variants; Whole exome sequencing; RNA-Seq; Somatic mutations; Allele frequency; RNA editing ID SOMATIC POINT MUTATIONS; WIDESPREAD RNA; GENOME; ADENOCARCINOMA; LANDSCAPE; DISCOVERY; FRAMEWORK; ALIGNMENT; GENE AB Whole exome sequencing (WES) and RNA sequencing (RNA-Seq) are two main platforms used for next-generation sequencing (NGS). While WES is primarily for DNA variant discovery and RNA-Seq is mainly for measurement of gene expression, both can be used for detection of genetic variants, especially single nucleotide variants (SNVs). How consistently variants can be detected from WES and RNA-Seq has not been systematically evaluated. In this study, we examined the technical and biological inconsistencies in SNV detection using WES and RNA-Seq data from 27 pairs of tumor and matched normal samples. We analyzed SNVs in three categories: WES unique - those only detected in WES, RNA-Seq unique those only detected in RNA-Seq, and shared - those detected in both. We found a small overlap (average similar to 14%) between the SNVs called in WES and RNA-Seq. The WES unique SNVs were mainly due to low coverage, low expression, or their location on the non-transcribed strand in RNA-Seq data, while the RNA-Seq unique SNVs were primarily due to their location out of the WES-capture boundary regions (accounting similar to 71%), as well as low coverage of the regions, low coverage of the mutant alleles or RNA-editing. The shared SNVs had high locus-specific coverage in both WES and RNA-Seq and high gene expression levels. Additionally, WES unique and RNA-Seq unique SNVs showed different nucleotide substitution patterns, e.g., similar to 55% of RNA-Seq unique variants were A:T -> G:C, a hallmark of RNA editing. This study provides an important evaluation on the inconsistencies of somatic SNVs called in WES and RNA-Seq data. (C) 2015 Elsevier Inc. All rights reserved. C1 [O'Brien, Timothy D.] Vanderbilt Univ, Ctr Human Genet Res, Sch Med, Nashville, TN 37232 USA. [O'Brien, Timothy D.; Jia, Peilin; Xia, Junfeng; Vuong, Huy; Kim, Pora; Wang, Qingguo; Zhao, Zhongming] Vanderbilt Univ, Dept Biomed Informat, Sch Med, Nashville, TN 37203 USA. [Saxena, Uma; Aryee, Martini J.; Mino-Kenudson, Mari; Le, Long P.; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Jin, Hailing; Pao, William] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA. [Engelman, Jeffrey A.; Heist, Rebecca S.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. [Zhao, Zhongming] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37232 USA. [Zhao, Zhongming] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. RP Zhao, ZM (reprint author), Vanderbilt Univ, Dept Biomed Informat, Sch Med, 2525 West End Ave,Suite 600, Nashville, TN 37203 USA. EM timothy.obrien@vanderbilt.edu; peilinjia@vanderbilt.edu; jfxia@ahu.edu.cn; stqa8350@gmail.com; hailing.jin@Vanderbilt.Edu; huy.vuong@gmail.com; pora.kim@vanderbilt.edu; josephw10000@gmail.com; Aryee.Martin@mgh.harvard.edu; MMINOKENUDSON@partners.org; JENGELMAN@partners.org; LPLE@partners.org; AIAFRATE@partners.org; RHEIST@partners.org; william.pao@Vanderbilt.Edu; zhongming.zhao@vanderbilt.edu OI Wang, Qingguo/0000-0002-5125-3724 FU LUNGevity Foundation; Upstage Lung Cancer; US National Institutes of Health [R01LM011177, P50CA095103, P50CA098131, P30CA068 485]; Vanderbilt Breast SPORE pilot grant; Ingram Professorship Funds; National Institute of General Medical Sciences [T32GM080178] FX This study was supported by a grant from LUNGevity Foundation and Upstage Lung Cancer. We also thank the financial support from US National Institutes of Health grants (R01LM011177, P50CA095103, P50CA098131, and P30CA068 485), a Vanderbilt Breast SPORE pilot grant, and Ingram Professorship Funds (ZZ). TO was supported by a National Institute of General Medical Sciences Training Grant (T32GM080178). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 5 Z9 5 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JUL 15 PY 2015 VL 83 BP 118 EP 127 DI 10.1016/j.ymeth.2015.04.016 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CN9GK UT WOS:000358755100015 PM 25913717 ER PT J AU Politikos, I Kim, HT Nikiforow, S Li, LQ Brown, J Antin, JH Cutler, C Ballen, K Ritz, J Boussiotis, VA AF Politikos, Ioannis Kim, Haesook T. Nikiforow, Sarah Li, Lequn Brown, Julia Antin, Joseph H. Cutler, Corey Ballen, Karen Ritz, Jerome Boussiotis, Vassiliki A. TI IL-7 and SCF Levels Inversely Correlate with T Cell Reconstitution and Clinical Outcomes after Cord Blood Transplantation in Adults SO PLOS ONE LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; RECENT THYMIC EMIGRANTS; IMMUNE RECONSTITUTION; IN-VIVO; PLASMA-LEVELS; STEM-CELLS; ACUTE GVHD; INTERLEUKIN-7; RECOVERY AB Recovery of thymopoiesis is critical for immune reconstitution after HSCT. IL-7 and SCF are two major thymotropic cytokines. We investigated whether the kinetics of circulating levels of these cytokines might provide insight into the prolonged immunodeficiency after double umbilical cord blood transplantation (dUCBT) in adults. We examined plasma levels of IL-7 and SCF, T-cell receptor rearrangement excision circle (TREC) levels and T cell subsets in 60 adult patients undergoing dUCBT. Median levels of IL-7 increased by more than 3-fold at 4 weeks and remained elevated through 100 days after dUCBT. SCF showed a less than 2-fold increase and more protracted elevation than IL-7. IL-7 levels inversely correlated with the reconstitution of various T cell subsets but not with TRECs. SCF levels inversely correlated with reconstitution of CD4(+)T cells, especially the naive CD4(+)CD45RA(+) subset, and with TRECs suggesting that SCF but not IL-7 had an effect on thymic regeneration. In Cox models, elevated levels of IL-7 and SCF were associated with higher non-relapse mortality (p = 0.03 and p = 0.01) and worse overall survival (p = 0.002 and p = 0.001). Elevated IL-7 but not SCF was also associated with development of GvHD (p = 0.03). Thus, IL-7 and SCF are elevated for a prolonged period after dUCBT and persistently high levels of these cytokines may correlate with worse clinical outcomes. C1 [Politikos, Ioannis; Li, Lequn; Brown, Julia; Boussiotis, Vassiliki A.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Politikos, Ioannis; Li, Lequn; Brown, Julia; Boussiotis, Vassiliki A.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Nikiforow, Sarah; Antin, Joseph H.; Cutler, Corey; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ballen, Karen] Massachusetts Gen Hosp, Bone Marrow Transplantat Unit, Boston, MA 02114 USA. RP Boussiotis, VA (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. EM vboussio@bidmc.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health [A1098129, CA183605, CA142106, CA183559, CA183560]; Leukemia and Lymphoma grant [TRP 6222-11]; HHV6 Foundation Pilot Grant FX This work was supported by the National Institutes of Health Grants A1098129 (V.A.B.), CA183605 (V.A.B.), CA142106 (J.R.), CA183559 (J.R.) and CA183560 (J.R.); the Leukemia and Lymphoma grant TRP 6222-11 (V.A.B.); and the HHV6 Foundation Pilot Grant (V.A.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 1 Z9 1 U1 1 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 JUL 15 PY 2015 VL 10 IS 7 AR e0132564 DI 10.1371/journal.pone.0132564 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1RL UT WOS:000358197600124 PM 26177551 ER PT J AU Tanner, NT Gebregziabher, M Halbert, CH Payne, E Egede, LE Silvestri, GA AF Tanner, Nichole T. Gebregziabher, Mulugeta Halbert, Chanita Hughes Payne, Elizabeth Egede, Leonard E. Silvestri, Gerard A. TI Racial Differences in Outcomes within the National Lung Screening Trial SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE lung cancer screening; race; mortality ID AFRICAN-AMERICANS; SOCIOECONOMIC-STATUS; SMOKING-CESSATION; COLORECTAL-CANCER; SMOKERS; STAGE; ATTITUDES; HEALTH; RISK; PHARMACOTHERAPY AB Rationale: Black individuals with lung cancer (LC) experience higher mortality because they present with more advanced disease and are less likely to undergo curative resection for early-stage disease. The National Lung Screening Trial (NLST) demonstrated improved LC mortality by screening high-risk patients with low-dose computed tomography (LDCT). The benefit of LDCT screening in black individuals is unknown. Objectives: Examine results of the NLST by race. Methods: This was a secondary analysis of a randomized trial (NCT00047385) performed in 33 U.S. centers. Measurements and Main Results: Overall and lung cancer-specific mortality were measured. Screening with LDCT reduced LC mortality in all racial groups but more so in black individuals (hazard ratio [HR], 0.61 vs. 0.86). Smoking increased the likelihood of death from LC, and when stratified by race black smokers were twice as likely to die as white smokers (HR, 4.10 vs. 2.25). Adjusting for sociodemographic and behavioral characteristics, black individuals experienced higher all-cause mortality than white individuals (HR, 1.35; 95% confidence interval, 1.22-1.49); however, black individuals screened with LDCT had a reduction in all-cause mortality. Black individuals were younger, were more likely to be current smokers, had more comorbidities, and had fewer years of formal education than white individuals (P < 0.05). Conclusions: Black individuals screened with LDCT had decreased mortality from lung cancer. However, the demographics associated with improved LC survival were less commonly found in black individuals. The overall mortality in the NLST was higher for black individuals than white individuals, but improved in black individuals screened, suggesting that this subgroup may have had improved access to care. To realize the reductions in mortality from LC screening, dissemination efforts need to be tailored to meet the needs of this community. C1 [Tanner, Nichole T.; Gebregziabher, Mulugeta; Halbert, Chanita Hughes; Egede, Leonard E.] Ralph H Johnson Vet Affairs Hosp, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. [Tanner, Nichole T.; Silvestri, Gerard A.] Med Univ S Carolina, Div Pulm & Crit Care Med, Charleston, SC 29425 USA. [Gebregziabher, Mulugeta; Payne, Elizabeth] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Halbert, Chanita Hughes] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Halbert, Chanita Hughes] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Egede, Leonard E.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Tanner, NT (reprint author), 96 Jonathan Lucas St,CSB 810, Charleston, SC 29425 USA. EM tripici@musc.edu FU OneBreath Foundation FX Funded by the OneBreath Foundation. NR 53 TC 9 Z9 9 U1 1 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2015 VL 192 IS 2 BP 200 EP 208 DI 10.1164/rccm.201502-0259OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CN2CW UT WOS:000358229100018 PM 25928649 ER PT J AU Choi, M Humar, M Kim, S Yun, SH AF Choi, Myunghwan Humar, Matjaz Kim, Seonghoon Yun, Seok-Hyun TI Step-Index Optical Fiber Made of Biocompatible Hydrogels SO ADVANCED MATERIALS LA English DT Article DE biocompatible; hydrogels; implantable; optical fibers; sensing ID WAVE-GUIDES; IN-VIVO; ENCAPSULATION C1 [Choi, Myunghwan; Humar, Matjaz; Kim, Seonghoon; Yun, Seok-Hyun] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Choi, Myunghwan; Humar, Matjaz; Kim, Seonghoon; Yun, Seok-Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Choi, Myunghwan] Sungkyunkwan Univ, Global Biomed Engn, Ctr Neurosci & Imaging Res, Inst Basic Sci, Suwon, Gyeong Gi Do, South Korea. [Humar, Matjaz] Jozef Stefan Inst, Condensed Matter Dept, SI-1000 Ljubljana, Slovenia. [Kim, Seonghoon] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol, Taejon 305701, South Korea. RP Yun, SH (reprint author), Harvard Univ, Sch Med, 65 Landsdowne St,UP 5, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu RI Humar, Matjaz/I-8862-2012; OI Humar, Matjaz/0000-0003-3338-6723; Choi, Myunghwan/0000-0002-4235-7003 FU U.S. National Institutes of Health [P41EB015903, R21EB013761]; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [627274] FX The authors thank Prof. Xiangwei Zhao for discussions. This work was funded by the U.S. National Institutes of Health ( Grant Nos. P41EB015903 and R21EB013761) and Marie Curie International Outgoing Fellowship No 627274 within the 7th European Community Framework Programme. NR 25 TC 7 Z9 7 U1 12 U2 55 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD JUL 15 PY 2015 VL 27 IS 27 BP 4081 EP 4086 DI 10.1002/adma.201501603 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA CM8YA UT WOS:000357988000019 PM 26045317 ER PT J AU Rubenstein, LV AF Rubenstein, Lisa V. TI Managing physician lipid management: a population wide, risk-based decision support approach SO ISRAEL JOURNAL OF HEALTH POLICY RESEARCH LA English DT Editorial Material ID HEALTH-CARE AB Successful implementation of clinical guidelines for preventing complications of dyslipidemias has been an ongoing challenge. The article by Vinker and colleagues in this journal investigates the results of implementing risk-based guidelines for LDL (Low Density Lipoprotein) management in comparison to the prior approach of using the same LDL cutoff for patients at all levels of risk. Results show LDL levels dropped across the primary care population using the new risk-based approach, suggesting that clinical decision aids that link to individual patient characteristics, rather than promoting a universal target for all, may provide a particularly strong stimulus for changing provider and patient behavior. Results also challenge healthcare organizations, providers and patients to learn more about the pathway from guidelines to clinical reminders and from reminders to lower LDL levels and better population health. C1 [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Sepulveda, CA 91343 USA. [Rubenstein, Lisa V.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA QUERI Ctr Implementat Practice & Res Support, Sepulveda, CA USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] UCLA Geffen Sch Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND Corp, RAND Hlth, Santa Monica, CA USA. RP Rubenstein, LV (reprint author), VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Sepulveda, CA 91343 USA. EM lisar@rand.org NR 10 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 2045-4015 J9 ISR J HEALTH POLICY JI Isr. J. Health Policy Res. PD JUL 15 PY 2015 VL 4 AR 34 DI 10.1186/s13584-015-0032-9 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CM7DT UT WOS:000357851300001 PM 26175893 ER PT J AU Rieder, SA Metidji, A Glass, DD Thornton, AM Ikeda, T Morgan, BA Shevach, EM AF Rieder, Sadiye Amcaoglu Metidji, Amina Glass, Deborah Dacek Thornton, Angela M. Ikeda, Tohru Morgan, Bruce A. Shevach, Ethan M. TI Eos Is Redundant for Regulatory T Cell Function but Plays an Important Role in IL-2 and Th17 Production by CD4(+) Conventional T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IKAROS FAMILY; RECEPTOR; DIFFERENTIATION; EXPRESSION; SIGNATURE; IMMUNITY AB Eos belongs to the Ikaros family of transcription factors. It was reported to be a regulatory T cell (Treg) signature gene, to play a critical role in Treg suppressor functions, and to maintain Treg stability. We used mice with a global deficiency in Eos to re-examine the role of Eos expression in both Tregs and conventional T cells (Tconvs). Tregs from Eos-deficient (Eos(-/-)) mice developed normally, displayed a normal Treg phenotype, and exhibited normal suppressor function in vitro. Eos(-/-) Tregs were as effective as Tregs from wild-type (WT) mice in suppressing inflammation in a model of inflammatory bowel disease. Bone marrow (BM) from Eos(-/-) mice was as effective as that from WT mice in controlling T cell activation when used to reconstitute immunodeficient mice in the presence of scurfy fetal liver cells. Surprisingly, Eos was expressed in activated Tconvs and was required for IL-2 production, CD25 expression, and proliferation in vitro by CD4(+) Tconvs. Eos(-/-) mice developed more severe experimental autoimmune encephalomyelitis than WT mice, displayed increased numbers of effector T cells in the periphery and CNS, and amplified IL-17 production. In conclusion, our studies are not consistent with a role for Eos in Treg development and function but demonstrate that Eos plays an important role in the activation and differentiation of Tconvs. C1 [Rieder, Sadiye Amcaoglu; Metidji, Amina; Glass, Deborah Dacek; Thornton, Angela M.; Shevach, Ethan M.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Ikeda, Tohru; Morgan, Bruce A.] Harvard Univ, Sch Med, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Ikeda, Tohru; Morgan, Bruce A.] Massachusetts Gen Hosp, Boston, MA 02129 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 19 TC 2 Z9 2 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 JUL 15 PY 2015 VL 195 IS 2 BP 553 EP 563 DI 10.4049/jimmunol.1500627 PG 11 WC Immunology SC Immunology GA CM9YM UT WOS:000358066800016 PM 26062998 ER PT J AU Causton, B Ramadas, RA Cho, JL Jones, K Pardo-Saganta, A Rajagopal, J Xavier, RJ Medoff, BD AF Causton, Benjamin Ramadas, Ravisankar A. Cho, Josalyn L. Jones, Khristianna Pardo-Saganta, Ana Rajagopal, Jayaraj Xavier, Ramnik J. Medoff, Benjamin D. TI CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; BRONCHIAL EPITHELIAL-CELLS; THYMIC STROMAL LYMPHOPOIETIN; PROTEASE-ACTIVATED RECEPTOR-2; COLONY-STIMULATING FACTOR; DUST MITE ALLERGEN; DENDRITIC CELLS; LYSOPHOSPHATIDIC ACID; T-CELLS; BRONCHOALVEOLAR LAVAGE AB Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-kappa B in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-kB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-kappa B activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. C1 [Causton, Benjamin; Cho, Josalyn L.; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Medoff, Benjamin D.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Causton, Benjamin; Cho, Josalyn L.; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Xavier, Ramnik J.; Medoff, Benjamin D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Causton, Benjamin; Cho, Josalyn L.; Jones, Khristianna; Medoff, Benjamin D.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Causton, Benjamin; Cho, Josalyn L.; Jones, Khristianna; Medoff, Benjamin D.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ramadas, Ravisankar A.] Merck Res Labs, Boston, MA 02115 USA. [Pardo-Saganta, Ana; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Medoff, BD (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM bmedoff@mgh.harvard.edu FU National Institutes of Health [R01 HL088297, R01 HL116756, T32 HL07874]; Massachusetts General Hospital Executive Committee on Research interim support award FX This work was supported by National Institutes of Health Grants R01 HL088297 (to B.D.M. and R.J.X.), R01 HL116756 (to J.R.), and T32 HL07874 (to B.D.M.), as well as by a Massachusetts General Hospital Executive Committee on Research interim support award (to B.D.M.). NR 109 TC 2 Z9 2 U1 2 U2 4 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 JUL 15 PY 2015 VL 195 IS 2 BP 683 EP 694 DI 10.4049/jimmunol.1402983 PG 12 WC Immunology SC Immunology GA CM9YM UT WOS:000358066800028 PM 26041536 ER PT J AU Vaduganathan, M Tahhan, AS Greene, SJ Kelkar, AA Georgiopoulou, VV Kalogeropoulos, AP Fonarow, GC Gheorghiade, M Butler, J AF Vaduganathan, Muthiah Tahhan, Ayman S. Greene, Stephen J. Kelkar, Anita A. Georgiopoulou, Vasiliki V. Kalogeropoulos, Andreas P. Fonarow, Gregg C. Gheorghiade, Mihai Butler, Javed TI Contemporary Cardiovascular Device Clinical Trials (Trends and Patterns 2001 to 2012) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MEDICAL DEVICES; HEART-FAILURE; GUIDELINES; THERAPY AB Device uptake and development have progressed over the last decade, but few quantitative data exist examining the overall operating characteristics and temporal trends of these clinical trials. We performed a systematic analysis of all cardiovascular device clinical trials from 2001 to 2012 published in medical and cardiovascular journals with the 8 highest impact factors. Of the 1,224 identified cardiovascular clinical trials, 299 (24.4%) focused specifically on devices. Each trial included a median of 335 patients (162 to 745) recruited from a median of 14 sites (3 to 38) over a median enrollment duration of 1.9 years (1.2 to 3.3). Median enrollment rate was 1.1 patients/site/month (0.5 to 4.2). Most device trials targeted coronary artery disease (55.2%), followed by arrhythmias (17.4%). Most were industry sponsored (53.6%) and included mortality as a primary end point (69.6%). The median number of patients (225 to 499, p <0.001 for trend) and enrolling sites (11 to 19, p = 0.07 for trend) increased from 2001 to 2012. During the study period, multinational enrollment grew and approached 50% (p = 0.03), whereas trials enrolling in North America exclusively decreased from 30% to 17% (p = 0.10 for trend). Approximately 70% of device trials met their primary end points; this rate did not significantly change over time. In conclusion, this descriptive study of the contemporary cardiovascular device clinical trials highlights recent trends toward larger, more international trial programs. These aggregate data may help inform future cardiovascular device development. (C) 2015 Elsevier Inc. All rights reserved. C1 [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Tahhan, Ayman S.; Kelkar, Anita A.; Georgiopoulou, Vasiliki V.; Kalogeropoulos, Andreas P.] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Greene, Stephen J.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY 11794 USA. RP Vaduganathan, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. EM muthu@md.northwestern.edu OI Vaduganathan, Muthiah/0000-0003-0885-1953 FU National Institutes of Health; European Union FX The authors had full access to the data, take responsibility for its integrity, and had complete control and authority over manuscript preparation and the decision to publish. Dr. Fonarow reports research support from the National Institutes of Health and consultant to Gambro and Medtronic. Dr. Gheorghiade reports relations with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Pharma, Otsuka, Palatin Technologies, Pericor Therapeutics, Protein Design, Sanofi-Aventis, Sigma Tau, Solvay, Sticares InterACT, Takeda, and Trevena. Dr. Butler reports research support from the National Institutes of Health and the European Union and is a consultant to Amgen, Bayer, BG Medicine, Celladon, Gambro, GE Healthcare, Harvest, Medtronic, Ono Pharma, Stemedica, and Trevena. All other authors have no relevant conflicts of interest to declare. NR 26 TC 0 Z9 0 U1 1 U2 2 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 JUL 15 PY 2015 VL 116 IS 2 BP 307 EP 312 DI 10.1016/j.amjcard.2015.03.062 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CM2YK UT WOS:000357548100022 PM 25963222 ER PT J AU Khan, M Dhammu, TS Matsuda, F Singh, AK Singh, I AF Khan, Mushfiquddin Dhammu, Tajinder S. Matsuda, Fumiyo Singh, Avtar K. Singh, Inderjit TI Blocking a vicious cycle nNOS/peroxynitrite/AMPK by S-nitrosoglutathione: implication for stroke therapy SO BMC NEUROSCIENCE LA English DT Article DE AMP-activated protein kinase; Neuronal nitric oxide synthase; Neuroprotection; Peroxynitrite; S-nitrosoglutathione; Stroke; Cerebral ischemia reperfusion ID NITRIC-OXIDE SYNTHASE; ACTIVATED PROTEIN-KINASE; FOCAL CEREBRAL-ISCHEMIA; TRAUMATIC BRAIN-INJURY; RAT MODEL; NEUROPROTECTIVE EFFICACY; PEROXYNITRITE FORMATION; NEUROVASCULAR UNIT; INFARCT VOLUME; BLOOD-FLOW AB Background: Stroke immediately sets into motion sustained excitotoxicity and calcium dysregulation, causing aberrant activity in neuronal nitric oxide synthase (nNOS) and an imbalance in the levels of nitric oxide (NO). Drugs targeting nNOS-originated toxicity may therefore reduce stroke-induced damage. Recently, we observed that a redox-modulating agent of the NO metabolome, S-nitrosoglutathione (GSNO), confers neurovascular protection by reducing the levels of peroxynitrite, a product of aberrant NOS activity. We therefore investigated whether GSNO-mediated neuroprotection and improved neurological functions depend on blocking nNOS/peroxynitrite-associated injurious mechanisms using a rat model of cerebral ischemia reperfusion (IR). Results: IR increased the activity of nNOS, the levels of neuronal peroxynitrite and phosphorylation at Ser(1412) of nNOS. GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser(1412). The Ser(1412) phosphorylation is associated with increased nNOS activity. Supporting the notion that nNOS activity and peroxynitrite are deleterious following IR, inhibition of nNOS by its inhibitor 7-nitroindazole or reducing peroxynitrite by its scavenger FeTPPS decreased IR injury. GSNO also decreased the activation of AMP Kinase (AMPK) and its upstream kinase LKB1, both of which were activated in IR brain. AMPK has been implicated in nNOS activation via Ser(1412) phosphorylation. To determine whether AMPK activation is deleterious in the acute phase of IR, we treated animals after IR with AICAR (an AMPK activator) and compound c (an AMPK inhibitor). While AICAR potentiated, compound c reduced the IR injury. Conclusions: Taken together, these results indicate an injurious nNOS/peroxynitrite/AMPK cycle following stroke, and GSNO treatment of IR inhibits this vicious cycle, resulting in neuroprotection and improved neurological function. GSNO is a natural component of the human body, and its exogenous administration to humans is not associated with any known side effects. Currently, the FDA-approved thrombolytic therapy suffers from a lack of neuronal protective activity. Because GSNO provides neuroprotection by ameliorating stroke's initial and causative injuries, it is a candidate of translational value for stroke therapy. C1 [Khan, Mushfiquddin; Dhammu, Tajinder S.; Matsuda, Fumiyo; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Matsuda, Fumiyo] Kagoshima Univ, Sch Hlth Sci, Kagoshima 890, Japan. [Singh, Avtar K.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Khan, M (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. EM khanm@musc.edu; singhi@musc.edu FU NIH [NS-72511]; VA merit award [BX001062, BX002829]; NIH, National Center for Research Resources [C06 RR018823, C06 RR015455] FX This work was supported by grants from NIH (NS-72511) and VA merit award (BX001062 and BX002829). This work was also supported by the NIH, Grants C06 RR018823 and No C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. We thank Ms. Joyce Bryan and Ms. Terry Hope for their technical help and secretarial assistance. We are grateful to Drs. Harutoshi Sakakima and Yoshihiro Yoshida for their scientific input and to Ms. Danielle Lowe (MD/PhD student at the MUSC) for statistical analysis. We also acknowledge Dr. Tom Smith from the MUSC Writing Center for his valuable editing of the manuscript. NR 62 TC 7 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUL 15 PY 2015 VL 16 AR 42 DI 10.1186/s12868-015-0179-x PG 12 WC Neurosciences SC Neurosciences & Neurology GA CM7CM UT WOS:000357848000001 PM 26174015 ER PT J AU Bauml, JM Chokshi, S Schapira, MM Im, EO Li, SQ Langer, CJ Ibrahim, SA Mao, JJ AF Bauml, Joshua M. Chokshi, Sagar Schapira, Marilyn M. Im, Eun-Ok Li, Susan Q. Langer, Corey J. Ibrahim, Said A. Mao, Jun J. TI Do attitudes and beliefs regarding complementary and alternative medicine impact its use among patients with cancer? A cross-sectional survey SO CANCER LA English DT Article DE CAM; complementary and alternative medicine; cancer; attitudes and beliefs; clinical characteristics; demographics ID PLANNED BEHAVIOR; BREAST-CANCER; LUNG-CANCER; SURVIVORS; TRIAL; QUALITY; CAM; ELECTROACUPUNCTURE; POPULATIONS; ARTHRALGIA AB BACKGROUNDComplementary and alternative medicine (CAM) incorporates treatments used by cancer survivors in an attempt to improve their quality of life. Although population studies have identified factors associated with its use, to the best of the authors knowledge, assessment of why patients use CAM or the barriers against its use have not been examined to date. METHODSThe authors conducted a cross-sectional survey study in the thoracic, breast, and gastrointestinal medical oncology clinics at an academic cancer center. Clinical and demographic variables were collected by self-report and chart abstraction. Attitudes and beliefs were measured using the validated Attitudes and Beliefs about CAM (ABCAM) instrument. This instrument divides attitudes and beliefs into 3 domains: expected benefits, perceived barriers, and subjective norms. RESULTSAmong 969 participants (response rate, 82.7%) surveyed between June 2010 and September 2011, patient age 65 years, female sex, and college education were associated with a significantly greater expected benefit from CAM (P<.0001 for all). Nonwhite patients reported more perceived barriers to CAM use compared with white patients (P<.0001), but had a similar degree of expected benefit (P=.76). In a multivariate logistic regression analysis, all domains of the ABCAM instrument were found to be significantly associated with CAM use (P<.01 for all) among patients with cancer. Attitudes and beliefs regarding CAM explained much more variance in CAM use than clinical and demographic variables alone. CONCLUSIONSAttitudes and beliefs varied by key clinical and demographic characteristics, and predicted CAM use. By developing CAM programs based upon attitudes and beliefs, barriers among underserved patient populations may be removed and more patient centered care may be provided. Cancer 2015;121:2431-2438. (c) 2015 American Cancer Society. Although population studies have identified factors associated with the use of complementary and alternative medicine (CAM), to the authors' knowledge assessment of why patients with cancer use CAM or the barriers against CAM use have not been examined to date. The results of the current study demonstrate that patients' attitudes and beliefs about CAM vary by key clinical and demographic characteristics, and appear to be predictive of CAM use. C1 [Bauml, Joshua M.; Schapira, Marilyn M.; Langer, Corey J.; Mao, Jun J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Bauml, Joshua M.; Langer, Corey J.] Univ Penn, Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Bauml, Joshua M.; Schapira, Marilyn M.; Ibrahim, Said A.] Philadelphia VA Med Ctr, CHERP, Philadelphia, PA USA. [Schapira, Marilyn M.; Ibrahim, Said A.] Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Chokshi, Sagar] Rowan Univ Sch Osteopath Med, Stratford, NJ USA. [Schapira, Marilyn M.; Li, Susan Q.; Ibrahim, Said A.; Mao, Jun J.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Im, Eun-Ok] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Li, Susan Q.; Mao, Jun J.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. RP Mao, JJ (reprint author), Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, 3400 Spruce St 2 Gates, Philadelphia, PA 19104 USA. EM jun.mao@uphs.upenn.edu FU Penn Institute on Aging Pilot Research Grants; National Institutes of Health [1K23 AT004112-05] FX Funded in part by the Penn Institute on Aging Pilot Research Grants. Dr. Mao is supported by the National Institutes of Health (grant 1K23 AT004112-05). NR 28 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2015 VL 121 IS 14 BP 2431 EP 2438 DI 10.1002/cncr.29173 PG 8 WC Oncology SC Oncology GA CM0AI UT WOS:000357340200020 PM 26011157 ER PT J AU Geller, JI Ehrlich, PF Cost, NG Khanna, G Mullen, EA Gratias, EJ Naranjo, A Dome, JS Perlman, EJ AF Geller, James I. Ehrlich, Peter F. Cost, Nicholas G. Khanna, Geetika Mullen, Elizabeth A. Gratias, Eric J. Naranjo, Arlene Dome, Jeffrey S. Perlman, Elizabeth J. TI Characterization of adolescent and pediatric renal cell carcinoma: A report from the Children's Oncology Group study AREN03B2 SO CANCER LA English DT Article DE translocation renal cell carcinoma; pediatric; adolescent; lymph node ID TRANSCRIPTION FACTOR E3; LYMPH-NODE INVOLVEMENT; WILMS-TUMOR STUDY-5; TRANSLOCATION CARCINOMAS; GENE FUSION; QUALITY ASSESSMENT; TARGETED THERAPY; TFE3 GENE; XP11.2; SUNITINIB AB BACKGROUNDThe current study was conducted to characterize the epidemiology, histology, and radiographic features of as well as the surgical approach to pediatric and adolescent renal cell carcinoma (pRCC). METHODSpRCC cases prospectively enrolled on the Children's Oncology Group study AREN03B2 underwent central pathology, radiology, surgery, and oncology review. RESULTSAs of June 2012, 120 of a total of 3250 patients enrolled on AREN03B2 (3.7%) were found to have unilateral RCC (median age, 12.9 years [range, 1.9-22.1 years]; 52.5% were female). Central review classified these as translocation morphology (56 patients), papillary (20 patients), renal medullary carcinoma (13 patients), chromophobe (4 patients), oncocytoma (1 patient), conventional clear cell (1 patient), and RCC not otherwise specified (25 patients). Lymph node (LN) involvement (N+) was found in 35 of 73 cases (47.9%) for which LNs were sampled, including 19 of 40 cases with primary tumors measuring <7 cm (47.5%). Using a size cutoff of 1 cm, imaging detection of LN involvement had a sensitivity of 57.14% (20 of 35 cases; 95% CI, 39.35%-73.68%) and a specificity of 94.59% (35 of 37 cases; 95% CI, 81.81%-99.34%). Distant metastases were present in 23 cases (19.2%). Initial surgery was radical nephrectomy in 88 patients (73.3%), nephron-sparing surgery in 18 patients (15.0%), and biopsy in 14 patients (11.7%). Compared with patients undergoing radical nephrectomy, those treated with nephron-sparing surgery were less likely to have LNs sampled (6 of 18 patients [33.3%] vs 65 of 88 patients [73.9%]; P=.002). CONCLUSIONSTranslocation RCC is the most common form of pediatric and adolescent RCC. Lymph node disease is common and observed among patients with small primary tumors. Imaging has a high specificity but relatively low sensitivity for the detection of such lymph node disease. Failure to sample LNs results in incomplete staging and potentially inadequate disease control for younger patients with RCC. Cancer 2015;121:2457-2464. (c) 2015 American Cancer Society. Pediatric and adolescent renal cell carcinoma typically presents at an advanced stage with frequent involvement of the lymph nodes and with translocation morphology as the most common histology. The high rate of positive lymph nodes noted even with small associated primary tumors, poor imaging sensitivity for lymph node involvement, and frequent failure to sample lymph nodes presents an opportunity for improved diagnostics and care. C1 [Geller, James I.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Pediat Oncol, Cincinnati, OH 45229 USA. [Ehrlich, Peter F.] Univ Michigan, Sch Med, Dept Surg, Sect Pediat Surg,CS Mott Childrens Hosp, Ann Arbor, MI USA. [Cost, Nicholas G.] Univ Colorado, Sch Med, Dept Surg, Div Urol, Aurora, CO USA. [Cost, Nicholas G.] Childrens Hosp Colorado, Aurora, CO USA. [Khanna, Geetika] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Mullen, Elizabeth A.] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Gratias, Eric J.] Univ Tennessee, Coll Med Chattanooga, TC Thompson Childrens Hosp, Div Pediat Hematol Oncol, Chattanooga, TN USA. [Naranjo, Arlene] Univ Florida, Childrens Oncol Grp, Stat & Data Ctr, Dept Biostat, Gainesville, FL USA. [Dome, Jeffrey S.] Childrens Natl Med Ctr, Div Pediat Oncol, Washington, DC 20010 USA. [Perlman, Elizabeth J.] Northwestern Univ, Dept Pathol, Lurie Childrens Hosp Chicago, Feinberg Sch Med, Chicago, IL 60611 USA. RP Geller, JI (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Pediat Oncol, 3333 Burnett Ave, Cincinnati, OH 45229 USA. EM James.Geller@cchmc.org FU National Institutes of Health [U10 CA98413, U10 CA98543] FX Supported by National Institutes of Health grants U10 CA98413 (Children's Oncology Group SDC grant) and U10 CA98543 (Children's Oncology Group Chair's Grant, Peter Adamson, PI). Dana-Farber Cancer Institute receives a portion of that grant for Dr. Mullen's role as the Study Chair. NR 53 TC 2 Z9 2 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2015 VL 121 IS 14 BP 2457 EP 2464 DI 10.1002/cncr.29368 PG 8 WC Oncology SC Oncology GA CM0AI UT WOS:000357340200023 PM 25845370 ER PT J AU Zhou, X Fan, LX Peters, DJM Trudel, M Bradner, JE Li, XG AF Zhou, Xia Fan, Lucy X. Peters, Dorien J. M. Trudel, Marie Bradner, James E. Li, Xiaogang TI Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD SO HUMAN MOLECULAR GENETICS LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; ACUTE LYMPHOBLASTIC-LEUKEMIA; MOLECULE HSP90 INHIBITOR; C-MYC; SELECTIVE-INHIBITION; BREAST-CANCER; CELL-CYCLE; EXPRESSION; MICE; PKD1 AB In this study, we identified a BET bromodomain (BRD) protein, Brd4, not only as a novel epigenetic regulator of autosomal dominant polycystic kidney disease (ADPKD) but also as a novel client protein of Hsp90. We found that Brd4 was upregulated in Pkd1 mutant mouse renal epithelial cells and tissues. This upregulation of Brd4 appears to result from the chaperone activity of Hsp90 and escape proteasomal degradation. We further identify that Brd4 is an upstream regulator of the expression of c-Myc which has been upregulated in all rodent models of PKD and ADPKD patients with unknown mechanism. Inhibition of Brd4 in Pkd1 mutant renal epithelial cells with JQ1, a selective small-molecular inhibitor of BET BRD protein(s), (1) decreased the levels of c-Myc mRNA and protein; (2) increased the levels of p21 mRNA and protein, which was transcriptionally repressed by c-Myc; (3) decreased the phosphorylation of Rb; and (4) decreased cystic epithelial cell proliferation as shown by inhibition of S-phase entry. Most importantly, treatment with JQ1 strikingly delayed cyst growth and kidney enlargement, and preserved renal function in two early stage genetic mouse strains with Pkd1 mutations. This study not only provides one of the mechanisms of how c-Myc is upregulated in PKD but also suggests that targeting Brd4 with JQ1 may function as a novel epigenetic approach in ADPKD. The unraveled link between Brd4 and Hsp90 in ADPKD may also be a general mechanism for the upregulation of Brd4 in cancer cells and opens up avenues for combination therapies against ADPKD and cancer. C1 [Zhou, Xia; Fan, Lucy X.; Li, Xiaogang] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66160 USA. [Zhou, Xia; Fan, Lucy X.; Li, Xiaogang] Univ Kansas, Med Ctr, Kidney Inst, Kansas City, KS 66160 USA. [Li, Xiaogang] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66160 USA. [Peters, Dorien J. M.] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Trudel, Marie] Univ Montreal, Fac Med, Inst Rech Clin Montreal, Mol Genet & Dev, Montreal, PQ H3C 3J7, Canada. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02215 USA. RP Li, XG (reprint author), Univ Kansas, Med Ctr, Dept Internal Med, Kidney Inst, Mail Stop 3018,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM xli3@kumc.edu FU Canadian Institutes of Health Research; NIDDK NIH HHS [R01 DK084097, R01DK084097] NR 51 TC 10 Z9 10 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2015 VL 24 IS 14 BP 3982 EP 3993 DI 10.1093/hmg/ddv136 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CM2PV UT WOS:000357524700009 PM 25877301 ER PT J AU Brivio, D Sajo, E Zygmanski, P AF Brivio, D. Sajo, E. Zygmanski, P. TI Towards thin-film self-powered radiation detectors employing disparate conductive layers SO JOURNAL OF PHYSICS D-APPLIED PHYSICS LA English DT Article DE dose monitoring; self-powered detector; Auger current; thin film detector AB A new class of self-powered thin film radiation detectors is experimentally explored via their IV-curve characteristics. These detectors are parallel-plane microstructures composed of disparate atomic number (Z) thin-film electrodes separated by air gaps. Large radiation-induced electron currents (RIC) are observed for zero external voltage bias. Compared to ionization chambers (composed of macroscopic non-disparate low-Z electrodes), this anomalous behavior is due to two independent effects: traversal of fast electrons leaking from the high-Z cathodes and the auto-collection of ionization electrons from the air gap due to the presence of contact potential. The zero voltage current reaches up to 80% of the saturation current measured for non-zero bias voltages. The magnitude of saturation currents increases with the total anode and cathode atomic numbers. The stopping potentials (i.e., external voltage bias resulting in zero RIC current) correspond to the differences in the electrodes' work functions (the contact potential) modified by the contributions from the fast electron current formed by the leaking electrons. These features make the thin film detector attractive for applications in x-ray medical or industrial imaging, dosimetry and radiation protection. C1 [Brivio, D.; Zygmanski, P.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Brivio, D.; Zygmanski, P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sajo, E.] Univ Massachusetts, Med Phys Program, Dept Phys & Appl Phys, Lowell, MA 01854 USA. RP Brivio, D (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM pzygmanski@lroc.harvard.edu RI Brivio, Davide/R-1330-2016 OI Brivio, Davide/0000-0002-4127-9955 NR 18 TC 3 Z9 3 U1 1 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0022-3727 EI 1361-6463 J9 J PHYS D APPL PHYS JI J. Phys. D-Appl. Phys. PD JUL 15 PY 2015 VL 48 IS 27 AR 275503 DI 10.1088/0022-3727/48/27/275503 PG 7 WC Physics, Applied SC Physics GA CL0IP UT WOS:000356625900020 ER PT J AU Al-Halabi, H Paetzold, P Sharp, GC Olsen, C Willers, H AF Al-Halabi, Hani Paetzold, Peter Sharp, Gregory C. Olsen, Christine Willers, Henning TI A Contralateral Esophagus-Sparing Technique to Limit Severe Esophagitis Associated With Concurrent High-Dose Radiation and Chemotherapy in Patients With Thoracic Malignancies SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CELL LUNG-CANCER; INTENSITY-MODULATED RADIOTHERAPY; PROSTATE-CANCER; THERAPY IMRT; TOXICITY; BALLOON; CHEMORADIATION; ESCALATION; EXPERIENCE; CARCINOMA AB Purpose: Severe (Radiation Therapy Oncology Group [RTOG] grade 3 or greater) esophagitis generally occurs in 15% to 25% of non-small cell lung cancer (NSCLC) patients undergoing concurrent chemotherapy and radiation therapy (CCRT), which may result in treatment breaks that compromise local tumor control and pose a barrier to dose escalation. Here, we report a novel contralateral esophagus-sparing technique (CEST) that uses intensity modulated radiation therapy (IMRT) to reduce the incidence of severe esophagitis. Methods and Materials: We reviewed consecutive patients with thoracic malignancies undergoing curative CCRT in whom CEST was used. The esophageal wall contralateral (CE) to the tumor was contoured as an avoidance structure, and IMRT was used to guide a rapid dose falloff gradient beyond the target volume in close proximity to the esophagus. Esophagitis was recorded based on the RTOG acute toxicity grading system. Results: We identified 20 consecutive patients treated with CCRT of at least 63 Gy in whom there was gross tumor within 1 cm of the esophagus. The median radiation dose was 70.2 Gy (range, 63-72.15 Gy). In all patients, >= 99% of the planning and internal target volumes was covered by >= 90% and 100% of prescription dose, respectively. Strikingly, no patient experienced grade >= 3 esophagitis (95% confidence limits, 0%-16%) despite the high total doses delivered. The median maximum dose, V45, and V55 of the CE were 60.7 Gy, 2.1 cc, and 0.4 cc, respectively, indicating effective esophagus cross-section sparing by CEST. Conclusion: We report a simple yet effective method to avoid exposing the entire esophagus cross-section to high doses. By using proposed CE dose constraints of V45 < 2.5 cc and V55 < 0.5 cc, CEST may improve the esophagus toxicity profile in thoracic cancer patients receiving CCRT even at doses above the standard 60- to 63-Gy levels. Prospective testing of CEST is warranted. (C) 2015 Elsevier Inc. All rights reserved. C1 [Al-Halabi, Hani; Paetzold, Peter; Sharp, Gregory C.; Olsen, Christine; Willers, Henning] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Willers, H (reprint author), Clark Ctr Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM hwillers@mgh.harvard.edu OI Paetzold, Peter/0000-0002-9887-7649 FU Canadian Association of Radiation Oncology - Elekta Fellowship Award FX Hani Al-Halabi received salary support from the Canadian Association of Radiation Oncology - Elekta Fellowship Award. NR 27 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2015 VL 92 IS 4 BP 803 EP 810 DI 10.1016/j.ijrobp.2015.03.018 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK8AR UT WOS:000356460300017 PM 26104934 ER PT J AU Anker, CJ Wo, JY AF Anker, Christopher J. Wo, Jennifer Y. TI Personalized Medicine in Radiation Oncology-A Work in Progress SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID STEREOTACTIC BODY RADIOTHERAPY; COLORECTAL LIVER METASTASES; CANCER; VALIDATION C1 [Anker, Christopher J.] Univ Vermont, Ctr Canc, Div Radiat Oncol, Burlington, VT 05405 USA. [Wo, Jennifer Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Anker, CJ (reprint author), Univ Vermont, Ctr Canc, Div Radiat Oncol, 111 Colchester Ave, Burlington, VT 05405 USA. NR 15 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2015 VL 92 IS 4 BP 843 EP 845 DI 10.1016/j.ijrobp.2015.04.020 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK8AR UT WOS:000356460300022 PM 26104937 ER PT J AU Horton, JK Blitzblau, RC Yoo, S Geradts, J Chang, Z Baker, JA Georgiade, GS Chen, W Siamakpour-Reihani, S Wang, CH Broadwater, G Groth, J Palta, M Dewhirst, M Barry, WT Duffy, EA Chi, JTA Hwang, ES AF Horton, Janet K. Blitzblau, Rachel C. Yoo, Sua Geradts, Joseph Chang, Zheng Baker, Jay A. Georgiade, Gregory S. Chen, Wei Siamakpour-Reihani, Sharareh Wang, Chunhao Broadwater, Gloria Groth, Jeff Palta, Manisha Dewhirst, Mark Barry, William T. Duffy, Eileen A. Chi, Jen-Tsan A. Hwang, E. Shelley TI Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID INTRAOPERATIVE RADIOTHERAPY; RANDOMIZED-TRIAL; 5-YEAR OUTCOMES; IRRADIATION; CANCER; EXPRESSION; TOXICITY; ONCOLOGY AB Purpose: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods and Materials: Women aged >= 55 years with clinically node-negative, estrogen receptorepositive, and/or progsterone receptor-positive HER2-, T1 invasive carcinomas, or low-to intermediate-grade in situ disease <= 2 cm were enrolled (n = 32). Intensity modulated radiation therapy was used to deliver 15 Gy (n = 8), 18 Gy (n = 8), or 21 Gy (n = 16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre-and postradiation magnetic resonance images and patient tumor samples were analyzed. Results: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers. (C) 2015 Elsevier Inc. All rights reserved. C1 [Horton, Janet K.; Blitzblau, Rachel C.; Yoo, Sua; Chang, Zheng; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Palta, Manisha; Dewhirst, Mark; Duffy, Eileen A.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA. [Geradts, Joseph; Groth, Jeff] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Baker, Jay A.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Georgiade, Gregory S.; Hwang, E. Shelley] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Chen, Wei] Duke Univ, Med Ctr, Dept Bioinformat, Durham, NC 27710 USA. [Broadwater, Gloria] Duke Univ, Med Ctr, Duke Canc Inst, Dept Biostat, Durham, NC 27710 USA. [Barry, William T.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Chi, Jen-Tsan A.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Chi, Jen-Tsan A.] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC 27710 USA. [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Horton, JK (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, DUMC 3085, Durham, NC 27710 USA. EM janet.horton@duke.edu FU National Institutes of Health grant - Building Interdisciplinary Research Careers in Women's Health [K12HD043446]; Susan G. Komen for the Cure [CCR12225923]; Varian Medical Systems FX Salary and research support for J.K.H. was provided by National Institutes of Health grant K12HD043446 - Building Interdisciplinary Research Careers in Women's Health. The research was also supported by grants from Susan G. Komen for the Cure (CCR12225923) and Varian Medical Systems. NR 24 TC 10 Z9 10 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2015 VL 92 IS 4 BP 846 EP 855 DI 10.1016/j.ijrobp.2015.03.007 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK8AR UT WOS:000356460300023 PM 26104938 ER PT J AU Krauss, DJ Hu, C Bahary, JP Souhami, L Gore, EM Chafe, SMJ Leibenhaut, MH Narayan, S Torres-Roca, J Michalski, J Zeitzer, KL Donavanik, V Sandler, H McGowan, DG Jones, CU Shipley, WU AF Krauss, Daniel J. Hu, Chen Bahary, Jean-Paul Souhami, Luis Gore, Elizabeth M. Chafe, Susan Maria Jacinta Leibenhaut, Mark H. Narayan, Samir Torres-Roca, Javier Michalski, Jeff Zeitzer, Kenneth L. Donavanik, Viroon Sandler, Howard McGowan, David G. Jones, Christopher U. Shipley, William U. TI Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PHASE-III TRIAL; ANDROGEN DEPRIVATION; RADIATION-THERAPY; BEAM RADIOTHERAPY; DOSE-ESCALATION; COMPETING RISK; SURVIVAL; MORBIDITY AB Purpose: The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. Methods and Materials: Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of <= 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. Results: A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score >= 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). Conclusions: Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors. (C) 2015 Elsevier Inc. All rights reserved. C1 [Krauss, Daniel J.] Oakland Univ, William Beaumont Sch Med, Dept Radiat Oncol, Royal Oak, MI 48073 USA. [Hu, Chen] NRG Stat & Data Management Ctr, Philadelphia, PA USA. [Bahary, Jean-Paul] Ctr Hosp Univ Montreal Notre Dame, Montreal, PQ, Canada. [Souhami, Luis] McGill Univ, Montreal, PQ, Canada. [Gore, Elizabeth M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Chafe, Susan Maria Jacinta; McGowan, David G.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Leibenhaut, Mark H.; Jones, Christopher U.] Sutter Community Hosp, Sacramento, CA USA. [Narayan, Samir] Michigan Canc Res Consortium CCOP, Tampa, FL USA. [Torres-Roca, Javier] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Michalski, Jeff] Washington Univ, St Louis, MO USA. [Zeitzer, Kenneth L.] Albert Einstein Med Ctr, New York, NY USA. [Donavanik, Viroon] Christiana Care Hlth Serv Inc CCOP, Newark, DE USA. [Sandler, Howard] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Shipley, William U.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Krauss, DJ (reprint author), Oakland Univ, William Beaumont Sch Med, Dept Radiat Oncol, 3601 W Thirteen Mile Rd, Royal Oak, MI 48073 USA. EM dkrauss@beaumont.edu FU National Cancer Institute [U10CA21661, U10CA180868, U10CA180822]; Pennsylvania Department of Health [4100062200] FX This project was supported by National Cancer Institute grants U10CA21661, U10CA180868, and U10CA180822 and, in part, by a grant from the Pennsylvania Department of Health (4100062200). The Department specifically declaims responsibility for any analyses, interpretations, or conclusions. NR 22 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2015 VL 92 IS 4 BP 863 EP 873 DI 10.1016/j.ijrobp.2015.03.017 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK8AR UT WOS:000356460300025 PM 26104939 ER PT J AU Wu, AJ Bosch, WR Chang, DT Hong, TS Jabbour, SK Kleinberg, LR Mamon, HJ Thomas, CR Goodman, KA AF Wu, Abraham J. Bosch, Walter R. Chang, Daniel T. Hong, Theodore S. Jabbour, Salma K. Kleinberg, Lawrence R. Mamon, Harvey J. Thomas, Charles R., Jr. Goodman, Karyn A. TI Expert Consensus Contouring Guidelines for Intensity Modulated Radiation Therapy in Esophageal and Gastroesophageal Junction Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; ELECTIVE NODAL IRRADIATION; TARGET VOLUME DELINEATION; ESOPHAGOGASTRIC JUNCTION; ATLAS IMPLEMENTATION; CHEMORADIOTHERAPY; CHEMORADIATION; FEASIBILITY; PATTERN AB Purpose/Objective(s): Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer. Methods and Materials: Eight expert academically based gastrointestinal radiation oncologists participated. Three sample cases were chosen: a GEJ cancer, a distal esophageal cancer, and a mid-upper esophageal cancer. Uniform computed tomographic (CT) simulation datasets and accompanying diagnostic positron emission tomographic/CT images were distributed to each expert, and the expert was instructed to generate gross tumor volume (GTV) and CTV contours for each case. All contours were aggregated and subjected to quantitative analysis to assess the degree of concordance between experts and to generate draft consensus contours. The panel then refined these contours to generate the contouring atlas. Results: The kappa statistics indicated substantial agreement between panelists for each of the 3 test cases. A consensus CTV atlas was generated for the 3 test cases, each representing common anatomic presentations of esophageal cancer. The panel agreed on guidelines and principles to facilitate the generalizability of the atlas to individual cases. Conclusions: This expert panel successfully reached agreement on contouring guidelines for esophageal and GEJ IMRT and generated a reference CTV atlas. This atlas will serve as a reference for IMRT contours for clinical practice and prospective trial design. Subsequent patterns of failure analyses of clinical datasets using these guidelines may require modification in the future. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wu, Abraham J.; Goodman, Karyn A.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Bosch, Walter R.] Washington Univ, St Louis, MO USA. [Chang, Daniel T.] Stanford Canc Inst, Stanford, CA USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jabbour, Salma K.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Kleinberg, Lawrence R.] Johns Hopkins Med Ctr, Baltimore, MD USA. [Mamon, Harvey J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Thomas, Charles R., Jr.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Wu, AJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10065 USA. EM wua@mskcc.org OI Wu, Abraham J./0000-0002-2597-7091 FU National Cancer Institute [U24CA81647, U24 CA180803] FX Supported by U24CA81647 and U24 CA180803 from the National Cancer Institute. NR 29 TC 6 Z9 7 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2015 VL 92 IS 4 BP 911 EP 920 DI 10.1016/j.ijrobp.2015.03.030 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CK8AR UT WOS:000356460300030 PM 26104943 ER PT J AU Iglesias, JE Augustinack, JC Nguyen, K Player, CM Player, A Wright, M Roy, N Frosch, MP McKee, AC Wald, LL Fischl, B Van Leemput, K AF Eugenio Iglesias, Juan Augustinack, Jean C. Khoa Nguyen Player, Christopher M. Player, Allison Wright, Michelle Roy, Nicole Frosch, Matthew P. McKee, Ann C. Wald, Lawrence L. Fischl, Bruce Van Leemput, Koen CA Alzheimers Dis Neuroimaging TI A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI SO NEUROIMAGE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; MEDIAL TEMPORAL-LOBE; ENTORHINAL CORTEX ATROPHY; EARLY ALZHEIMERS-DISEASE; DENTATE GYRUS FUNCTION; T2-WEIGHTED MRI; EPISODIC MEMORY; HUMAN-BRAIN; MAXIMUM-LIKELIHOOD; PATTERN SEPARATION AB Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13 mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1 mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1 mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy). (C) 2015 The Authors. Published by Elsevier Inc. C1 [Eugenio Iglesias, Juan] Basque Ctr Cognit Brain & Language, San Sebastian, Spain. [Eugenio Iglesias, Juan; Augustinack, Jean C.; Khoa Nguyen; Player, Christopher M.; Player, Allison; Wright, Michelle; Roy, Nicole; Wald, Lawrence L.; Fischl, Bruce; Van Leemput, Koen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. [Frosch, Matthew P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, CS Kubik Lab Neuropathol,Pathol Serv, Boston, MA USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.] US Dept Vet Affairs, VA Boston Healthcare Syst, Boston, MA USA. [McKee, Ann C.] Bedford Vet Adm Med Ctr, Bedford, MA USA. [Fischl, Bruce] MIT, Comp Sci & AI Lab, Cambridge, MA 02139 USA. [Van Leemput, Koen] Tech Univ Denmark, Dept Appl Math & Comp Sci, Lyngby, Denmark. [Van Leemput, Koen] Aalto Univ, Dept Informat & Comp Sci, Helsinki, Finland. [Van Leemput, Koen] Aalto Univ, Dept Biomed Engn & Computat Sci, Helsinki, Finland. RP Iglesias, JE (reprint author), Basque Ctr Cognit Brain & Language, San Sebastian, Spain. EM e.iglesias@bcbl.eu RI Iglesias, Juan Eugenio/K-1184-2014; Van Leemput, Koen/A-9197-2009; Wald, Lawrence/D-4151-2009; OI Iglesias, Juan Eugenio/0000-0001-7569-173X; Van Leemput, Koen/0000-0001-6466-5309; Preda, Adrian /0000-0003-3373-2438 FU National Center for Research Resources (NCRR BIRN Morphometric Project) [BIRN002, U24 RR021382]; National Institute for Biomedical Imaging and Bioengineering [R01EB013565, R01EB006758]; National Institute on Aging [AG022381, 5R01AG008122-22, K01AG028521]; National Institute on Aging (BU Alzheimer's Disease Center) [P30AG13846]; National Institute on Aging (BU Framingham Heart Study) [R01AG1649]; National Center for Research Resources [P41EB015896]; National Center for Alternative Medicine [RC1 AT005728-01]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, R01NS083534]; Shared Instrumentation Grant [1S10RR023401, 1S10RR019307, 1S10RR023043]; Autism & Dyslexia Project - Ellison Medical Foundation; NIH Blueprint for Neuroscience Research, multi-institutional Human Connectome Project [5U01-MH093765]; Finnish Funding Agency for Technology and Innovation (ComBrain); Gipuzkoako Foru Aldundia (Fellows Gipuzkoa Program); NIH [P30-AG010129, K01-AG030514]; ADNI 2 add-on project "Hippocampal Subfield Volumetry" [ADNI 2-12-233036]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01 AG024904]; DOD ADNI (Department of Defense award) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Northern California Institute for Research and Education FX Support for this research was provided in part by the National Center for Research Resources (P41EB015896, and the NCRR BIRN Morphometric Project BIRN002, U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01EB013565, R01EB006758), the National Institute on Aging (AG022381, 5R01AG008122-22, K01AG028521, BU Alzheimer's Disease Center P30AG13846, BU Framingham Heart Study R01AG1649), the National Center for Alternative Medicine (RC1 AT005728-01), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, R01NS083534), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation, by the NIH Blueprint for Neuroscience Research (5U01-MH093765), which is part of the multi-institutional Human Connectome Project, and the Finnish Funding Agency for Technology and Innovation (ComBrain). JEI acknowledges financial support from the Gipuzkoako Foru Aldundia (Fellows Gipuzkoa Program). This research was also supported by NIH grants P30-AG010129 and K01-AG030514, as well as the ADNI 2 add-on project "Hippocampal Subfield Volumetry" (ADNI 2-12-233036). The authors would also like to acknowledge Rohit Koppula and Lianne Cagnazzi for their help with the manual segmentation of the ex vivo MRI data; and Susanne Mueller and Paul Yushkevich for their help with the comparison with their methods (Table 4).; The collection and sharing of the MRI data used in the evaluation was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 80 TC 27 Z9 27 U1 1 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2015 VL 115 BP 117 EP 137 DI 10.1016/j.neuroimage.2015.04.042 PG 21 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CK0XU UT WOS:000355929800012 PM 25936807 ER PT J AU Costanzo, EY Villarreal, M Drucaroff, LJ Ortiz-Villafane, M Castro, MN Goldschmidt, M Wainsztein, AE Ladron-de-Guevara, MS Romero, C Brusco, LI Camprodon, JA Nemeroff, C Guinjoan, SM AF Yolanda Costanzo, Elsa Villarreal, Mirta Javier Drucaroff, Lucas Ortiz-Villafane, Manuel Nair Castro, Mariana Goldschmidt, Micaela Edith Wainsztein, Agustina Soledad Ladron-de-Guevara, Maria Romero, Carlos Ignacio Brusco, Luis Camprodon, Joan A. Nemeroff, Charles Martin Guinjoan, Salvador TI Hemispheric specialization in affective responses, cerebral dominance for language, and handedness Lateralization of emotion, language, and dexterity SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Emotion; Lateralization; fMRI; Amygdala; Subgenual cingulate; Anterior insula ID HEART-RATE-VARIABILITY; DEPRESSIVE SYMPTOMS; FUNCTIONAL MRI; NEGATIVE MOOD; OLDER-ADULTS; HUMAN BRAIN; WADA TEST; ASYMMETRY; AMYGDALA; ACTIVATION AB Hemispheric specialization in affective responses has received little attention in the literature. This is a fundamental variable to understand circuit dynamics of networks subserving emotion. In this study we put to test a modified "valence" hypothesis of emotion processing, considering that sadness and happiness are processed by each hemisphere in relation to dominance for language and handedness. Mood induction and language activation during functional magnetic resonance imaging (fMRI) were used in 20 right-handed and 20 nonright-handed subjects, focusing on interconnected regions known to play critical roles in affective responses: subgenual cingulate cortex, amygdala, and anterior insular cortex. We observed a consistent relationship between lateralization of affective processing, motor dexterity, and language in individuals with clear right-handedness. Sadness induces a greater activation of right-hemisphere cortical structures in right-handed, left-dominant individuals, which is not evident in nonright-handed subjects who show no consistent hemispheric dominance for language. In anterior insula, right-handed individuals displayed reciprocal activation of either hemisphere depending upon mood valence, whereas amygdala activation was predominantly left-sided regardless of mood valence. Nonright-handed individuals exhibited less consistent brain lateralization of affective processing regardless of language and motor dexterity lateralization. In contrast with traditional views on emotion processing lateralization, hemispheric specialization in affective responses is not a unitary process but is specific to the brain structure being activated. (C) 2015 Elsevier B.V. All rights reserved. C1 [Yolanda Costanzo, Elsa; Villarreal, Mirta; Javier Drucaroff, Lucas; Ortiz-Villafane, Manuel; Nair Castro, Mariana; Goldschmidt, Micaela; Edith Wainsztein, Agustina; Soledad Ladron-de-Guevara, Maria; Romero, Carlos; Martin Guinjoan, Salvador] FLENI Psychiat & Neuroimaging, Buenos Aires, DF, Argentina. [Yolanda Costanzo, Elsa; Javier Drucaroff, Lucas; Ortiz-Villafane, Manuel; Nair Castro, Mariana; Goldschmidt, Micaela; Edith Wainsztein, Agustina; Soledad Ladron-de-Guevara, Maria; Martin Guinjoan, Salvador] Univ Buenos Aires, Sch Med, Dept Mental Hlth, FLENI Teaching Unit, Buenos Aires, DF, Argentina. [Villarreal, Mirta; Javier Drucaroff, Lucas; Nair Castro, Mariana; Soledad Ladron-de-Guevara, Maria; Ignacio Brusco, Luis; Martin Guinjoan, Salvador] Argentine Natl Council Sci & Technol Res CONICET, Buenos Aires, DF, Argentina. [Yolanda Costanzo, Elsa; Nair Castro, Mariana; Martin Guinjoan, Salvador] Univ Buenos Aires, Sch Psychol, Dept Neurophysiol, Buenos Aires, DF, Argentina. [Ignacio Brusco, Luis] Univ Buenos Aires, Fac Med, Hosp Clin Jose de San Martin, Ctr Neuropsychiat & Behav Neurol CENECON, Buenos Aires, DF, Argentina. [Nemeroff, Charles] Univ Miami, Leonard M Miller Sch Med, Dept Psychiat & Behav Sci, Coral Gables, FL 33124 USA. [Villarreal, Mirta] Univ Buenos Aires, Sch Sci, Dept Phys, Buenos Aires, DF, Argentina. [Camprodon, Joan A.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Guinjoan, SM (reprint author), Univ Buenos Aires, Sch Med, Dept Mental Hlth FLENI, Montaneses 23258th Floor,C1428AQK, Buenos Aires, DF, Argentina. EM sguinjoan@fleni.org.ar OI Goldschmidt, Micaela/0000-0003-4531-8816 FU National Institutes of Health (NIH) FX Charles B. Nemeroff, M.D., Ph.D. Declaration of Financial/Propriety Interest 2011-2014. Research/Grants: National Institutes of Health (NIH). Consulting: Xhale, Takeda, SK Pharma, Shire, Roche, Lilly, Allergan, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Lundbeck, Prismic Pharmaceutical. Stockholder: CeNeRxBioPharma, PharmaNeuroBoost, Revaax Pharma, Xhale, Celgene, Seattle Ge-netics, Abbvie. Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), CeNeRxBioPharma (2012), National Alliance for Research on Schizophrenia and Depression (NARSAD), Xhale, PharmaNeuroBoost (2012), Anxiety Disorders Association of America (ADAA), Skyland Trail. Board of Directors: AFSP, NovaDel (2011), Skyland Trail, Gratitude America, ADAA. Income sources or equity of $10,000 or more:PharmaNeuroBoost, CeNeRxBioPharma, NovaDel Pharma, ReevaxPharma, American Psychiatric Publishing, Xhale. Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1). Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). Speakers Bureau: None. Honoraria: Various. Royalties: Various. Expert Witness: Various. NR 50 TC 8 Z9 8 U1 7 U2 42 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 15 PY 2015 VL 288 BP 11 EP 19 DI 10.1016/j.bbr.2015.04.006 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CJ8RP UT WOS:000355771500002 PM 25882724 ER PT J AU Liu, C Li, CM Yang, J Gui, L Zhao, L Evans, AC Yin, XT Wang, J AF Liu, Chen Li, Chuanming Yang, Jun Gui, Li Zhao, Lu Evans, Alan C. Yin, Xuntao Wang, Jian TI Characterizing brain iron deposition in subcortical ischemic vascular dementia using susceptibility-weighted imaging: An in vivo MR study SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Cognitive impairment; Iron deposition; Phase changes; SIVD; SWI; Vascular dementia ID MILD COGNITIVE IMPAIRMENT; MAGNETIC-RESONANCE; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; ATROPHY; AGE; ACCUMULATION; HIPPOCAMPAL; DIAGNOSIS; PATHOLOGY AB The aim of this study was to investigate the brain iron accumulation in subcortical ischemic vascular dementia (SIVD) and its correlation with the severity of cognitive impairment. Thirty five patients with SIVD and 35 healthy controls underwent high-resolution susceptibility-weighted imaging. The phase shift value of the bilateral hippocampus (HP), caudate nucleus (CN), globus pallidus (GP), putamen (PU), thalamus (TH), red nucleus (RN), substantia nigra (SN), anterior cingulate cortex (ACC), posterior cingulate (PCC), parietal cortex (PC) and frontal white matter (FWM) were examined and correlated with neuropsychological scores for SIVD patients. They exhibited significant increased phase shift values in the bilateral HP, CN, PU, right GP and left SN (P<0.05). Close correlations were found between the phase shift value of the left HP, right CN and neuropsychological scores. Our results suggest that brain iron deposition may be a biomarker of SIVD and play an important role in the pathophysiological mechanism. (C) 2015 Elsevier B.V. All rights reserved. C1 [Liu, Chen; Li, Chuanming; Yang, Jun; Yin, Xuntao; Wang, Jian] Third Mil Med Univ, Southwest Hosp, Dept Radiol, Chongqing 400038, Peoples R China. [Liu, Chen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Gui, Li] Third Mil Med Univ, Southwest Hosp, Dept Neurol, Chongqing 400038, Peoples R China. [Zhao, Lu; Evans, Alan C.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada. RP Yin, XT (reprint author), Third Mil Med Univ, Southwest Hosp, Dept Radiol, Chongqing 400038, Peoples R China. EM willyxt@163.com; wangjian811@gmail.com OI Yin, Xuntao/0000-0002-8228-6908 FU National Natural Science Foundation of China for Young Scholars [81000607]; Forefront & Applied Basic Research Foundation of Chongqing City [cstc2014jcyjA0884] FX This study was supported by National Natural Science Foundation of China for Young Scholars (No. 81000607) and Forefront & Applied Basic Research Foundation of Chongqing City (No. cstc2014jcyjA0884). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 2 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JUL 15 PY 2015 VL 288 BP 33 EP 38 DI 10.1016/j.bbr.2015.04.003 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CJ8RP UT WOS:000355771500005 PM 25862942 ER PT J AU Kumar, P Slavich, GM Berghorst, LH Treadway, MT Brooks, NH Dutra, SJ Greve, DN O'Donovan, A Bleil, ME Maninger, N Pizzagalli, DA AF Kumar, Poornima Slavich, George M. Berghorst, Lisa H. Treadway, Michael T. Brooks, Nancy H. Dutra, Sunny J. Greve, Douglas N. O'Donovan, Aoife Bleil, Maria E. Maninger, Nicole Pizzagalli, Diego A. TI Perceived life stress exposure modulates reward-related medial prefrontal cortex responses to acute stress in depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Stress; Depression; Anhedonia; Life events; fMRI; Reward processing ID POSITRON-EMISSION-TOMOGRAPHY; PSYCHOSOCIAL STRESS; DOPAMINE RELEASE; MAJOR DEPRESSION; RESILIENCE; RESPONSIVENESS; REGISTRATION; TRANSDUCTION; DETERMINES; DISORDER AB Introduction: Major depressive disorder (MDD) is often precipitated by life stress and growing evidence suggests that stress induced alterations in reward processing may contribute to such risk. However, no human imaging studies have examined how recent life stress exposure modulates the neural systems that underlie reward processing in depressed and healthy individuals. Methods: In this proof-of-concept study, 12 MDD and 10 psychiatrically healthy individuals were interviewed using the Life Events arid Difficulties Schedule (LEDS) to assess their perceived levels of recent acute and chronic life stress exposure. Additionally, each participant performed a monetary incentive delay task under baseline (no stress) and stress (social evaluative) conditions during functional MRL Results: Across groups, medial prefrontal cortex (mPFC) activation to reward feedback was greater during acute stress versus no-stress conditions in individuals with greater perceived stressor severity. Under acute stress, depressed individuals showed a positive correlation between perceived stressor severity levels and reward-related mPFC activation (r=0.79, p=0.004), whereas no effect was found in healthy controls. Moreover, for depressed (but not healthy) individuals, the correlations between the stress (r=0.79) and no-stress (r=0.48) conditions were significantly different. Finally, reMtive to controls, depressed participants showed significantly reduced mPFC gray matter, but functional findings remained robust while accounting for structural differences. Limitation: Small sample size, which warrants replication. Conclusion: Depressed individuals experiencing greater recent life stress recruited the mPFC more under stress when processing rewards. Our results represent an initial step toward elucidating mechanisms underlying stress sensitization and recurrence in depression. (C) 2015 Elsevier B.V. All rights reserved. C1 [Kumar, Poornima; Brooks, Nancy H.; Pizzagalli, Diego A.] McLean Hosp, Ctr Depress Anxiety & Stress Res, Belmont, MA 02478 USA. [Kumar, Poornima; Pizzagalli, Diego A.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Slavich, George M.] Univ Calif Los Angeles, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [Slavich, George M.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Berghorst, Lisa H.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Treadway, Michael T.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Dutra, Sunny J.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Greve, Douglas N.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [O'Donovan, Aoife] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [O'Donovan, Aoife] San Francisco VA Med Ctr, San Francisco, CA USA. [Bleil, Maria E.] Univ Washington, Dept Family & Child Nursing, Seattle, WA 98195 USA. [Maninger, Nicole] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. RP Kumar, P (reprint author), McLean Hosp, Ctr Depress Anxiety & Stress Res, 115 Mill St, Belmont, MA 02478 USA. EM pkumar@mclean.harvard.edu; dap@mclean.harvard.edu FU NIMH [R01 MH068376, KOS MH103443]; NARSAD; John and Charlene Madison Cassidy Fellowship in Translational Neuroscience through McLean Hospital, a Livingston and a NARSAD Young Investigator award; Sackler Fellowship in Psychobiology; NRSA FX This work was supported by NIMH R01 MH068376 and a NARSAD Independent Investigator award to DAP. PK was supported by the John and Charlene Madison Cassidy Fellowship in Translational Neuroscience through McLean Hospital, a Livingston and a NARSAD Young Investigator award. LB was supported in part by the Sackler Fellowship in Psychobiology and an NRSA Precloctoral Training Grant in Advanced Multimoclal Neuroimaging. GS was partially supported by NIMH KOS MH103443. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 1 Z9 1 U1 2 U2 23 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 JUL 15 PY 2015 VL 180 BP 104 EP 111 DI 10.1016/j.jad.2015.03.035 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CI2WF UT WOS:000354607700015 PM 25898329 ER PT J AU Hebenstreit, CL Maguen, S Koo, KH DePrince, AP AF Hebenstreit, Claire L. Maguen, Shira Koo, Kelly H. DePrince, Anne P. TI Latent profiles of PTSD symptoms in women exposed to intimate partner violence SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Intimate partner violence; Posttraumatic stress disorder; Appraisal; Female ID POSTTRAUMATIC-STRESS-DISORDER; SEXUAL ASSAULT; SOCIAL SUPPORT; SELF-BLAME; PSYCHOLOGICAL DISTRESS; DISSOCIATIVE SUBTYPE; PREDICTING PTSD; ABUSE; IMPACT; MODEL AB Background: Studies have utilized latent class analysis ([CA) and latent profile analysis ([PA) to examine posttraumatic stress disorder (PTSD) symptom profiles in a range of populations. Further study is needed to explore symptom profiles among women exposed to intimate partner violence (IPV). The current study examined latent symptom profiles in a sample of IPV-exposed women, and explored traumarelated cognitive appraisals associated with these PTSD symptom presentations. Methods: An LPA was conducted using cross-sectional data from a non-treatment seeking community sample of women recruited following a police-reported incident of IPV by a male perpetrator (N_229), Nlultinomial regression analyses determined associations between latent profile membership and trauma-related appraisals. Results: The LPA identified five PTSD symptom profiles: Low Symptom (46% of the sample); Low Symptom with High Hypervigilance (17%); Intermediate Symptom (16%); Intermediate Symptom with High Hypervigilance (11%); and High Symptom (10%). Trauma-related appraisals, including fear, alienation, and self-blame, were the strongest independent predictors of PTSD symptom profile membership. Limitations: The study focused on female victims of IPV by a male partner, and findings may not generalize to other gender configurations (e.g. same sex couples, male victims, etc.). The LPA is crosssectional, and the stability of these profiles over time warrants further study. Conclusions: These findings suggest the need for careful consideration of differences among IPV-exposed women within the larger context of PTSD research and clinical intervention. Identifying latent subgroups may provide an empirical basis for practitioners to design and implement PTSD intervention efforts that are tailored to specific symptom profiles. Published by Elsevier B.V. C1 [Hebenstreit, Claire L.; Maguen, Shira; Koo, Kelly H.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Hebenstreit, Claire L.; Maguen, Shira; Koo, Kelly H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [DePrince, Anne P.] Univ Denver, Denver, CO 80208 USA. RP Hebenstreit, CL (reprint author), San Francisco VA Med Ctr, Gen Internal Med 111A1, 4150 Clement St, San Francisco, CA 94121 USA. EM Claire.Hebenstreit@va.gov OI Hebenstreit, Claire/0000-0001-5970-2195 FU National Institute of Justice Office of Justice Programs, U.S. Department of Justice [2007-WG-RX-0002]; Department of Veterans Affairs Advanced Fellowship Program in Women's Health FX This project was supported by Award no. 2007-WG-RX-0002 awarded by the National Institute of Justice Office of Justice Programs, U.S. Department of Justice, and by the Department of Veterans Affairs Advanced Fellowship Program in Women's Health. The opinions, findings, and conclusions or recommendations expressed in this manuscript are those of the authors and do not necessarily reflect those of the Department of Justice or the U.S. Department of Veterans Affairs. NR 54 TC 2 Z9 2 U1 7 U2 31 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 JUL 15 PY 2015 VL 180 BP 122 EP 128 DI 10.1016/j.jad.2015.03.047 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CI2WF UT WOS:000354607700018 PM 25898332 ER PT J AU Bradley, SM O'Donnell, CI Grunwald, GK Liu, CF Hebert, PL Maddox, TM Jesse, RL Fihn, SD Rumsfeld, JS Ho, PM AF Bradley, Steven M. O'Donnell, Colin I. Grunwald, Gary K. Liu, Chuan-Fen Hebert, Paul L. Maddox, Thomas M. Jesse, Robert L. Fihn, Stephan D. Rumsfeld, John S. Ho, P. Michael TI Facility-Level Variation in Hospitalization, Mortality, and Costs in the 30 Days After Percutaneous Coronary Intervention Insights on Short-Term Healthcare Value From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System (VA CART) Program SO CIRCULATION LA English DT Article DE costs and cost analysis; hospitalization; outcome assessment (health care); percutaneous coronary intervention ID MEDICARE BENEFICIARIES; READMISSION RATES; QUALITY; PERFORMANCE; EFFICIENCY; OUTCOMES; ACCESS; SITE AB Background-Policies to reduce unnecessary hospitalizations after percutaneous coronary intervention (PCI) are intended to improve healthcare value by reducing costs while maintaining patient outcomes. Whether facility-level hospitalization rates after PCI are associated with cost of care is unknown. Methods and Results-We studied 32 080 patients who received PCI at any 1 of 62 Veterans Affairs hospitals from 2008 to 2011. We identified facility outliers for 30-day risk-standardized hospitalization, mortality, and cost. Compared with the risk-standardized average, 2 hospitals (3.2%) had a lower-than-expected hospitalization rate, and 2 hospitals (3.2%) had a higher-than-expected hospitalization rate. We observed no statistically significant variation in facility-level risk-standardized mortality. The facility-level unadjusted median per patient 30-day total cost was $23 820 (interquartile range, $19604-$29958). Compared with the risk-standardized average, 17 hospitals (27.4%) had lower-than-expected costs, and 14 hospitals (22.6%) had higher-than-expected costs. At the facility level, the index PCI accounted for 83.1% of the total cost (range, 60.3%-92.2%), whereas hospitalization after PCI accounted for only 5.8% (range, 2.0%-12.7%) of the 30-day total cost. Facilities with higher hospitalization rates were not more expensive (Spearman rho= 0.16; 95% confidence interval, -0.09 to 0.39; P=0.21). Conclusions-In this national study, hospitalizations in the 30 day after PCI accounted for only 5.8% of 30-day cost, and facility-level cost was not correlated with hospitalization rates. This challenges the focus on reducing hospitalizations after PCI as an effective means of improving healthcare value. Opportunities remain to improve PCI value by reducing the variation in total cost of PCI without compromising patient outcomes. C1 [Bradley, Steven M.; O'Donnell, Colin I.; Grunwald, Gary K.; Maddox, Thomas M.; Rumsfeld, John S.; Ho, P. Michael] VA Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. [Bradley, Steven M.; Maddox, Thomas M.; Rumsfeld, John S.; Ho, P. Michael] Univ Colorado, Sch Med, Aurora, CO USA. [O'Donnell, Colin I.; Grunwald, Gary K.] Univ Colorado, Sch Publ Hlth, Aurora, CO USA. [Liu, Chuan-Fen; Hebert, Paul L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Jesse, Robert L.; Fihn, Stephan D.] US Dept Vet Affairs, Vet Hlth Adm, Washington, DC USA. RP Bradley, SM (reprint author), VA Eastern Colorado Hlth Care Syst, Dept Vet Affairs, 1055 Clermont St 111B, Denver, CO 80220 USA. EM Steven.Bradley@va.gov FU VA Health Services Research Development [HSRD-CDA2 10-199, HSRD-CDA2 08-021] FX Drs Bradley and Maddox are supported by Career Development Awards (HSR&D-CDA2 10-199 and HSR&D-CDA2 08-021, respectively) from the VA Health Services Research & Development. NR 38 TC 3 Z9 3 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 JUL 14 PY 2015 VL 132 IS 2 BP 101 EP 108 DI 10.1161/CIRCULATIONAHA.115.015351 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IN UT WOS:000369254800011 PM 25951833 ER PT J AU Sturzu, AC Rajarajan, K Passer, D Plonowska, K Riley, A Tan, TC Sharma, A Xu, AF Engels, MC Feistritzer, R Li, G Selig, MK Geissler, R Robertson, KD Scherrer-Crosbie, M Domian, IJ Wu, SM AF Sturzu, Anthony C. Rajarajan, Kuppusamy Passer, Derek Plonowska, Karolina Riley, Alyssa Tan, Timothy C. Sharma, Arun Xu, Adele F. Engels, Marc C. Feistritzer, Rebecca Li, Guang Selig, Martin K. Geissler, Richard Robertson, Keston D. Scherrer-Crosbie, Marielle Domian, Ibrahim J. Wu, Sean M. TI Fetal Mammalian Heart Generates a Robust Compensatory Response to Cell Loss SO CIRCULATION LA English DT Article DE heart; mice; myocytes, cardiac; regeneration; stem cells ID CARDIAC PROGENITOR CELLS; EMBRYONIC STEM-CELLS; HIPPO PATHWAY; IN-VIVO; ZEBRAFISH; PROLIFERATION; REGENERATION; DIFFERENTIATION; EXPRESSION; CARDIOMYOCYTES AB Background-Heart development is tightly regulated by signaling events acting on a defined number of progenitor and differentiated cardiac cells. Although loss of function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration after extensive cell loss. Methods and Results-By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of cardiac progenitor cell or cardiomyocyte ablation. Remarkably, ablation of up to 60% of cardiac progenitor cells at embryonic day 7.5 was well tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50% to 60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size. Conclusion-Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development. C1 [Sturzu, Anthony C.; Rajarajan, Kuppusamy; Plonowska, Karolina; Sharma, Arun; Xu, Adele F.; Li, Guang; Wu, Sean M.] Stanford Univ, Stanford Cardiovasc Inst, Sch Med, Stanford, CA 94305 USA. [Sturzu, Anthony C.; Wu, Sean M.] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. [Geissler, Richard] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Wu, Sean M.] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA. [Wu, Sean M.] Stanford Univ, Sch Med, Child Hlth Res Inst, Stanford, CA 94305 USA. [Sturzu, Anthony C.; Rajarajan, Kuppusamy; Passer, Derek; Riley, Alyssa; Tan, Timothy C.; Engels, Marc C.; Feistritzer, Rebecca; Robertson, Keston D.; Scherrer-Crosbie, Marielle; Domian, Ibrahim J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Selig, Martin K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Wu, SM (reprint author), Stanford Univ, Sch Med, Lokey Stem Cell Res Bldg,Room G1120A,265 Campus D, Stanford, CA 94305 USA. EM smwu@stanford.edu FU Harvard Stem Cell Institute Seed Grant; National Institutes of Health/National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium [U01HL009976]; California Institute for Regenerative Medicine [RB3-05129]; Lucile Packard Foundation for Children/Child Health Research Institute at Stanford; National Institutes of Health [T32 (HL007208), HL94274, DP2OD000041]; American Heart Association Founders Affiliate; Lawrence J. & Florence A. DeGeorge Charitable Trust FX This work was supported in part by a Harvard Stem Cell Institute Seed Grant, a National Institutes of Health Director's New Innovator Award (DP2OD000041), the National Institutes of Health/National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium (U01HL009976), the California Institute for Regenerative Medicine (RB3-05129), an Endowed Faculty Scholar Award from the Lucile Packard Foundation for Children/Child Health Research Institute at Stanford (to Dr Wu), the National Institutes of Health T32 (HL007208 and HL94274), and a post-doctoral fellowship award from the American Heart Association Founders Affiliate and the Lawrence J. & Florence A. DeGeorge Charitable Trust (to Dr Sturzu). NR 39 TC 13 Z9 13 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 14 PY 2015 VL 132 IS 2 BP 109 EP 121 DI 10.1161/CIRCULATIONAHA.114.011490 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IN UT WOS:000369254800012 PM 25995316 ER PT J AU Choi, HJ Sun, D Jakobs, TC AF Choi, Hee Joo Sun, Daniel Jakobs, Tatjana C. TI Astrocytes in the optic nerve head express putative mechanosensitive channels SO MOLECULAR VISION LA English DT Article ID RETINAL GANGLION-CELLS; ELEVATED HYDROSTATIC-PRESSURE; RETROGRADE AXOPLASMIC-TRANSPORT; STRETCH-ACTIVATED CHANNELS; POLYCYSTIC KIDNEY-DISEASE; EPIDERMAL MERKEL CELLS; TUMOR-NECROSIS-FACTOR; INTRAOCULAR-PRESSURE; GENE-EXPRESSION; EPITHELIAL-CELLS AB Purpose: To establish whether optic nerve head astrocytes express candidate molecules to sense tissue stretch. Methods: We used conventional PCR, quantitative PCR, and single-cell reverse transcription PCR (RT-PCR) to assess the expression of various members of the transient receptor potential (TRP) channel family and of the recently characterized mechanosensitive channels Piezo1 and 2 in optic nerve head tissue and in single, isolated astrocytes. Results: Most TRP subfamilies (TRPC, TRPM, TRPV, TRPA, and TRPP) and Piezo1 and 2 were expressed in the optic nerve head of the mouse. Quantitative real-time PCR analysis showed that TRPC1, TRPM7, TRPV2, TRPP2, and Piezo1 are the dominant isoforms in each subfamily. Single-cell RT-PCR revealed that many TRP isoforms, TRPC1-2, TRPC6, TRPV2, TRPV4, TRPM2, TRPM4, TRPM6-7, TRPP1-2, and Piezo1-2, are expressed in astrocytes of the optic nerve head, and that most astrocytes express TRPC1 and TRPP1-2. Comparisons of the TRPP and Piezo expression levels between different tissue regions showed that Piezo2 expression was higher in the optic nerve head and the optic nerve proper than in the brain and the corpus callosum. TRPP2 also showed higher expression in the optic nerve head. Conclusions: Astrocytes in the optic nerve head express multiple putative mechanosensitive channels, in particular the recently identified channels Piezo1 and 2. The expression of putative mechanosensitive channels in these cells may contribute to their responsiveness to traumatic or glaucomatous injury. C1 [Choi, Hee Joo; Sun, Daniel; Jakobs, Tatjana C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Jakobs, TC (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM Tatjana_Jakobs@meei.harvard.edu FU NIH [R01EY019703, R01EY022092]; Lefler Foundation FX This work was supported by NIH grants R01EY019703 and R01EY022092, and the Lefler Foundation. The authors wish to thank Dr. Richard Masland for critically reading the manuscript, and Rong Guo, MS, for advice on statistical tests. NR 113 TC 4 Z9 4 U1 0 U2 5 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 14 PY 2015 VL 21 PG 18 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA CO2VR UT WOS:000359015400001 ER PT J AU Ladha, K Melo, MFV McLean, DJ Wanderer, JP Grabitz, SD Kurth, T Eikermann, M AF Ladha, Karim Melo, Marcos F. Vidal McLean, Duncan J. Wanderer, Jonathan P. Grabitz, Stephanie D. Kurth, Tobias Eikermann, Matthias TI Intraoperative protective mechanical ventilation and risk of postoperative respiratory complications: hospital based registry study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID ACUTE LUNG INJURY; QUALITY IMPROVEMENT PROGRAM; TIDAL-VOLUME VENTILATION; GENERAL-ANESTHESIA; ABDOMINAL-SURGERY; NONCARDIAC SURGERY; DISTRESS-SYNDROME; FRACTIONAL POLYNOMIALS; PATIENT SAFETY; FAILURE AB OBJECTIVE To evaluate the effects of intraoperative protective ventilation on major postoperative respiratory complications and to define safe intraoperative mechanical ventilator settings that do not translate into an increased risk of postoperative respiratory complications. DESIGN Hospital based registry study. SETTING Academic tertiary care hospital and two affiliated community hospitals in Massachusetts, United States. PARTICIPANTS 69 265 consecutively enrolled patients over the age of 18 who underwent a non-cardiac surgical procedure between January 2007 and August 2014 and required general anesthesia with endotracheal intubation. INTERVENTIONS Protective ventilation, defined as a median positive end expiratory pressure (PEEP) of 5 cmH(2)O or more, a median tidal volume of less than 10 mL/kg of predicted body weight, and a median plateau pressure of less than 30 cmH(2)O. MAIN OUTCOME MEASURE Composite outcome of major respiratory complications, including pulmonary edema, respiratory failure, pneumonia, and re-intubation. RESULTS Of the 69 265 enrolled patients 34 800 (50.2%) received protective ventilation and 34 465 (49.8%) received non-protective ventilation intraoperatively. Protective ventilation was associated with a decreased risk of postoperative respiratory complications in multivariable regression (adjusted odds ratio 0.90, 95% confidence interval 0.82 to 0.98, P = 0.013). The results were similar in the propensity score matched cohort (odds ratio 0.89, 95% confidence interval 0.83 to 0.97, P = 0.004). A PEEP of 5 cmH(2)O and median plateau pressures of 16 cmH(2)O or less were associated with the lowest risk of postoperative respiratory complications. CONCLUSIONS Intraoperative protective ventilation was associated with a decreased risk of postoperative respiratory complications. A PEEP of 5 cmH(2)O and a plateau pressure of 16 cmH(2)O or less were identified as protective mechanical ventilator settings. These findings suggest that protective thresholds differ for intraoperative ventilation in patients with normal lungs compared with those used for patients with acute lung injury. C1 [Ladha, Karim; Melo, Marcos F. Vidal; McLean, Duncan J.; Grabitz, Stephanie D.; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care, Pain Med, Boston, MA 02114 USA. [Wanderer, Jonathan P.] Vanderbilt Univ, Dept Anesthesiol, Nashville, TN 37235 USA. [Kurth, Tobias] INSERM, Res Ctr Epidemiol & Biostat U897, Team Neuroepidemiol, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Bordeaux, France. [Kurth, Tobias] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Eikermann, Matthias] Essen Duisburg Univ, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care, Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org RI Ladha, Karim/K-7170-2015; Kurth, Tobias/A-9243-2012 OI Ladha, Karim/0000-0001-7303-2458; Kurth, Tobias/0000-0001-7169-2620 FU Buzen's Foundation FX This study was funded by a grant from the Buzen's Foundation. NR 43 TC 29 Z9 31 U1 2 U2 11 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 JUL 14 PY 2015 VL 351 AR h3646 DI 10.1136/bmj.h3646 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CN3CO UT WOS:000358301600008 PM 26174419 ER PT J AU Sage, PT Tan, CL Freeman, GJ Haigis, M Sharpe, AH AF Sage, Peter T. Tan, Catherine L. Freeman, Gordon J. Haigis, Marcia Sharpe, Arlene H. TI Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging SO CELL REPORTS LA English DT Article ID REGULATORY T-CELLS; FOLLICULAR HELPER-CELLS; AGED MICE; INFLUENZA VACCINE; RESPONSES; HOMEOSTASIS; GENERATION AB Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice. C1 [Sage, Peter T.; Tan, Catherine L.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Sage, Peter T.; Tan, Catherine L.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Sage, Peter T.; Tan, Catherine L.; Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Haigis, Marcia] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu FU NIH [BAA-NIAID-DAIT-NIHAI2010085, R37 AI38310, P01 56299, 5T32HL007627]; Glenn Foundation for Medical Research; Evergrande Center for Immunologic Diseases FX This work was supported by the NIH; BAA-NIAID-DAIT-NIHAI2010085 (to A.H.S., M.H., and G.F.), R37 AI38310 (to A.H.S.), and P01 56299 (to A.H.S., G.F.), 5T32HL007627 (to P.S.), the Glenn Foundation for Medical Research (to M.H.), and the Evergrande Center for Immunologic Diseases (to A.H.S.). G.F. and A.H.S. have patents and pending royalties on the PD-1 pathway from Bristol-Myers-Squibb (G.F.), Roche (G.F. and A.H.S.), Merck (G.F.), EMD-Serono (G.F.), Boehringer-Ingelheim (G.F.), AstraZeneca (G.F.), and Novartis (G.F. and A.H.S.). G.F. has served on advisory boards for CoStim, Novartis, Roche, and Bristol-Myers-Squibb, and A.H.S. has served on advisory boards for CoStim, Novartis, and Surface Oncology. NR 29 TC 9 Z9 9 U1 3 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 14 PY 2015 VL 12 IS 2 BP 163 EP 171 DI 10.1016/j.celrep.2015.06.015 PG 9 WC Cell Biology SC Cell Biology GA CN3KF UT WOS:000358324200001 PM 26146074 ER PT J AU Chun, E Lavoie, S Michaud, M Gallini, CA Kim, J Soucy, G Odze, R Glickman, JN Garrett, WS AF Chun, Eunyoung Lavoie, Sydney Michaud, Monia Gallini, Carey Ann Kim, Jason Soucy, Genevieve Odze, Robert Glickman, Jonathan N. Garrett, Wendy S. TI CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function SO CELL REPORTS LA English DT Article ID TUMOR-ASSOCIATED MACROPHAGES; BLOOD MONONUCLEAR-CELLS; T-BET DEFICIENCY; COLON-CARCINOMA; INTESTINAL TUMORIGENESIS; CHRONIC INFLAMMATION; ULCERATIVE-COLITIS; IMMUNE-SYSTEM; CANCER; METASTASIS AB Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention. C1 [Chun, Eunyoung; Lavoie, Sydney; Michaud, Monia; Gallini, Carey Ann; Kim, Jason; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Chun, Eunyoung; Lavoie, Sydney; Michaud, Monia; Gallini, Carey Ann; Kim, Jason; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Soucy, Genevieve; Odze, Robert; Glickman, Jonathan N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Soucy, Genevieve; Odze, Robert; Garrett, Wendy S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Glickman, Jonathan N.] Miraca Life Sci, Newton, MA 02464 USA. [Garrett, Wendy S.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu FU NCI [R01CA154426]; NIAID [K08AI078942]; Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award; Cancer Research Institute Investigator Award FX We thank members of the Garrett lab and Dr. Mikael Pittet for discussions and advice. We thank Yo Sup Moon and Dr. Curtis Huttenhower for thoughtful discussions about transcriptomics and cancer. This study was supported by R01CA154426 (NCI), K08AI078942 (NIAID), a Burroughs Wellcome Career in Medical Sciences Award, a Searle Scholars Award, and a Cancer Research Institute Investigator Award. NR 62 TC 26 Z9 27 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 14 PY 2015 VL 12 IS 2 BP 244 EP 257 DI 10.1016/j.celrep.2015.06.024 PG 14 WC Cell Biology SC Cell Biology GA CN3KF UT WOS:000358324200008 PM 26146082 ER PT J AU Augustine, EF Perez, A Dhall, R Umeh, CC Videnovic, A Cambi, F Wills, AMA Elm, JJ Zweig, RM Shulman, LM Nance, MA Bainbridge, J Suchowersky, O AF Augustine, Erika F. Perez, Adriana Dhall, Rohit Umeh, Chizoba C. Videnovic, Aleksandar Cambi, Franca Wills, Anne-Marie A. Elm, Jordan J. Zweig, Richard M. Shulman, Lisa M. Nance, Martha A. Bainbridge, Jacquelyn Suchowersky, Oksana TI Sex Differences in Clinical Features of Early, Treated Parkinson's Disease SO PLOS ONE LA English DT Article ID GENDER-DIFFERENCES; PREVALENCE; RISK; STROKE; WOMEN; MEN; EPIDEMIOLOGY; PROGRESSION; MECHANISMS; DEMENTIA AB Introduction To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial. Methods Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning). Results 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001). Conclusions Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted. C1 [Augustine, Erika F.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Perez, Adriana] Univ Texas Austin, Sch Publ Hlth, Austin, TX 78712 USA. [Dhall, Rohit] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Umeh, Chizoba C.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Umeh, Chizoba C.; Cambi, Franca] Harvard Univ, Sch Med, Boston, MA USA. [Videnovic, Aleksandar] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. [Cambi, Franca] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA. [Wills, Anne-Marie A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Elm, Jordan J.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Zweig, Richard M.] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Shulman, Lisa M.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Nance, Martha A.] Struthers Parkinsons Ctr, Minneapolis, MN USA. [Bainbridge, Jacquelyn] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. [Suchowersky, Oksana] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Suchowersky, Oksana] Univ Alberta, Dept Med Genet, Edmonton, AB, Canada. [Suchowersky, Oksana] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. RP Augustine, EF (reprint author), Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. EM erika_augustine@urmc.rochester.edu FU National Institute for Neurological Disorders and Stroke [U01NS43128, U01NS043127] FX The NET-PD LS-1 trial received funding support from the National Institute for Neurological Disorders and Stroke (U01NS43128 and U01NS043127). For the current report, a secondary analysis of trial data, the authors received no specific funding to support this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 6 Z9 7 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2015 VL 10 IS 7 AR e0133002 DI 10.1371/journal.pone.0133002 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1QN UT WOS:000358194900115 PM 26171861 ER PT J AU Matsui, A Stephens, D Kantarci, A Rittling, SR AF Matsui, Aritsune Stephens, Danielle Kantarci, Alpdogan Rittling, Susan R. TI Early Cytokine Response to Infection with Pathogenic vs Non-Pathogenic Organisms in a Mouse Model of Endodontic Infection SO PLOS ONE LA English DT Article ID PERIAPICAL BONE DESTRUCTION; RESORPTION IN-VIVO; EXPERIMENTAL PERIODONTITIS; INTERLEUKIN-6 DEFICIENCY; DIFFERENT PATTERNS; MICE; INFLAMMATION; RECEPTOR; SUSCEPTIBILITY; RECRUITMENT AB Using the subcutaneous chamber model of infection, we showed previously that a mixture of four endodontic pathogens (EP: P. intermedia, F. nucleatum, S. intermedius and P. micra) are able to persist without clearance for up to seven days, while a non-pathogenic oral species, S. mitis, was substantially cleared in this time. Here we have compared the cytokine response inside the chambers against these microorganisms. A majority of cytokines tested (17/24) showed different patterns of expression. Several cytokines had a peak of expression at 2 h after infection in response to the EP, while none showed this pattern in S. mitis infections. Chemokines were uniformly present at similar or higher levels in response to S. mitis, with redundant expression of CXCR2 ligands, while several growth/survival factors were present at higher levels in EP infections. Protease activity expressed by EP may be responsible for the lower levels of some chemokines. T-cell associated cytokines were in general expressed at extremely low levels, and did not differ between the two infections. The inflammatory markers IL-6, IL-1 alpha and IL1-beta were expressed at similar levels in both infections at early times, while TNF alpha was preferentially present in S. mitis infections. In EP infected chambers, reciprocal changes in levels of IL-6 and IL-1 alpha were observed at later times suggesting a switch in the inflammatory response. Analysis of the cytokine response to infection with the individual species from the EP mix suggests that P. intermedia drives this inflammatory switch. Together these results show a surprising level of divergence of the host response to pathogenic and non-pathogenic organisms associated with oral infections, and supports a dominant effect of P. intermedia in polymicrobial endodontic infections. C1 [Matsui, Aritsune; Stephens, Danielle; Kantarci, Alpdogan; Rittling, Susan R.] Forsyth Inst, Cambridge, MA 02142 USA. [Matsui, Aritsune; Kantarci, Alpdogan; Rittling, Susan R.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Rittling, SR (reprint author), Forsyth Inst, Cambridge, MA 02142 USA. EM srittling@forsyth.org FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [RO1-DE22380]; Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health under award number #RO1-DE22380 to SRR. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. www.nidcr.nih.gov. Support for statistical analysis was provided through 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 32 TC 1 Z9 1 U1 1 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 JUL 14 PY 2015 VL 10 IS 7 AR e0132752 DI 10.1371/journal.pone.0132752 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1QN UT WOS:000358194900081 PM 26171605 ER PT J AU Janne, PA Smith, I McWalter, G Mann, H Dougherty, B Walker, J Orr, MCM Hodgson, DR Shaw, AT Pereira, JR Jeannin, G Vansteenkiste, J Barrios, CH Franke, FA Crino, L Smith, P AF Jaenne, P. A. Smith, I. McWalter, G. Mann, H. Dougherty, B. Walker, J. Orr, M. C. M. Hodgson, D. R. Shaw, A. T. Pereira, J. R. Jeannin, G. Vansteenkiste, J. Barrios, C. H. Franke, F. A. Crino, L. Smith, P. TI Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE selumetinib; docetaxel; KRAS; mutation; codon; non-small-cell lung cancer ID MUTATIONS; ADENOCARCINOMAS; SURVIVAL; ONCOGENE; BEHAVIOR AB Background: Selumetinib (AZD6244, ARRY-142886) + docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). Methods: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. Results: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Conclusion: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity. C1 [Jaenne, P. A.] Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Jaenne, P. A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Smith, I.; McWalter, G.; Mann, H.; Walker, J.; Orr, M. C. M.; Hodgson, D. R.; Smith, P.] AstraZeneca, Macclesfield SK10 4TF, Cheshire, England. [Dougherty, B.] AstraZeneca, Waltham, MA 02451 USA. [Shaw, A. T.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Pereira, J. R.] Inst Brasileiro Cancerol Torac, BR-01224010 Sao Paulo, Brazil. [Jeannin, G.] Hop Gabriel Montpied, Dept Pneumol, F-63000 Clermont Ferrand, France. [Vansteenkiste, J.] Univ Hosp Gasthuisberg, Dept Pneumol, B-3000 Leuven, Belgium. [Barrios, C. H.] PUCRS Sch Med, Dept Med, BR-90570080 Porto Alegre, RS, Brazil. [Franke, F. A.] Hosp Caridade Ijui, CACON, BR-98700000 Ijui, RS, Brazil. [Crino, L.] Univ Med Sch Perugia, Dept Oncol, I-06123 Perugia, Italy. RP Janne, PA (reprint author), Lowe Ctr Thorac Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM pjanne@partners.org FU AstraZeneca FX This study was funded by AstraZeneca. Medical writing services were provided by Tom Hudson of iMed Comms, Macclesfield, UK and were funded by AstraZeneca. We thank the investigators who participated in this study. NR 13 TC 19 Z9 19 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 14 PY 2015 VL 113 IS 2 BP 199 EP 203 DI 10.1038/bjc.2015.215 PG 5 WC Oncology SC Oncology GA CM8JZ UT WOS:000357947800002 PM 26125448 ER PT J AU Pursnani, A Massaro, JM D'Agostino, RB O'Donnell, CJ Hoffmann, U AF Pursnani, Amit Massaro, Joseph M. D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Hoffmann, Udo TI Guideline-Based Statin Eligibility, Coronary Artery Calcification, and Cardiovascular Events SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ADULT TREATMENT PANEL; BLOOD CHOLESTEROL; CALCIUM; RISK; ASSOCIATION; PROGRESSION; ACCURACY AB IMPORTANCE The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for cholesterol management defined new eligibility criteria for statin therapy. However, it is unclear whether this approach improves identification of adults at higher risk of cardiovascular events. OBJECTIVE To determine whether the ACC/AHA guidelines improve identification of individuals who develop incident cardiovascular disease (CVD) and/or have coronary artery calcification (CAC) compared with the National Cholesterol Education Program's 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. DESIGN, SETTING, AND PARTICIPANTS Longitudinal community-based cohort study, with participants for this investigation drawn from the offspring and third-generation cohorts of the Framingham Heart Study. Participants underwent multidetector computed tomography for CAC between 2002 and 2005 and were followed up for a median of 9.4 years for incident CVD. EXPOSURES Statin eligibility was determined based on Framingham risk factors and low-density lipoprotein thresholds for ATP III, whereas the pooled cohort calculator was used for ACC/AHA. MAIN OUTCOMES AND MEASURES The primary outcome was incident CVD (myocardial infarction, death due to coronary heart disease [CHD], or ischemic stroke). Secondary outcomes were CHD and CAC (as measured by the Agatston score). RESULTS Among 2435 statin-naive participants (mean age, 51.3 [SD, 8.6] years; 56% female), 39%(941/2435) were statin eligible by ACC/AHA compared with 14%(348/2435) by ATP III (P<.001). There were 74 incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal ischemic strokes, and 3 fatal CHD events). Participants who were statin eligible by ACC/AHA had increased hazard ratios for incident CVD compared with those eligible by ATP III: 6.8 (95% CI, 3.8-11.9) vs 3.1 (95% CI, 1.9-5.0), respectively (P<001). Similar results were seen for CVD in participants with intermediate Framingham Risk Scores and for CHD. Participants who were newly statin eligible (n = 593 [24%]) had an incident CVD rate of 5.7%, yielding a number needed to treat of 39 to 58. Participants with CAC were more likely to be statin eligible by ACC/AHA than by ATP III: CAC score >0 (n = 1015): 63% vs 23%; CAC score >100 (n = 376): 80% vs 32%; and CAC score >300 (n = 186): 85% vs 34%(all P<.001). A CAC score of 0 identified a low-risk group among ACC/AHA statin-eligible participants (306/941 [33%]) with a CVD rate of 1.6%. CONCLUSIONS AND RELEVANCE In this community-based primary prevention cohort, the ACC/AHA guidelines for determining statin eligibility, compared with the ATP III, were associated with greater accuracy and efficiency in identifying increased risk of incident CVD and subclinical coronary artery disease, particularly in intermediate-risk participants. C1 [Pursnani, Amit; Hoffmann, Udo] Harvard Univ, Cardiac MR PET CT Program, Massachusetts Gen Hosp, Dept Radiol,Med Sch, Boston, MA 02114 USA. [Pursnani, Amit] NorthShore Univ Hlth Syst, Div Cardiol, Evanston, IL USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; O'Donnell, Christopher J.] Boston Univ, Framingham, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.; Hoffmann, Udo] Harvard Univ, Div Cardiol, Dept Med, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 100 Charles River Plaza,Ste 400, Boston, MA 02114 USA. EM uhoffmann@mgh.harvard.edu FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385]; National Institutes of Health [T32 HL076136] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and HL107385). Dr Pursnani was supported by National Institutes of Health grant T32 HL076136. NR 23 TC 40 Z9 40 U1 0 U2 4 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 JUL 14 PY 2015 VL 314 IS 2 BP 134 EP 141 DI 10.1001/jama.2015.7515 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CM7JI UT WOS:000357867500013 PM 26172893 ER PT J AU Bakris, GL Pitt, B Weir, MR Freeman, MW Mayo, MR Garza, D Stasiv, Y Zawadzki, R Berman, L Bushinsky, DA AF Bakris, George L. Pitt, Bertram Weir, Matthew R. Freeman, Mason W. Mayo, Martha R. Garza, Dahlia Stasiv, Yuri Zawadzki, Rezi Berman, Lance Bushinsky, David A. CA AMETHYST-DN Investigators TI Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease The AMETHYST-DN Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ANGIOTENSIN-ALDOSTERONE SYSTEM; CHRONIC HEART-FAILURE; POLYSTYRENE SULFONATE; MANAGEMENT; THERAPY; SAFETY; GUIDELINES; INHIBITORS; EFFICACY; SOCIETY AB IMPORTANCE Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. OBJECTIVES To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. DESIGN, SETTING, AND PARTICIPANTS Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m(2) and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. INTERVENTIONS Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. MAIN OUTCOMES AND MEASURES The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. RESULTS A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P<.001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. CONCLUSIONS AND RELEVANCE Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. C1 [Bakris, George L.] Univ Chicago Med, ASH Comprehens Hypertens Ctr, Div Endocrinol Diabet & Metab, Dept Med, Chicago, IL 60637 USA. [Pitt, Bertram] Univ Michigan, Ann Arbor, MI 48109 USA. [Weir, Matthew R.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Freeman, Mason W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Zawadzki, Rezi; Berman, Lance] Relypsa, Redwood City, CA USA. [Bushinsky, David A.] Univ Rochester, Dept Med, Div Nephrol, Rochester, NY USA. RP Bakris, GL (reprint author), Univ Chicago Med, ASH Comprehens Hypertens Ctr, Div Endocrinol Diabet & Metab, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM gbakris@gmail.com FU Relypsa FX This study was sponsored and funded by Relypsa. NR 35 TC 58 Z9 58 U1 2 U2 11 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 JUL 14 PY 2015 VL 314 IS 2 BP 151 EP 161 DI 10.1001/jama.2015.7446 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CM7JI UT WOS:000357867500015 PM 26172895 ER PT J AU Bianchi, DW Chudova, D Sehnert, AJ Bhatt, S Murray, K Prosen, TL Garber, JE Wilkins-Haug, L Vora, NL Warsof, S Goldberg, J Ziainia, T Halks-Miller, M AF Bianchi, Diana W. Chudova, Darya Sehnert, Amy J. Bhatt, Sucheta Murray, Kathryn Prosen, Tracy L. Garber, Judy E. Wilkins-Haug, Louise Vora, Neeta L. Warsof, Stephen Goldberg, James Ziainia, Tina Halks-Miller, Meredith TI Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CLINICAL-LABORATORY-EXPERIENCE; CELL-FREE DNA; FETAL ANEUPLOIDIES; DIAGNOSIS; SOCIETY; BLOOD AB IMPORTANCE Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignanciesmay explain results that are discordant with the fetal karyotype and improve maternal clinical care. OBJECTIVE To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. DESIGN, SETTING, AND PARTICIPANTS Case series identified from 125 426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation. EXPOSURES NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). MAIN OUTCOMES AND MEASURES Detailed genome-wide bioinformatics analysiswas performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort. RESULTS From a cohort of 125 426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95% CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. CONCLUSIONS AND RELEVANCE In this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research. C1 [Bianchi, Diana W.] Tufts Med Ctr, Mother Infant Res Inst, Boston, MA 02111 USA. [Chudova, Darya; Sehnert, Amy J.; Bhatt, Sucheta; Halks-Miller, Meredith] Illumina, Redwood City, CA USA. [Murray, Kathryn] Ctr Genet & Maternal Fetal Med, Springfield, OR USA. [Prosen, Tracy L.] Univ Minnesota, Dept Obstet & Gynecol, Div Maternal Fetal Med, Minneapolis, MN 55455 USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wilkins-Haug, Louise] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med & Reprod Genet, Boston, MA 02115 USA. [Vora, Neeta L.] Univ N Carolina, Chapel Hill, NC USA. [Warsof, Stephen] Eastern Virginia Med Sch, Div Maternal Fetal Med, Norfolk, VA 23501 USA. [Goldberg, James] San Francisco Perinatal Associates, San Francisco, CA USA. [Ziainia, Tina] Sharp Rees Stealy Med Grp, San Diego, CA USA. RP Bianchi, DW (reprint author), Tufts Med Ctr, Mother Infant Res Inst, 800Washington St,Box 394, Boston, MA 02111 USA. EM dbianchi@tuftsmedicalcenter.org FU Illumina FX Funding for the study was provided by Illumina. Sponsored research funding from Illumina that is administered through Tufts Medical Center paid for the time that Dr Bianchi spent working with the full-time Illumina employees to design the study, analyze the data, and prepare the manuscript. NR 23 TC 51 Z9 51 U1 5 U2 13 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 JUL 14 PY 2015 VL 314 IS 2 BP 162 EP 169 DI 10.1001/jama.2015.7120 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CM7JI UT WOS:000357867500016 PM 26168314 ER PT J AU Toledo, JB Bjerke, M Chen, KW Rozycki, M Jack, CR Weiner, MW Arnold, SE Reiman, EM Davatzikos, C Shaw, LM Trojanowski, JQ AF Toledo, Jon B. Bjerke, Maria Chen, Kewei Rozycki, Martin Jack, Clifford R. Weiner, Michael W. Arnold, Steven E. Reiman, Eric M. Davatzikos, Christos Shaw, Leslie M. Trojanowski, John Q. TI Memory, executive, and multidomain subtle cognitive impairment Clinical and biomarker findings SO NEUROLOGY LA English DT Article ID ALZHEIMERS ASSOCIATION WORKGROUPS; NEUROIMAGING INITIATIVE ADNI; DIAGNOSTIC GUIDELINES; CEREBROSPINAL-FLUID; NATIONAL INSTITUTE; COMPOSITE SCORE; CSF BIOMARKERS; DISEASE; DECLINE; RECOMMENDATIONS AB Objective: We studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group. Methods: We studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants. Results: Using a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively. Conclusions: Our results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment. C1 [Toledo, Jon B.; Bjerke, Maria; Shaw, Leslie M.; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med,Inst Aging, Philadelphia, PA 19104 USA. [Arnold, Steven E.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Chen, Kewei; Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ USA. [Rozycki, Martin; Davatzikos, Christos] Ctr Biomed Image Comp & Analyt, Philadelphia, PA USA. [Jack, Clifford R.] Mayo Clin, Coll Med, Rochester, MN USA. [Weiner, Michael W.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Radiol, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA. RP Trojanowski, JQ (reprint author), Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med,Inst Aging, Philadelphia, PA 19104 USA. EM trojanow@mail.med.upenn.edu RI Kowall, Neil/G-6364-2012; Jack, Clifford/F-2508-2010; OI Kowall, Neil/0000-0002-6624-0213; Jack, Clifford/0000-0001-7916-622X; Toledo, Jon/0000-0003-4366-9268; Preda, Adrian /0000-0003-3373-2438 FU ADNI (NIH) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes Health Research; NIH [R01AG039478, P30AG10124, R01DA025201, U01DK057135, U01AG024904, R01-AG011378, U01-HL096917, U01-AG024904, RO1 AG041851, R01 AG37551, R01AG043392, U01-AG06786]; BrightFocus Foundation; Marian S. Ware Charitable Giving Fund; Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation; Nomis Foundation; Banner Alzheimer's Foundation; state of Arizona; [P01 AG032953]; [PO1 AG017586]; [P30 AG010124]; [P50 NS053488] FX Dr. Toledo is supported by P01 AG032953, PO1 AG017586, P30 AG010124, and P50 NS053488. Dr. Trojanowski is the William Maul Measey-Truman G. Schnabel Jr., Professor of Geriatric Medicine and Gerontology. Data collection and sharing for this project was funded by the ADNI (NIH grant U01 AG024904) and DOD ADNI (Department of Defense award W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Dr. Arnold receives research funding from NIH (R01AG039478, P30AG10124, R01DA025201, U01DK057135, U01AG024904), the BrightFocus Foundation (principal investigator), and the Marian S. Ware Charitable Giving Fund. Dr. Jack receives research funding from the NIH (R01-AG011378, U01-HL096917, U01-AG024904, RO1 AG041851, R01 AG37551, R01AG043392, U01-AG06786) and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. Dr. Reiman receives research funding from National Institute on Aging, Nomis Foundation, Banner Alzheimer's Foundation, and the state of Arizona. NR 38 TC 8 Z9 8 U1 2 U2 13 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 JUL 14 PY 2015 VL 85 IS 2 BP 144 EP 153 DI 10.1212/WNL.0000000000001738 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CM6NG UT WOS:000357804900007 PM 26085606 ER PT J AU Wingerchuk, DM Banwell, B Bennett, JL Cabre, P Carroll, W Chitnis, T de Seze, J Fujihara, K Greenberg, B Jacob, A Jarius, S Lana-Peixoto, M Levy, M Simon, JH Tenembaum, S Traboulsee, AL Waters, P Wellik, KE Weinshenker, BG AF Wingerchuk, Dean M. Banwell, Brenda Bennett, Jeffrey L. Cabre, Philippe Carroll, William Chitnis, Tanuja de Seze, Jerome Fujihara, Kazuo Greenberg, Benjamin Jacob, Anu Jarius, Sven Lana-Peixoto, Marco Levy, Michael Simon, Jack H. Tenembaum, Silvia Traboulsee, Anthony L. Waters, Patrick Wellik, Kay E. Weinshenker, Brian G. TI International consensus diagnostic criteria for neuromyelitis optica spectrum disorders SO NEUROLOGY LA English DT Review ID OLIGODENDROCYTE GLYCOPROTEIN ANTIBODIES; PARTIAL TRANSVERSE MYELITIS; TERM-FOLLOW-UP; MULTIPLE-SCLEROSIS; BRAIN ABNORMALITIES; NMO-IGG; AQUAPORIN-4 AUTOIMMUNITY; CLINICAL-COURSE; LESIONS; MULTICENTER AB Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS. C1 [Wingerchuk, Dean M.] Mayo Clin, Dept Neurol, Scottsdale, AZ 85259 USA. [Wellik, Kay E.] Mayo Clin, Dept Lib Serv, Scottsdale, AZ USA. [Banwell, Brenda] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Bennett, Jeffrey L.] Univ Colorado Denver, Dept Neurol, Aurora, CO USA. [Bennett, Jeffrey L.] Univ Colorado Denver, Dept Ophthalmol, Aurora, CO USA. [Cabre, Philippe] Ctr Hosp Univ Ft de France, Serv Neurol, Fort De France, Martinique. [Carroll, William] Sir Charles Gairdner Hosp, Dept Neurol, Perth, WA, Australia. [Chitnis, Tanuja] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [de Seze, Jerome] Strasbourg Univ, Dept Neurol, Strasbourg, France. [Fujihara, Kazuo] Tohoku Univ, Grad Sch Med, Dept Multiple Sclerosis Therapeut, Sendai, Miyagi 980, Japan. [Greenberg, Benjamin] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Greenberg, Benjamin] Univ Texas SW Med Ctr Dallas, Dept Neurotherapeut, Dallas, TX 75390 USA. [Jacob, Anu] Walton Ctr NHS Trust, Liverpool, Merseyside, England. [Jarius, Sven] Univ Heidelberg Hosp, Dept Neurol, Mol Neuroimmunol Grp, Heidelberg, Germany. [Lana-Peixoto, Marco] Univ Fed Minas Gerais, Sch Med, Ctr Multiple Sclerosis Invest, Belo Horizonte, MG, Brazil. [Levy, Michael] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Simon, Jack H.] Portland VA Med Ctr, Portland, VA USA. [Simon, Jack H.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Tenembaum, Silvia] Natl Pediat Hosp Dr Juan P Garrahan, Dept Neurol, Buenos Aires, DF, Argentina. [Traboulsee, Anthony L.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Waters, Patrick] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX1 2JD, England. [Weinshenker, Brian G.] Mayo Clin, Dept Neurol, Rochester, MN USA. RP Wingerchuk, DM (reprint author), Mayo Clin, Dept Neurol, Scottsdale, AZ 85259 USA. EM wingerchuk.dean@mayo.edu; weinb@mayo.edu RI De Seze, Jerome/M-8316-2016 OI De Seze, Jerome/0000-0002-7197-7578 FU Guthy Jackson Charitable Foundation FX The International Panel for Neuromyelitis Optica Diagnosis was supported by the Guthy Jackson Charitable Foundation. NR 60 TC 228 Z9 246 U1 14 U2 34 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 JUL 14 PY 2015 VL 85 IS 2 BP 177 EP 189 DI 10.1212/WNL.0000000000001729 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA CM6NG UT WOS:000357804900012 PM 26092914 ER PT J AU Mukerji, SS Buchbinder, BR Singhal, AB AF Mukerji, Shibani S. Buchbinder, Bradley R. Singhal, Aneesh B. TI Reversible cerebral vasoconstriction syndrome with reversible renal artery stenosis SO NEUROLOGY LA English DT Editorial Material C1 [Mukerji, Shibani S.; Buchbinder, Bradley R.; Singhal, Aneesh B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mukerji, Shibani S.; Buchbinder, Bradley R.; Singhal, Aneesh B.] Harvard Univ, Sch Med, Boston, MA USA. [Mukerji, Shibani S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM asinghal@partners.org NR 2 TC 3 Z9 3 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 JUL 14 PY 2015 VL 85 IS 2 BP 201 EP 202 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CM6NG UT WOS:000357804900016 PM 26170400 ER PT J AU Sung, YJ Segars, WP Pan, A Ando, M Sheppard, CJR Gupta, R AF Sung, Yongjin Segars, W. Paul Pan, Adam Ando, Masami Sheppard, Colin J. R. Gupta, Rajiv TI Realistic wave-optics simulation of X-ray phase-contrast imaging at a human scale SO SCIENTIFIC REPORTS LA English DT Article ID DIFFRACTION TOMOGRAPHY; SYNCHROTRON-RADIATION; RYTOV APPROXIMATION; DARK-FIELD; RECONSTRUCTION; RETRIEVAL; NOISE; CT AB X-ray phase-contrast imaging (XPCI) can dramatically improve soft tissue contrast in X-ray medical imaging. Despite worldwide efforts to develop novel XPCI systems, a numerical framework to rigorously predict the performance of a clinical XPCI system at a human scale is not yet available. We have developed such a tool by combining a numerical anthropomorphic phantom defined with non-uniform rational B-splines (NURBS) and a wave optics-based simulator that can accurately capture the phase-contrast signal from a human-scaled numerical phantom. Using a synchrotron-based, high-performance XPCI system, we provide qualitative comparison between simulated and experimental images. Our tool can be used to simulate the performance of XPCI on various disease entities and compare proposed XPCI systems in an unbiased manner. C1 [Sung, Yongjin; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sung, Yongjin; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Segars, W. Paul] Duke Univ, Dept Radiol, Durham, NC 27705 USA. [Pan, Adam] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Ando, Masami] Tokyo Univ Sci, Res Inst Sci & Technol, Noda, Chiba 2788510, Japan. [Sheppard, Colin J. R.] Ist Italiano Tecnol, I-16163 Genoa, Italy. RP Sung, YJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM ysung4@mgh.harvard.edu FU DARPA AXiS program [N66001-11-4204, 1300217190]; Ministry of Education, Culture, Sports, Science and Technology, Japan [18206011] FX This research was funded by the DARPA AXiS program (Grant No. N66001-11-4204, P.R. No. 1300217190) and by Grant-in-Aid for Scientific Research (No. 18206011) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors thank Professor George Barbastathis, Dr. Omid Khalilzadeh and Dr. Janet Miller for helpful discussions, and Dr. Anlin Wu for the help with XDFI measurements. NR 53 TC 1 Z9 1 U1 2 U2 13 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 JUL 14 PY 2015 VL 5 AR 12011 DI 10.1038/srep12011 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM7HJ UT WOS:000357862000001 PM 26169570 ER PT J AU Allegretti, AS Hundemer, G Chorghade, R Cosgrove, K Bajwa, E Bhan, I AF Allegretti, Andrew S. Hundemer, Gregory Chorghade, Rajeev Cosgrove, Katherine Bajwa, Ednan Bhan, Ishir TI Perspectives of continuous renal replacement therapy in the intensive care unit: a paired survey study of patient, physician, and nurse views SO BMC NEPHROLOGY LA English DT Article DE Continuous renal replacement therapy; Intensive care unit; Kidney injury; Mismatch; Patient and provider perspectives; Survey ID CRITICALLY-ILL PATIENTS; ACUTE KIDNEY INJURY; RANDOMIZED CONTROLLED-TRIAL; CARDIOPULMONARY-RESUSCITATION VIDEO; SURROGATE DECISION-MAKERS; CANCER-PATIENTS; SURVIVAL PREDICTIONS; TERMINALLY-ILL; CLINICAL-TRIAL; SUPPORT TOOL AB Background: Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to assess patient and provider understanding of outcomes around CRRT. Methods: From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy [HCP]), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used. Results: Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature. Conclusions: There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap. C1 [Allegretti, Andrew S.; Chorghade, Rajeev; Bhan, Ishir] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Hundemer, Gregory] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Cosgrove, Katherine; Bajwa, Ednan] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. RP Allegretti, AS (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 7 Whittier Pl,Suite 106, Boston, MA 02114 USA. EM aallegretti@partners.org FU National Institutes of Health (NIH) [5T32DK007540-29]; NIH [5K23DK081677, K23HL087934] FX The authors would like to thank Julia Wenger for her advice regarding statistical analyses. The authors report no relevant disclosures or competing interests. ASA is supported by a grant from the National Institutes of Health (NIH) 5T32DK007540-29. IB is supported by NIH grant 5K23DK081677. EB is supported by NIH grant K23HL087934. None of the funding sources had any role in the study design, collection, analysis, interpretation of data, writing of the manuscript, or decision to submit the manuscript for publication. NR 53 TC 0 Z9 0 U1 5 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 14 PY 2015 VL 16 AR 105 DI 10.1186/s12882-015-0086-5 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CM7CG UT WOS:000357847400001 PM 26169052 ER PT J AU Singh, P Staller, K Barshop, K Dai, E Newman, J Yoon, S Castel, S Kuo, B AF Singh, Prashant Staller, Kyle Barshop, Kenneth Dai, Elaine Newman, Jennifer Yoon, Sonia Castel, Shahar Kuo, Braden TI Patients with irritable bowel syndrome-diarrhea have lower disease-specific quality of life than irritable bowel syndrome-constipation SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Irritable bowel syndrome; Irritable bowel syndrome subtype; Quality of life; Irritable bowel syndrome-quality of life; Constipation; Diarrhea ID FUNCTIONAL GASTROINTESTINAL DISORDERS; IBS PATIENTS; SYMPTOM SEVERITY; UNITED-STATES; IMPACT; PREVALENCE; HABIT; VALIDATION; PATTERNS; THERAPY AB AIM: To determine effect of irritable bowel syndrome (IBS) subtype on IBS-specific quality of life (QOL) questionnaire and its subscales. METHODS: We studied IBS patients visiting our functional gastroenterology disorder clinic at a tertiary care center of Unites States. IBS and IBS subtype were diagnosed using Rome-. questionnaire. QOL was assessed using IBS-QOL questionnaire. IBS-QOL assesses quality of life along eight subscales: dysphoria, interference with activities, body image, health worry, food avoidance, social reactions, sexual health, and effect on relationships. IBS-QOL and its subscales were both scored on a range of 0-100 with higher scores suggestive of better QOL. Results of overall IBS-QOL scores and subscale scores are expressed as means with 95% CI. We compared mean IBS-QOL score and its subscales among various IBS-subtypes. Analysis of variance (ANOVA) was used to compare the mean difference between more than two groups after controlling for age and gender. A post-hoc analysis using Bonferroni correction was used only when P value for ANOVA was less than 0.05. RESULTS: Of 542 patients screened, 243 had IBS as per Rome-. criteria. IBS-mixed (IBS-M) was the most common IBS subtype (121 patients, 49.8%) followed by IBS-diarrhea (IBS-D) (56 patients, 23.1%), IBS-constipation (IBS-C) (54 patients, 22.2%) and IBS-unspecified (IBS-U) (12 patients, 4.9%). Overall IBS-QOL scores were significantly different among various IBS-subtypes (P = 0.01). IBS-QOL of patients with IBS-D (61.6, 95% CI: 54.0-69.1) and IBS-M (63.0, 95% CI: 58.1-68.0) was significantly lower than patients with IBS-C (74.5, 95% CI: 66.9-82.1) (P = 0.03 and 0.02 respectively). IBS-D patients scored significantly lower than IBS-C on food avoidance (45.0, 95% CI: 34.8-55.2 vs 61.1, 95% CI: 50.8-71.3, P = 0.04) and interference with activity (59.6, 95% CI: 51.4-67.7 vs 82.3, 95% CI: 74.1-90.6, P < 0.001). IBS-M patients had more interference in their activities (61.6, 95% CI: 56.3-66.9 vs 82.3, 95% CI: 74.1-90.6, P = 0.001) and greater impact on their relationships (73.3, 95% CI: 68.4-78.2 vs 84.7, 95% CI: 77.2-92.2, P = 0.02) than IBS-C patients. Patients with IBS-M also scored significantly lower than IBS-C on food avoidance (47.2, 95% CI: 40.7-53.7 vs 61.1, 95% CI: 50.8-71.3, P = 0.04) and social reaction (66.1, 95% CI: 61.1-71.1 vs 80.0, 95% CI: 72.1-87.7, P = 0.005). CONCLUSION: IBS-D and IBS-M patients have lower IBS-QOL than IBS-C patients. Clinicians should recognize food avoidance, effects on daily activities and relationship problems in these patients. C1 [Singh, Prashant; Staller, Kyle; Dai, Elaine; Newman, Jennifer; Castel, Shahar; Kuo, Braden] Massachussets Gen Hosp, GI Unit, Dept Med, Boston, MA 02124 USA. [Barshop, Kenneth] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Yoon, Sonia] Weill Cornell Med Coll, Div Gastroenterol, New York, NY 10021 USA. RP Kuo, B (reprint author), Massachussets Gen Hosp, GI Unit, Dept Med, GRJ 719,55 Fruit St, Boston, MA 02124 USA. EM bkuo@partners.org OI Staller, Kyle/0000-0003-4925-4290 FU Furiex Pharmaceuticals FX Dr. Braden Kuo has received fees for serving as consultant for Takeda, Furiex Pharmaceuticals and Genova Dignostics; and reveived research funding from Furiex Pharmaceuticals. NR 36 TC 6 Z9 6 U1 1 U2 5 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 14 PY 2015 VL 21 IS 26 BP 8103 EP 8109 DI 10.3748/wjg.v21.i26.8103 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CM5SR UT WOS:000357749400017 PM 26185382 ER PT J AU Chan, SC Selth, LA Li, YM Nyquist, MD Miao, L Bradner, JE Raj, GV Tilley, WD Dehm, SM AF Chan, Siu Chiu Selth, Luke A. Li, Yingming Nyquist, Michael D. Miao, Lu Bradner, James E. Raj, Ganesh V. Tilley, Wayne D. Dehm, Scott M. TI NAR Breakthrough Article Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RECEPTOR SPLICE VARIANTS; BET BROMODOMAIN PROTEINS; LENGTH ANDROGEN RECEPTOR; TRANSCRIPTIONAL REGULATION; SELECTIVE-INHIBITION; PROGRESSION; ENZALUTAMIDE; CELLS; AR-V7; ACTIVATION AB Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chro-matin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. C1 [Chan, Siu Chiu; Li, Yingming; Dehm, Scott M.] Univ Minnesota, Mason Canc Ctr, Rochester, MN 55905 USA. [Selth, Luke A.; Tilley, Wayne D.] Univ Adelaide, Sch Med, Dame Roma Mitchell Canc Res Labs, Adelaide, SA 5005, Australia. [Selth, Luke A.; Tilley, Wayne D.] Univ Adelaide, Sch Med, Freemasons Fdn Ctr Mens Hlth, Adelaide, SA 5005, Australia. [Nyquist, Michael D.] Univ Minnesota, Grad Program Mol Cellular Dev Biol & Genet, Rochester, MN 55905 USA. [Miao, Lu; Raj, Ganesh V.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dehm, Scott M.] Univ Minnesota, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Dehm, SM (reprint author), Univ Minnesota, Mason Canc Ctr, Rochester, MN 55905 USA. EM dehm@umn.edu RI MIAO, LU/K-6150-2015 FU National Institutes of Health [R01CA174777]; American Cancer Society [RSG-12-031-01]; U.S. Department of Defense Prostate Cancer Research Program [W81XWH-13-2-0093]; Prostate Cancer Foundation of Australia [1012337, 1043482, 2011/0452]; Masonic Cancer Center Phillip G. Semmer Scholarship; Ray and Shirl Norman Cancer Research Trust; Prostate Cancer Foundation FX National Institutes of Health [R01CA174777 to S.M.D.]; the American Cancer Society [Research Scholar Grant RSG-12-031-01 to S.M.D.]; the U.S. Department of Defense Prostate Cancer Research Program [Transformative Impact Award W81XWH-13-2-0093 to L.A.S., G.V.R., W.D.T., and S.M.D.]; the Prostate Cancer Foundation of Australia [1012337, 1043482, and 2011/0452 to L.A.S. and W.D.T.]; the Masonic Cancer Center Phillip G. Semmer Scholarship [to S.M.D.]; the Ray and Shirl Norman Cancer Research Trust (to L.A.S. and W.D.T.); the Prostate Cancer Foundation [Young Investigator Award to L.A.S.]. Funding for open access charge: National Institutes of Health [R01CA174777]. NR 57 TC 26 Z9 26 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 13 PY 2015 VL 43 IS 12 BP 5880 EP 5897 DI 10.1093/nar/gkv262 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CP3JM UT WOS:000359775200023 PM 25908785 ER PT J AU Roussakis, E Li, ZX Nichols, AJ Evans, CL AF Roussakis, Emmanuel Li, Zongxi Nichols, Alexander J. Evans, Conor L. TI Oxygen-Sensing Methods in Biomedicine from the Macroscale to the Microscale SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Review DE hypoxia; molecular imaging; oxygen sensing; phosphorescence quenching; tissue oxygenation ID ELECTRON-PARAMAGNETIC-RESONANCE; OPTICAL COHERENCE TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; QUANTITATIVE TISSUE OXIMETRY; NEAR-INFRARED PHOSPHORS; IN-VIVO; CLINICAL-APPLICATIONS; TUMOR OXYGENATION; SKELETAL-MUSCLE AB Oxygen monitoring has been a topic of exhaustive study given its central role in the biochemistry of life. The ability to quantify the physiological distribution and real-time dynamics of oxygen from subcellular to macroscopic levels is required to fully understand the mechanisms associated with both normal physiology and disease states. This Review will present the most significant recent advances in the development of oxygen-sensing materials and techniques, including polarographic, nuclear medicine, magnetic resonance, and optical approaches, that can be applied specifically for the real-time monitoring of oxygen dynamics in cellular and tissue environments. As some of the most exciting recent advances in synthetic methods and biomedical applications have been in the field of optical oxygen sensors, a major focus will be on the development of these toolkits. C1 [Roussakis, Emmanuel; Li, Zongxi; Nichols, Alexander J.; Evans, Conor L.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Charlestown, MA 02129 USA. [Nichols, Alexander J.; Evans, Conor L.] Harvard Univ, Program Biophys, Boston, MA 02115 USA. [Nichols, Alexander J.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Evans, CL (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, CNY 149-3210 13th St, Charlestown, MA 02129 USA. EM evans.conor@mgh.harvard.edu NR 224 TC 16 Z9 16 U1 18 U2 79 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JUL 13 PY 2015 VL 54 IS 29 BP 8340 EP 8362 DI 10.1002/anie.201410646 PG 23 WC Chemistry, Multidisciplinary SC Chemistry GA CM9SW UT WOS:000358050300005 PM 26084034 ER PT J AU Wei, W Birrer, MJ AF Wei, Wei Birrer, Michael J. TI Spleen Tyrosine Kinase Confers Paclitaxel Resistance in Ovarian Cancer SO CANCER CELL LA English DT Editorial Material ID CELLS AB Adaptive chemoresistance and consequent tumor recurrence present major obstacles to the improvement of the prognosis and quality-of-life of patients with advanced-stage ovarian cancer. In this issue of Cancer Cell, Yu and colleagues describe the critical role of spleen tyrosine kinase (SYK) in paclitaxel resistance by modulating the stability of microtubules. C1 [Wei, Wei; Birrer, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. RP Birrer, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. EM mbirrer@partners.org OI WEI, WEI/0000-0002-2315-3558 NR 10 TC 2 Z9 2 U1 0 U2 2 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 JUL 13 PY 2015 VL 28 IS 1 BP 7 EP 9 DI 10.1016/j.ccell.2015.06.008 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CN0NT UT WOS:000358111300004 PM 26175410 ER PT J AU Wu, SC Li, LS Kopp, N Montero, J Chapuy, B Yoda, A Christie, AL Liu, HY Christodoulou, A van Bodegom, D van der Zwet, J Layer, JV Tivey, T Lane, AA Ryan, JA Ng, SY DeAngelo, DJ Stone, RM Steensma, D Wadleigh, M Harris, M Mandon, E Ebel, N Andraos, R Romanet, V Dolemeyer, A Sterker, D Zender, M Rodig, SJ Murakami, M Hofmann, F Kuo, F Eck, MJ Silverman, LB Sallan, SE Letai, A Baffert, F Vangrevelinghe, E Radimerski, T Gaul, C Weinstock, DM AF Wu, Shuo-Chieh Li, Loretta S. Kopp, Nadja Montero, Joan Chapuy, Bjoern Yoda, Akinori Christie, Amanda L. Liu, Huiyun Christodoulou, Alexandra van Bodegom, Diederik van der Zwet, Jordy Layer, Jacob V. Tivey, Trevor Lane, Andrew A. Ryan, Jeremy A. Ng, Samuel Y. DeAngelo, Daniel J. Stone, Richard M. Steensma, David Wadleigh, Martha Harris, Marian Mandon, Emeline Ebel, Nicolas Andraos, Rita Romanet, Vincent Doelemeyer, Arno Sterker, Dario Zender, Michael Rodig, Scott J. Murakami, Masato Hofmann, Francesco Kuo, Frank Eck, Michael J. Silverman, Lewis B. Sallan, Stephen E. Letai, Anthony Baffert, Fabienne Vangrevelinghe, Eric Radimerski, Thomas Gaul, Christoph Weinstock, David M. TI Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia SO CANCER CELL LA English DT Article ID C-MYC; RECEPTOR; CRLF2; ACTIVATION; MUTATIONS; KINASE; TRANSFORMATION; PROLIFERATION; RESISTANCE; EXPRESSION AB A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphos-phorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders. C1 [Wu, Shuo-Chieh; Li, Loretta S.; Kopp, Nadja; Montero, Joan; Chapuy, Bjoern; Yoda, Akinori; Christie, Amanda L.; Liu, Huiyun; Christodoulou, Alexandra; van Bodegom, Diederik; van der Zwet, Jordy; Layer, Jacob V.; Tivey, Trevor; Lane, Andrew A.; Ryan, Jeremy A.; Ng, Samuel Y.; DeAngelo, Daniel J.; Stone, Richard M.; Steensma, David; Wadleigh, Martha; Letai, Anthony; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Li, Loretta S.; Harris, Marian; Silverman, Lewis B.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Mandon, Emeline; Ebel, Nicolas; Andraos, Rita; Romanet, Vincent; Doelemeyer, Arno; Sterker, Dario; Zender, Michael; Murakami, Masato; Hofmann, Francesco; Baffert, Fabienne; Vangrevelinghe, Eric; Radimerski, Thomas; Gaul, Christoph] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. [Rodig, Scott J.; Kuo, Frank] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Weinstock, David M.] Broad Inst, Cambridge, MA 02142 USA. RP Gaul, C (reprint author), Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. EM christoph.gaul@novartis.com; dweinstock@partners.org FU Dana-Farber/Novartis Drug Discovery Program; National Cancer Institute [R01 CA151898-01, T32 CA136432]; Novartis; National Heart, Lung, and Blood Institute [T32 HL116324] FX We thank Oliver Weigert for technical advice and previous constructs; IIene Galinsky, Samia Ahmed, and Katharine Majewski for sample procurement; and Shai lzraeli for thoughtful comments. We thank all the patients who contributed invaluable samples. We thank Aaron Thorner, Paul Van Hummelen, Matthew Ducar, and Bruce Wollison of the DFCI Center for Cancer Genome Discovery for assistance with genomic characterization. We thank Jerome Tamburini, Michael McKeown, and Elizabeth Townsend for their technical advice. This work was supported by the Dana-Farber/Novartis Drug Discovery Program (D.M.W.), the National Cancer Institute (R01 CA151898-01 to D.M.W. and T32 CA136432 to L.S.L.), and the National Heart, Lung, and Blood Institute (T32 HL116324 to L.S.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, National Heart, Lung, and Blood Institute, or the NIH. E.M., N.E., R.A., V.R., A.D., D.S., M.Z., M.M., F.H., F.B., E.V., T.R., and C.G. are or have been employees of Novartis Pharma AG. D.M.W. and M.J.E. received research funding from Novartis. NR 35 TC 6 Z9 6 U1 0 U2 5 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 JUL 13 PY 2015 VL 28 IS 1 BP 29 EP 41 DI 10.1016/j.ccell.2015.06.005 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CN0NT UT WOS:000358111300008 PM 26175414 ER PT J AU Zou, HY Friboulet, L Kodack, DP Engstrom, LD Li, QH West, M Tang, RW Wang, H Tsaparikos, K Wang, JW Timofeevski, S Katayama, R Dinh, DM Lam, H Lam, JL Yamazaki, S Hu, WY Patel, B Bezwada, D Frias, RL Lifshits, E Mahmood, S Gainor, JF Affolter, T Lappin, PB Gukasyan, H Lee, N Deng, SB Jain, RK Johnson, TW Shaw, AT Fantin, VR Smeal, T AF Zou, Helen Y. Friboulet, Luc Kodack, David P. Engstrom, Lars D. Li, Qiuhua West, Melissa Tang, Ruth W. Wang, Hui Tsaparikos, Konstantinos Wang, Jinwei Timofeevski, Sergei Katayama, Ryohei Dinh, Dac M. Lam, Hieu Lam, Justine L. Yamazaki, Shinji Hu, Wenyue Patel, Bhushankumar Bezwada, Divya Frias, Rosa L. Lifshits, Eugene Mahmood, Sidra Gainor, Justin F. Affolter, Timothy Lappin, Patrick B. Gukasyan, Hovhannes Lee, Nathan Deng, Shibing Jain, Rakesh K. Johnson, Ted W. Shaw, Alice T. Fantin, Valeria R. Smeal, Tod TI PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models SO CANCER CELL LA English DT Article ID CELL LUNG-CANCER; ANAPLASTIC LYMPHOMA KINASE; ROS ONCOGENE 1; ACQUIRED-RESISTANCE; CRIZOTINIB RESISTANCE; BRAIN METASTASES; MUTATIONS; REARRANGEMENT; ALECTINIB; EML4-ALK AB We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases. C1 [Zou, Helen Y.; Engstrom, Lars D.; Li, Qiuhua; West, Melissa; Tang, Ruth W.; Wang, Hui; Tsaparikos, Konstantinos; Wang, Jinwei; Timofeevski, Sergei; Dinh, Dac M.; Lam, Hieu; Lam, Justine L.; Yamazaki, Shinji; Hu, Wenyue; Affolter, Timothy; Lappin, Patrick B.; Gukasyan, Hovhannes; Lee, Nathan; Deng, Shibing; Johnson, Ted W.; Fantin, Valeria R.; Smeal, Tod] Pfizer World Wide Res & Dev, San Diego, CA 92121 USA. [Friboulet, Luc; Frias, Rosa L.; Lifshits, Eugene; Mahmood, Sidra; Gainor, Justin F.; Shaw, Alice T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, Boston, MA 02114 USA. [Kodack, David P.; Patel, Bhushankumar; Bezwada, Divya; Jain, Rakesh K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. [Katayama, Ryohei] Japanese Fdn Canc Res, Canc Chemotherapy Ctr, Tokyo 1358550, Japan. RP Smeal, T (reprint author), Pfizer World Wide Res & Dev, 10724 Sci Ctr Dr, San Diego, CA 92121 USA. EM tod.smeal@pfizer.com RI friboulet, luc/N-7276-2015 OI friboulet, luc/0000-0002-1129-4978 FU NIH [5R01CA164273-02]; USA Department of Defense Breast Cancer Research Innovator Award [W81XWH-10-1-0016, P01-CA080124]; Uniting Against Lung Cancer FX This work was supported by a grant from the NIH (5R01CA164273-02 to A.T.S.). The study was also supported by a grant from the USA Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016 and P01-CA080124 (to R.K.J.). This study was also supported, in part, by Uniting Against Lung Cancer (to L.F.). The authors H.Y.Z., L.D.E., Q.L., M.W., R.W.T., H.W., K.T., J.W., S.T., D.M.D., H.L., J.L.L., S.Y., W.H., T.A., P.B.L., H.G., N.L., S.D., T.W.J., V.R.F., and T.S. are employees and shareholders of Pfizer, Inc. NR 47 TC 57 Z9 57 U1 4 U2 16 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 JUL 13 PY 2015 VL 28 IS 1 BP 70 EP 81 DI 10.1016/j.ccell.2015.05.010 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CN0NT UT WOS:000358111300011 PM 26144315 ER PT J AU Schnabel, RB Yin, XY Gona, P Larson, MG Beiser, AS McManus, DD Newton-Cheh, C Lubitz, SA Magnani, JW Ellinor, PT Seshadri, S Wolf, PA Vasan, RS Benjamin, EJ Levy, D AF Schnabel, Renate B. Yin, Xiaoyan Gona, Philimon Larson, Martin G. Beiser, Alexa S. McManus, David D. Newton-Cheh, Christopher Lubitz, Steven A. Magnani, Jared W. Ellinor, Patrick T. Seshadri, Sudha Wolf, Philip A. Vasan, Ramachandran S. Benjamin, Emelia J. Levy, Daniel TI 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study SO LANCET LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; MEDICARE BENEFICIARIES; UNITED-STATES; US; HYPERTENSION; ANTICOAGULATION; PROJECTIONS; POPULATION; SURVIVAL; FAILURE AB Background Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years. Methods We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958-67, 1968-77, 1978-87, 1988-97, and 1998-2007), stratified by sex. Findings During 50 years of observation (202 417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 [47%] were women). Between 1958-67 and 1998-2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20.4 to 96.2 cases per 1000 person-years in men and from 13.7 to 49.4 cases per 1000 person-years in women; age-adjusted incidence increased from 3.7 to 13.4 new cases per 1000 person-years in men and from 2.5 to 8.6 new cases per 1000 person-years in women (p(trend) < 0.0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12.6 in 1958-67 to 25.7 in 1998-2007 in men, p(trend) = 0.0007; 8.1 to 11.8 in women, p(trend) = 0.009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50-86%) decrease in stroke (hazards ratio [HR] 3.77, 95% CI 1.98-7.20 in 1958-1967 compared with 1998-2007; p(trend) = 0.0001) and a 25% (95% CI -3-46%) decrease in mortality (HR 1.34, 95% CI 0.97-1.86 in 1958-1967 compared with 1998-2007; p(trend) = 0.003) in 20 years following atrial fibrillation onset. Interpretation Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention. C1 [Schnabel, Renate B.; Yin, Xiaoyan; Gona, Philimon; Larson, Martin G.; Beiser, Alexa S.; Newton-Cheh, Christopher; Seshadri, Sudha; Wolf, Philip A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Levy, Daniel] Natl Heart Lung & Blood Inst Framingham Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Larson, Martin G.; Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Beiser, Alexa S.; Seshadri, Sudha; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Wolf, Philip A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Levy, Daniel] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Boston, MA 02125 USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Biostat & Hlth Serv Res, Boston, MA 02125 USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Newton-Cheh, Christopher; Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Newton-Cheh, Christopher; Lubitz, Steven A.; Ellinor, Patrick T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Newton-Cheh, Christopher; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med Populat Genet, Cambridge, MA USA. [Schnabel, Renate B.] Deutsch Zentrum Herz Kreislauf Forsch, Univ Heart Ctr, Dept Gen & Intervent Cardiol, Hamburg, Germany. RP Schnabel, RB (reprint author), Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany. EM r.schnabel@uke.de OI Seshadri, Sudha/0000-0001-6135-2622; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778 FU NIH; NHLBI; NINDS; Deutsche Forschungsgemeinschaft; NIH/NHLBI [N01-HC-25195, 1K23HL114724]; NIH [1RC1HL101056, HL102214, AG028321, 2R01HL092577, 1R01HL092577, 1R01HL102214, 1R01AG028321, R01HL104156, 1K24HL105780, HL080124, HL077477, HL71039, HL093328, 6RO1-NS-17950, HL080025, 1U01HL105268-01, KL2RR031981]; Fondation Leducq [14CVD01]; American Heart Association [13EIA14220013]; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/3-2]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund Career Award for Medical Scientists FX NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft.; EJB was supported by NIH/NHLBI contract N01-HC-25195 and NIH grants 1RC1HL101056, HL102214, and AG028321. EJB and PTE were supported by NIH grant 2R01HL092577. PTE was supported by Fondation Leducq (14CVD01) and NIH grants 1R01HL092577, 1RC1HL101056, 1R01HL102214, 1R01AG028321, R01HL104156, and 1K24HL105780 and received the American Heart Association Established Investigator Award 13EIA14220013. RSV was supported by NIH grants HL080124, HL077477, HL71039, and HL093328. PAW, SS, and ASB were supported by NIH grant 6RO1-NS-17950. RBS was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) Emmy Noether Program SCHN 1149/3-2. CNC was supported by the NIH grant HL080025 and received the Doris Duke Charitable Foundation Clinical Scientist Development Award and the Burroughs Wellcome Fund Career Award for Medical Scientists. SAL was supported by the NIH/NHLBI grant 1K23HL114724. DDM received additional partial salary support by NIH grants 1U01HL105268-01 and KL2RR031981. NR 30 TC 75 Z9 76 U1 1 U2 17 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 JUL 11 PY 2015 VL 386 IS 9989 BP 154 EP 162 DI 10.1016/S0140-6736(14)61774-8 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CM5QC UT WOS:000357742200032 PM 25960110 ER PT J AU Sanders, RW van Gils, MJ Derking, R Sok, D Ketas, TJ Burger, JA Ozorowski, G Cupo, A Simonich, C Goo, L Arendt, H Kim, HJ Lee, JH Pugach, P Williams, M Debnath, G Moldt, B van Breemen, MJ Isik, G Medina-Ramirez, M Back, JW Koff, WC Julien, JP Rakasz, EG Seaman, MS Guttman, M Lee, KK Klasse, PJ LaBranche, C Schief, WR Wilson, IA Overbaugh, J Burton, DR Ward, AB Montefiori, DC Dean, H Moore, JP AF Sanders, Rogier W. van Gils, Marit J. Derking, Ronald Sok, Devin Ketas, Thomas J. Burger, Judith A. Ozorowski, Gabriel Cupo, Albert Simonich, Cassandra Goo, Leslie Arendt, Heather Kim, Helen J. Lee, Jeong Hyun Pugach, Pavel Williams, Melissa Debnath, Gargi Moldt, Brian van Breemen, Marielle J. Isik, Gozde Medina-Ramirez, Max Back, Jaap Willem Koff, Wayne C. Julien, Jean-Philippe Rakasz, Eva G. Seaman, Michael S. Guttman, Miklos Lee, Kelly K. Klasse, Per Johan LaBranche, Celia Schief, William R. Wilson, Ian A. Overbaugh, Julie Burton, Dennis R. Ward, Andrew B. Montefiori, David C. Dean, Hansi Moore, John P. TI HIV-1 neutralizing antibodies induced by native-like envelope trimers SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; GLYCOPROTEIN TRIMERS; MONOCLONAL-ANTIBODIES; ENV TRIMERS; IMMUNOGEN DESIGN; VACCINE; INFECTION; RESPONSES; GP120; GP140 AB A challenge for HIV-1 immunogen design is the difficulty of inducing neutralizing antibodies (NAbs) against neutralization-resistant (tier 2) viruses that dominate human transmissions. We show that a soluble recombinant HIV-1 envelope glycoprotein trimer that adopts a native conformation, BG505 SOSIP.664, induced NAbs potently against the sequence-matched tier 2 virus in rabbits and similar but weaker responses in macaques. The trimer also consistently induced cross-reactive NAbs against more sensitive (tier 1) viruses. Tier 2 NAbs recognized conformational epitopes that differed between animals and in some cases overlapped with those recognized by broadly neutralizing antibodies (bNAbs), whereas tier 1 responses targeted linear V3 epitopes. A second trimer, B41 SOSIP. 664, also induced a strong autologous tier 2 NAb response in rabbits. Thus, native-like trimers represent a promising starting point for the development of HIV-1 vaccines aimed at inducing bNAbs. C1 [Sanders, Rogier W.; Ketas, Thomas J.; Cupo, Albert; Pugach, Pavel; Williams, Melissa; Debnath, Gargi; Klasse, Per Johan; Moore, John P.] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Sanders, Rogier W.; van Gils, Marit J.; Derking, Ronald; Burger, Judith A.; van Breemen, Marielle J.; Isik, Gozde; Medina-Ramirez, Max] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Sok, Devin; Moldt, Brian; Schief, William R.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Sok, Devin; Ozorowski, Gabriel; Kim, Helen J.; Lee, Jeong Hyun; Moldt, Brian; Julien, Jean-Philippe; Schief, William R.; Wilson, Ian A.; Burton, Dennis R.; Ward, Andrew B.] Scripps Res Inst, Neutralizing Antibody Ctr, Int AIDS Vaccine Initiat, La Jolla, CA 92037 USA. [Sok, Devin; Ozorowski, Gabriel; Kim, Helen J.; Lee, Jeong Hyun; Moldt, Brian; Julien, Jean-Philippe; Schief, William R.; Wilson, Ian A.; Burton, Dennis R.; Ward, Andrew B.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA. [Sok, Devin; Ozorowski, Gabriel; Kim, Helen J.; Lee, Jeong Hyun; Moldt, Brian; Julien, Jean-Philippe; Schief, William R.; Wilson, Ian A.; Burton, Dennis R.; Ward, Andrew B.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Ozorowski, Gabriel; Kim, Helen J.; Lee, Jeong Hyun; Julien, Jean-Philippe; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Simonich, Cassandra; Goo, Leslie; Overbaugh, Julie] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Arendt, Heather; Koff, Wayne C.; Schief, William R.; Dean, Hansi] Int AIDS Vaccine Initiat, New York, NY 10004 USA. [Back, Jaap Willem] Pepscan Therapeut, NL-8243 RC Lelystad, Netherlands. [Rakasz, Eva G.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Seaman, Michael S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Seaman, Michael S.; Schief, William R.; Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Boston, MA 02114 USA. [Guttman, Miklos; Lee, Kelly K.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Sanders, RW (reprint author), Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. EM rws2002@med.cornell.edu; jpm2003@med.cornell.edu RI Ward, Andrew/F-9203-2014; Back, JW/B-3641-2009 OI Ward, Andrew/0000-0001-7153-3769; Back, JW/0000-0002-1310-4373 FU NIH [P01 AI082362, R37 AI036082, R01 AI084817, R01 AI076105, P51OD011106]; NIAID-NIH [HHSN27201100016C]; Scripps CHAVI-ID [UM1 AI100663]; Aids Fonds Netherlands [2011032, 2012041]; Canadian Institutes of Health Research (CIHR) Fellowship; Vidi grant from the Netherlands Organization for Scientific Research (NWO); Starting Investigator Grant from the European Research Council [ERC-StG-2011-280829-SHEV]; IAVI; USAID; Bill & Melinda Gates Foundation FX Supported by NIH grants P01 AI082362, R37 AI036082, R01 AI084817, R01 AI076105, NIAID-NIH Contract HHSN27201100016C, by Scripps CHAVI-ID (UM1 AI100663), by NIH grant P51OD011106, and by Aids Fonds Netherlands grants 2011032 and 2012041. J.-P.J. is a recipient of a Canadian Institutes of Health Research (CIHR) Fellowship. R.W.S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). This work was partially funded by IAVI with the generous support of USAID and the Bill & Melinda Gates Foundation; a full list of IAVI donors is available at www.iavi.org. The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the U.S. Government. We thank K. Sliepen, J. Korzun, M. Golabek, K. de los Reyes, L. Kong, K. Weisgrau, N. Pomplun, J. Hsueh, K. L. Saye-Francisco, A. Ramos for technical support; S. Schmidt, J. Gorman and N. Doria-Rose for advice; and G. Stewart-Jones, D. Kubitz, P. Kwong, J. Mascola, B. Haynes, A. McKnight, H. Katinger, S. Zolla-Pazner, P. Poignard, and M. Nussenzweig for reagents. The International AIDS Vaccine Initiative has previously filed a patent relating to the BG505 SOSIP.664 trimer: U.S. Provisional Application no. 61/772,739, titled "HIV-1 envelope glycoprotein," with inventors M. Caulfield, A.C., H. D., S. Hoffenberg, C. R. King, P. J. K., A. Marozsan, J. P. M., R. S., A.B.W., I.A.W., and J.-P.J. This does not alter our adherence to all Science policies on sharing data and materials. NR 60 TC 83 Z9 84 U1 8 U2 15 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 JUL 10 PY 2015 VL 349 IS 6244 AR aac4223 DI 10.1126/science.aac4223 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM4OM UT WOS:000357664300033 PM 26089353 ER PT J AU Wang, D Zhang, Q Eisenberg, BL Kane, JM Li, XA Lucas, D Petersen, IA DeLaney, TF Freeman, CR Finkelstein, SE Hitchcock, YJ Bedi, M Singh, AK Dundas, G Kirsch, DG AF Wang, Dian Zhang, Qiang Eisenberg, Burton L. Kane, John M. Li, X. Allen Lucas, David Petersen, Ivy A. DeLaney, Thomas F. Freeman, Carolyn R. Finkelstein, Steven E. Hitchcock, Ying J. Bedi, Manpreet Singh, Anurag K. Dundas, George Kirsch, David G. TI Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOFT-TISSUE SARCOMA; POSTOPERATIVE RADIOTHERAPY; RANDOMIZED-TRIAL; LOCAL-CONTROL; PHASE-2 AB Purpose We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume. Patients and Methods Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years. Results In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001). Conclusion The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS. (C) 2015 by American Society of Clinical Oncology C1 [Wang, Dian] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Zhang, Qiang] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Eisenberg, Burton L.] Hoag Univ South Calif, Norris Canc Ctr, Los Angeles, CA USA. [Kane, John M.; Singh, Anurag K.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Li, X. Allen; Bedi, Manpreet] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Lucas, David] Univ Michigan, Ann Arbor, MI 48109 USA. [Petersen, Ivy A.] Mayo Clin, Rochester, MN USA. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Freeman, Carolyn R.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Dundas, George] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Finkelstein, Steven E.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Hitchcock, Ying J.] Univ Utah, Salt Lake City, UT USA. [Kirsch, David G.] Duke Univ, Med Ctr, Durham, NC USA. RP Wang, D (reprint author), Rush Univ, Med Ctr, Dept Radiat Oncol, 500 S Paulina St,Atrium Bldg Ground Floor, Chicago, IL 60612 USA. EM Dian_Wang@Rush.edu FU National Cancer Institute [U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA180803] FX Supported by Grants No. U10CA21661, U10CA180868, U10CA180822, U10CA37422, and U24CA180803 from the National Cancer Institute. NR 15 TC 22 Z9 23 U1 0 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 JUL 10 PY 2015 VL 33 IS 20 BP 2231 EP U14 DI 10.1200/JCO.2014.58.5828 PG 11 WC Oncology SC Oncology GA CR9DM UT WOS:000361653400002 PM 25667281 ER PT J AU Warner, ET Tamimi, RM Hughes, ME Ottesen, RA Wong, YN Edge, SB Theriault, RL Blayney, DW Niland, JC Winer, EP Weeks, JC Partridge, AH AF Warner, Erica T. Tamimi, Rulla M. Hughes, Melissa E. Ottesen, Rebecca A. Wong, Yu-Ning Edge, Stephen B. Theriault, Richard L. Blayney, Douglas W. Niland, Joyce C. Winer, Eric P. Weeks, Jane C. Partridge, Ann H. TI Racial and Ethnic Differences in Breast Cancer Survival: Mediating Effect of Tumor Characteristics and Sociodemographic and Treatment Factors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT HORMONAL-THERAPY; WHITE AMERICAN PATIENTS; AFRICAN-AMERICAN; SOCIOECONOMIC-STATUS; CLINICOPATHOLOGICAL FEATURES; RACIAL/ETHNIC DIFFERENCES; PATIENT NAVIGATION; MOLECULAR SUBTYPES; UNITED-STATES; ASIAN WOMEN AB Purpose To evaluate the relationship between race/ethnicity and breast cancer-specific survival according to subtype and explore mediating factors. Patients and Methods Participants were women presenting with stage I to III breast cancer between January 2000 and December 2007 at National Comprehensive Cancer Network centers with survival follow-up through December 2009. Cox proportional hazards regression was used to compare breast cancer-specific survival among Asians (n = 533), Hispanics (n = 1,122), and blacks (n = 1,345) with that among whites (n = 14,268), overall and stratified by subtype (luminal A like, luminal B like, human epidermal growth factor receptor 2 type, and triple negative). Model estimates were used to derive mediation proportion and 95% CI for selected risk factors. Results In multivariable adjusted models, overall, blacks had 21% higher risk of breast cancer-specific death (hazard ratio [HR], 1.21; 95% CI, 1.00 to 1.45). For estrogen receptor-positive tumors, black and white survival differences were greatest within 2 years of diagnosis (years 0 to 2: HR, 2.65; 95% CI, 1.34 to 5.24; year 2 to end of follow-up: HR, 1.50; 95% CI, 1.12 to 2.00). Blacks were 76% and 56% more likely to die as a result of luminal A-like and luminal B-like tumors, respectively. No disparities were observed for triple-negative or human epidermal growth factor receptor 2-type tumors. Asians and Hispanics were less likely to die as a result of breast cancer compared with whites (Asians: HR, 0.56; 95% CI, 0.37 to 0.85; Hispanics: HR, 0.74; 95% CI, 0.58 to 0.95). For blacks, tumor characteristics and stage at diagnosis were significant disparity mediators. Body mass index was an important mediator for blacks and Asians. Conclusion Racial disparities in breast cancer survival vary by tumor subtype. Interventions are needed to reduce disparities, particularly in the first 2 years after diagnosis among black women with estrogen receptor-positive tumors. (C) 2015 by American Society of Clinical Oncology C1 [Warner, Erica T.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Warner, Erica T.; Tamimi, Rulla M.; Hughes, Melissa E.; Winer, Eric P.; Weeks, Jane C.; Partridge, Ann H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hughes, Melissa E.; Winer, Eric P.; Weeks, Jane C.; Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ottesen, Rebecca A.; Niland, Joyce C.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Blayney, Douglas W.] Stanford Univ, Ctr Canc, Palo Alto, CA 94304 USA. [Wong, Yu-Ning] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Edge, Stephen B.] Baptist Canc Ctr, Memphis, TN USA. [Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Warner, ET (reprint author), Harvard Univ, Dept Epidemiol, Sch Publ Hlth, 181 Longwood Ave,Room 452, Boston, MA 02115 USA. EM ewarner@hsph.harvard.edu FU National Cancer Institute (NCI) [NIH P50 CA089393, 5T32CA009001-36, K01CA188075-01]; National Comprehensive Cancer Network FX Supported by the National Cancer Institute (NCI) Specialized Program of Research Excellence in Breast Cancer Grant No. NIH P50 CA089393; by the National Comprehensive Cancer Network; and by NCI Grants No. 5T32CA009001-36 and K01CA188075-01 (E.T.W.). NR 61 TC 18 Z9 18 U1 3 U2 6 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 JUL 10 PY 2015 VL 33 IS 20 BP 2254 EP U44 DI 10.1200/JCO.2014.57.1349 PG 10 WC Oncology SC Oncology GA CR9DM UT WOS:000361653400005 PM 25964252 ER PT J AU Bielack, SS Smeland, S Whelan, JS Marina, N Jovic, G Hook, JM Krailo, MD Gebhardt, M Papai, Z Meyer, J Nadel, H Randall, RL Deffenbaugh, C Nagarajan, R Brennan, B Letson, GD Teot, LA Goorin, A Baumhoer, D Kager, L Werner, M Lau, CC Hall, KS Gelderblom, H Meyers, P Gorlick, R Windhager, R Helmke, K Eriksson, M Hoogerbrugge, PM Schomberg, P Tunn, PU Kuhne, T Jurgens, H van den Berg, H Bohling, T Picton, S Renard, M Reichardt, P Gerss, J Butterfass-Bahloul, T Morris, C Hogendoorn, PCW Seddon, B Calaminus, G Michelagnoli, M Dhooge, C Sydes, MR Bernstein, M AF Bielack, Stefan S. Smeland, Sigbjorn Whelan, Jeremy S. Marina, Neyssa Jovic, Gordana Hook, Jane M. Krailo, Mark D. Gebhardt, Mark Papai, Zsuzsanna Meyer, James Nadel, Helen Randall, R. Lor Deffenbaugh, Claudia Nagarajan, Rajaram Brennan, Bernadette Letson, G. Douglas Teot, Lisa A. Goorin, Allen Baumhoer, Daniel Kager, Leo Werner, Mathias Lau, Ching C. Hall, Kirsten Sundby Gelderblom, Hans Meyers, Paul Gorlick, Richard Windhager, Reinhard Helmke, Knut Eriksson, Mikael Hoogerbrugge, Peter M. Schomberg, Paula Tunn, Per-Ulf Kuehne, Thomas Juergens, Heribert van den Berg, Henk Bohling, Tom Picton, Susan Renard, Marleen Reichardt, Peter Gerss, Joachim Butterfass-Bahloul, Trude Morris, Carol Hogendoorn, Pancras C. W. Seddon, Beatrice Calaminus, Gabriele Michelagnoli, Maria Dhooge, Catharina Sydes, Matthew R. Bernstein, Mark CA EURAMOS-1 Investigators TI Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-DOSE METHOTREXATE; ADJUVANT THERAPY; MURAMYL TRIPEPTIDE; CLINICAL-TRIALS; ALPHA; SURVIVAL; CANCER; MELANOMA; IFOSFAMIDE; EXPERIENCE AB Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-alpha-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age <= 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included >= two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-alpha-2b (0.5 to 1.0 mu g/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-alpha-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-alpha-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-alpha-2b and for stopping prematurely, respectively. Median IFN-alpha-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-alpha-2b and provided toxicity information reported grade >= 3 toxicity during IFN-alpha-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-alpha-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-alpha-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-alpha-2b or stopped prematurely. Long-term follow-up for events and survival continues. (C) 2015 American Society of Clinical Oncology. C1 [Bielack, Stefan S.] Olga Hosp, Klinikum Stuttgart, Stuttgart, Germany. [Werner, Mathias] Helios Klinikum Emil Von Behring, Berlin, Germany. [Tunn, Per-Ulf] Helios Klinikum Berlin Buch, Berlin, Germany. [Helmke, Knut] Altonaer Kinderkrankenhaus, Hamburg, Germany. [Juergens, Heribert; Gerss, Joachim; Butterfass-Bahloul, Trude; Calaminus, Gabriele] Univ Klinikum Munster, Munster, Germany. [Reichardt, Peter] Klin Interdisziplinare Onkol, Bad Saarow Pieskow, Germany. [Smeland, Sigbjorn; Hall, Kirsten Sundby] Oslo Univ Hosp, Oslo, Norway. [Hall, Kirsten Sundby] Norwegian Radium Hosp, Oslo, Norway. [Whelan, Jeremy S.] Univ Coll London Hosp, London, England. [Jovic, Gordana; Hook, Jane M.; Sydes, Matthew R.] UCL, London WC1E 6BT, England. [Seddon, Beatrice; Michelagnoli, Maria] Univ Coll Hosp, London, England. [Brennan, Bernadette] Christie Hosp, Manchester, England. [Brennan, Bernadette] Royal Manchester Childrens Hosp, Manchester, England. [Picton, Susan] Univ Leeds, Leeds, W Yorkshire, England. [Marina, Neyssa] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Deffenbaugh, Claudia] Lucille Salter Packard Childrens Hosp, Palo Alto, CA USA. [Krailo, Mark D.] Childrens Oncol Grp, Arcadia, CA USA. [Gebhardt, Mark; Goorin, Allen] Dana Farber Canc Inst, Boston, MA USA. [Gebhardt, Mark; Teot, Lisa A.] Childrens Hosp, Boston, MA 02115 USA. [Papai, Zsuzsanna] Natl Med Ctr, Budapest, Hungary. [Meyer, James] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Meyer, James] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Nadel, Helen] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Nadel, Helen] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Bernstein, Mark] Dalhousie Univ, Halifax, NS, Canada. [Randall, R. Lor] Univ Utah, Salt Lake City, UT USA. [Nagarajan, Rajaram] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Letson, G. Douglas] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Baumhoer, Daniel] Univ Spital Basel, Basel, Switzerland. [Kuehne, Thomas] Univ Childrens Hosp Basel, Basel, Switzerland. [Kager, Leo] St Annas Children Hosp, Vienna, Austria. [Windhager, Reinhard] Med Univ Vienna, Vienna, Austria. [Lau, Ching C.] Baylor Coll Med, Houston, TX 77030 USA. [Gelderblom, Hans; Hogendoorn, Pancras C. W.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Hoogerbrugge, Peter M.] Radbound Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [van den Berg, Henk] Emma Childrens Hosp, Acad Med Ctr, Amsterdam, Netherlands. [Meyers, Paul; Morris, Carol] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Gorlick, Richard] Montefiore Med Ctr, Bronx, NY 10467 USA. [Eriksson, Mikael] Skane Univ Hosp, Lund, Sweden. [Schomberg, Paula] Mayo Clin, Rochester, MN USA. [Bohling, Tom] Univ Helsinki, Helsinki, Finland. [Bohling, Tom] Hosp Dist Helsinki, Helsinki, Finland. [Bohling, Tom] Uusimaa Lab, Helsinki, Finland. [Renard, Marleen] Univ Hosp Leuven, Leuven, Belgium. [Dhooge, Catharina] Univ Hosp, Ghent, Belgium. RP Sydes, MR (reprint author), UCL, MRC, Clin Trials Unit, Aviat House 5th Floor,125 Kingsway, London WC2B 6NH, England. EM m.sydes@ucl.ac.uk RI GerSS, Joachim/B-5702-2013 FU National Cancer Institute; European Science Foundation under the EUROCORES Program European Clinical Trials from the European Commission [ERASCT-2003-980409]; DG Research, FP6 [MM/NG/EMRC/0202]; St Anna Kinderkrebsforschung (Austria); Fonds National de la Recherche Scientifique (Belgium); Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Belgium); Parents Organisation (Czech Republic); Danish Medical Research Council (Denmark); Academy of Finland (Finland); Deutsche Forschungsgemeinschaft [BI 1045/1-1, 1-2]; Deutsche Krebshilfe [50-2723-Bi2]; Federal Ministry of Education and Research (Germany) [BMBF 01KN1105]; Semmelweis Foundation (Hungary); Council for Medical Research (the Netherlands); Research Council of Norway (Norway); Scandinavian Sarcoma Group (Sweden); Swiss Paediatric Oncology Group (Switzerland); Cancer Research UK (United Kingdom) [CRUK/05/013]; Medical Research Council (United Kingdom); National Institute for Health Research at University College London Hospitals, and Biomedical Research Centre (United Kingdom) FX Supported by governmental, nongovernmental, scientific, and charitable body funders in each participating country, with additional funding for pan-European trial coordination. Pegylated interferon-alfa-2b was provided by Merck, which reviewed this report. EURAMOS-1 was supported by multiple national and international governmental agencies and cancer charities, including the National Cancer Institute, which provided funding to the Children's Oncology Group (North America, Australasia, and Switzerland); the European Science Foundation under the EUROCORES Program European Clinical Trials through Contract No. ERASCT-2003-980409 from the European Commission, DG Research, FP6 (Reference No. MM/NG/EMRC/0202); St Anna Kinderkrebsforschung (Austria); Fonds National de la Recherche Scientifique and Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Belgium); Parents Organisation (Czech Republic); Danish Medical Research Council (Denmark); Academy of Finland (Finland); Deutsche Forschungsgemeinschaft Ref No. BI 1045/1-1 & 1-2), Deutsche Krebshilfe (Reference No. 50-2723-Bi2), and Federal Ministry of Education and Research (Reference No. BMBF 01KN1105; Germany); Semmelweis Foundation (Hungary); Council for Medical Research (the Netherlands); Research Council of Norway (Norway); Scandinavian Sarcoma Group (Sweden); Swiss Paediatric Oncology Group (Switzerland); Cancer Research UK (Reference No. CRUK/05/013), Medical Research Council, National Institute for Health Research at University College London Hospitals, and Biomedical Research Centre (United Kingdom). NR 35 TC 33 Z9 33 U1 1 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 JUL 10 PY 2015 VL 33 IS 20 BP 2279 EP U92 DI 10.1200/JCO.2014.60.0734 PG 20 WC Oncology SC Oncology GA CR9DM UT WOS:000361653400008 PM 26033801 ER PT J AU Thiruvoipati, T Kielhorn, CE Armstrong, EJ AF Thiruvoipati, Thejasvi Kielhorn, Caitlin E. Armstrong, Ehrin J. TI Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes SO WORLD JOURNAL OF DIABETES LA English DT Review DE Peripheral artery disease; Epidemiology; Pathophysiology; Outcomes; Diabetes ID ENDOTHELIUM-DEPENDENT VASODILATION; ACUTE MYOCARDIAL-INFARCTION; CRITICAL LIMB ISCHEMIA; C-REACTIVE PROTEIN; VASCULAR-DISEASE; NITRIC-OXIDE; CARDIOVASCULAR-DISEASE; CLINICAL CONSEQUENCES; INSULIN-RESISTANCE; METABOLIC SYNDROME AB Peripheral artery disease (PAD) is the atherosclerosis of lower extremity arteries and is also associated with atherothrombosis of other vascular beds, including the cardiovascular and cerebrovascular systems. The presence of diabetes mellitus greatly increases the risk of PAD, as well as accelerates its course, making these patients more susceptible to ischemic events and impaired functional status compared to patients without diabetes. To minimize these cardiovascular risks it is critical to understand the pathophysiology of atherosclerosis in diabetic patients. This, in turn, can offer insights into the therapeutic avenues available for these patients. This article provides an overview of the epidemiology of PAD in diabetic patients, followed by an analysis of the mechanisms by which altered metabolism in diabetes promotes atherosclerosis and plaque instability. Outcomes of PAD in diabetic patients are also discussed, with a focus on diabetic ulcers and critical limb ischemia. C1 [Thiruvoipati, Thejasvi; Kielhorn, Caitlin E.; Armstrong, Ehrin J.] Denver VA Med Ctr, Cardiol Sect, Denver, CO 80220 USA. [Thiruvoipati, Thejasvi; Kielhorn, Caitlin E.; Armstrong, Ehrin J.] Univ Colorado, Sch Med, Denver, CO 80220 USA. RP Armstrong, EJ (reprint author), Denver VA Med Ctr, Cardiol Sect, Denver, CO 80220 USA. EM ehrin.armstrong@ucdenver.edu NR 86 TC 5 Z9 6 U1 0 U2 2 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1948-9358 J9 WORLD J DIABETES JI World J. Diabetes PD JUL 10 PY 2015 VL 6 IS 7 BP 961 EP 969 DI 10.4239/wjd.v6.i7.961 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CR0EA UT WOS:000360989900007 PM 26185603 ER PT J AU Beauchamp, RL James, MF DeSouza, PA Wagh, V Zhao, WN Jordan, JT Stemmer-Rachamimov, A Plotkin, SR Gusella, JF Haggarty, SJ Ramesh, V AF Beauchamp, Roberta L. James, Marianne F. DeSouza, Patrick A. Wagh, Vilas Zhao, Wen-Ning Jordan, Justin T. Stemmer-Rachamimov, Anat Plotkin, Scott R. Gusella, James F. Haggarty, Stephen J. Ramesh, Vijaya TI A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas SO ONCOTARGET LA English DT Article DE NF2; meningioma; mTOR signaling; SGK1; AZD2014 ID TUMOR-SUPPRESSOR GENE; NEUROFIBROMATOSIS TYPE-2; MTOR COMPLEX; VESTIBULAR SCHWANNOMAS; P21-ACTIVATED KINASES; BREAST-CANCER; PHASE-II; NF2 GENE; GROWTH; PHOSPHORYLATION AB Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and similar to 60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells. Among the emerging top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-deficient meningioma cells, inhibition of SGK1 rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 also leads to attenuated mTORC1 but not mTORC2 signaling, suggesting that mTORC2/SGK1 and Rac1/PAK1 pathways are independently responsible for mTORC1 activation in NF2-deficient meningiomas. Using (CRISPR)-Cas9 genome editing, we generated isogenic human arachnoidal cell lines (ACs), the origin cell type for meningiomas, expressing or lacking NF2. NF2-null CRISPR ACs recapitulates the signaling of NF2-deficient meningioma cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2-negative meningioma lines. Moreover, we demonstrate that the dual mTORC1/mTORC2 inhibitor, AZD2014 is superior to rapamycin and PAK inhibitor FRAX597 in blocking proliferation of meningioma cells. Importantly, AZD2014 is currently in use in several clinical trials of cancer. Therefore, we believe that AZD2014 may provide therapeutic advantage over rapalogs for recurrent and progressive meningiomas. C1 [Beauchamp, Roberta L.; James, Marianne F.; DeSouza, Patrick A.; Wagh, Vilas; Zhao, Wen-Ning; Gusella, James F.; Haggarty, Stephen J.; Ramesh, Vijaya] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Jordan, Justin T.; Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Jordan, Justin T.; Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Chem Neurobiol Lab, Dept Neurol, Boston, MA 02114 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Chem Neurobiol Lab, Dept Psychiat, Boston, MA 02114 USA. RP Ramesh, V (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM ramesh@helix.mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU U.S. Army Medical Research and Material Command [W81XWH-11-1-0264]; Children's Tumor Foundation (CTF); NF Inc.,; NIH [NS082482] FX This work was supported by U.S. Army Medical Research and Material Command contract W81XWH-11-1-0264, NIH NS082482, Children's Tumor Foundation (CTF) and NF Inc., MA and the Manth family. NR 52 TC 4 Z9 4 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 10 PY 2015 VL 6 IS 19 BP 16981 EP 16997 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2VB UT WOS:000359013600034 PM 26219339 ER PT J AU Feng, S Wang, JH Zhang, YQ Creighton, CJ Ittmann, M AF Feng, Shu Wang, Jianghua Zhang, Yiqun Creighton, Chad J. Ittmann, Michael TI FGF23 promotes prostate cancer progression SO ONCOTARGET LA English DT Article DE prostate cancer; FGF23; signal transduction; fibroblast growth factors; endocrine fibroblast growth factors ID GROWTH-FACTOR; SERUM-CALCIUM; FUSION; GENE; RECEPTOR; CELLS; DIFFERENTIATION; EXPRESSION; PROGNOSIS; PATHWAYS AB Prostate cancer is the most common cancer in US men and the second leading cause of cancer deaths. Fibroblast growth factor 23 (FGF23) is an endocrine FGF, normally expressed by osteocytes, which plays a critical role in phosphate homeostasis via a feedback loop involving the kidney and vitamin D. We now show that FGF23 is expressed as an autocrine growth factor in all prostate cancer cell lines tested and is present at increased levels in prostate cancer tissues. Exogenous FGF23 enhances proliferation, invasion and anchorage independent growth in vitro while FGF23 knockdown in prostate cancer cell lines decreases these phenotypes. FGF23 knockdown also decreases tumor growth in vivo. Given that classical FGFs and FGF19 are also increased in prostate cancer, we analyzed expression microarrays hybridized with RNAs from of LNCaP cells stimulated with FGF2, FGF19 or FGF23. The different FGF ligands induce overlapping as well as unique patterns of gene expression changes and thus are not redundant. We identified multiple genes whose expression is altered by FGF23 that are associated with prostate cancer initiation and progression. Thus FGF23 can potentially also act as an autocrine, paracrine and/or endocrine growth factor in prostate cancer that can promote prostate cancer progression. C1 [Feng, Shu; Wang, Jianghua; Ittmann, Michael] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Feng, Shu; Wang, Jianghua; Ittmann, Michael] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX USA. [Zhang, Yiqun; Creighton, Chad J.] Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Ittmann, M (reprint author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. EM mittmann@bcm.tmc.edu FU Dept of Veterans Affairs Merit Review program; Prostate Cancer Foundation; National Cancer Institute [P30 CA125123] FX This work was supported by grants from the Dept of Veterans Affairs Merit Review program (MI); the Prostate Cancer Foundation (MI); the National Cancer Institute to the Dan L. Duncan Cancer (P30 CA125123) supporting Human Tissue Acquisition and Pathology Core and by the use of the facilities of the Michael E. DeBakey VAMC. NR 39 TC 6 Z9 6 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 10 PY 2015 VL 6 IS 19 BP 17291 EP 17301 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2VB UT WOS:000359013600056 PM 26019137 ER PT J AU Hong, JX Shi, WY Liu, ZG Pineda, R Cui, XH Sun, XH Xu, JJ AF Hong, Jiaxu Shi, Weiyun Liu, Zuguo Pineda, Roberto Cui, Xinhan Sun, Xinghuai Xu, Jianjiang TI Limitations of Keratoplasty in China: A Survey Analysis SO PLOS ONE LA English DT Article AB Purpose Each year, over 8,000 corneal transplantation surgeries are performed in China. Unlike developed countries, which have established standard requirements for operative experience for corneal specialists, little information exists on surgical training for keratoplasty in China. The aim of this study was to assess the keratoplasty experience of Chinese corneal specialists and to characterize their surgical patterns. Methods One hundred and twenty-one corneal specialists in 16 provinces (65 cities) in China were invited to complete an anonymous survey at the 2014 Chinese Corneal Society annual meeting, which consisted of questions with single or multiple-choice answers. Demographics, the number and type of keratoplasties performed, and the perceived limiting factors for performing keratoplasties were analyzed. Results An overwhelming 89% response rate was achieved. Of the 108 respondents, 76% worked in tertiary centers, and only 23% held a medical doctorate degree. Furthermore, 69% of the participants had received corneal fellowship training of less than one year. Only 71% were capable of keratoplasties. Among those doing keratoplasty, 68% performed less than 50 keratoplasties each year. Of the same group of keratoplasty surgeons, 88% of corneal specialists capable of keratoplasties had performed penetrating keratoplasties, 87% had performed lamellar keratoplasties, 12% had performed deep anterior lamellar keratoplasties, and 5% had performed Descemet's stripping endothelial keratoplasties. When questioned on the reasons for the low number of keratoplasties performed in China, the respondents deemed the following factors most important: lack of surgical training (71%), a shortage of donor supply (52%), and a lack of curricula (42%). A multivariate logistic regression analysis showed that corneal transplantation capabilities are significantly associated with responders' education levels and training time. Conclusion Keratoplasty surgery experience is suboptimal for Chinese corneal specialists. Penetrating and lamellar keratoplasties are the preferred surgical patterns. Our findings raise concerns about the adequacy of keratoplasty training in China. C1 [Hong, Jiaxu; Cui, Xinhan; Sun, Xinghuai; Xu, Jianjiang] Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, Shanghai 200433, Peoples R China. [Shi, Weiyun] Shandong Eye Hosp, Shandong Eye Inst, Qingdao, Peoples R China. [Hong, Jiaxu; Liu, Zuguo] Xiamen Univ, Inst Eye, Xiamen, Fujian, Peoples R China. [Hong, Jiaxu; Pineda, Roberto] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Xu, JJ (reprint author), Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, Shanghai 200433, Peoples R China. EM jianjiangxu@126.com FU Key Clinic Medicine Research Program, the Ministry of Health, China [201302015]; National Science and Technology Research Program, the Ministry of Science and Technology, China [2012BAI08B01]; National Natural Science Foundation of China [81170817, 81200658, 81300735, 81270978, U1205025, 81330022]; Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai [13441900900, 13430720400]; New Technology Joint Research Project in Shanghai Hospitals [SHDC12014114] FX The authors were supported by grants from the Key Clinic Medicine Research Program, the Ministry of Health, China (201302015); the National Science and Technology Research Program, the Ministry of Science and Technology, China (2012BAI08B01); the National Natural Science Foundation of China (81170817, 81200658, 81300735, 81270978, U1205025, and 81330022); and the Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai (13441900900, 13430720400); New Technology Joint Research Project in Shanghai Hospitals (SHDC12014114). The sponsor or funding organization had no role in the design or conduct of this research. NR 7 TC 2 Z9 2 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2015 VL 10 IS 7 AR e0132268 DI 10.1371/journal.pone.0132268 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1FD UT WOS:000358162300109 PM 26161870 ER PT J AU Zhao, J Zhu, TH Chen, WJ Fan, BJ He, LM Yang, BC Deng, ZH AF Zhao, Jun Zhu, Tianhui Chen, Wenjie Fan, Bao Jian He, Liumei Yang, Baocheng Deng, Zhihui TI Human Leukocyte Antigens-B and -C Loci Associated with Posner-Schlossman Syndrome in a Southern Chinese Population SO PLOS ONE LA English DT Article ID ACUTE ANTERIOR UVEITIS; OPEN-ANGLE GLAUCOMA; VASCULAR ENDOTHELIAL DYSFUNCTION; BIRDSHOT RETINOCHOROIDOPATHY; GLAUCOMATOCYCLITIC CRISIS; HLA; CYTOMEGALOVIRUS; SUSCEPTIBILITY; HLA-B27; FLOW AB The etiology of Posner-Schlossman syndrome (PSS) remains unknown. The association of human leukocyte antigens (HLA) allelic diversity with PSS has been poorly investigated. To evaluate the association of allelic polymorphisms of class I HLA-A, -B and -C and class II HLA-DRB1 and -DQB1 with PSS, 100 unrelated patients with PSS and 128 age-and ethnically matched control subjects were recruited from a southern Chinese Han population. Polymorphisms in exons 2-4 for HLA-A, -B, -C loci, exon 2 for HLA-DRB1 and exons 2,3 for HLA-DQB1 were analyzed for association with PSS at allele and haplotype levels. The allele frequency of HLA-C* 1402 in PSS patients was significantly higher than that in controls (P = 0.002, OR = 4.12). This association survived the Bonferroni correction (P-C = 0.04). The allele frequency of HLA-B* 1301 in PSS patients was lower than that in the control group (P = 0.003, OR = 0.21), although this association did not survive the Bonferroni correction (P-C = 0.16). In PSS patients, the haplotype frequencies of HLA-A* 1101 similar to C* 1402 and B* 5101 similar to C* 1402 were higher than that in controls (P = 0.03, OR = 4.44; P = 0.02, OR = 3.20; respectively), while the HLA-B* 1301 similar to C* 0304 was lower than that in controls (P = 0.007, OR = 0.23), although these associations did not survive the Bonferroni correction (P-C > 0.16). This study for the first time demonstrated that polymorphisms at the HLA-B and HLA-C loci were nominally associated with PSS in the southern Chinese Han population. Our results suggest that HLA-C* 1402, A* 1101 similar to C* 1402 and B* 5101 similar to C* 1402 might be risk factors for PSS, whereas HLA-B* 1301 plus B* 1301 similar to C* 0304 might be protective factors against PSS, but even larger datasets are required to confirm these findings. Findings from this study provide valuable new clues for investigating the mechanisms and development of new diagnosis and treatment for PSS. C1 [Zhao, Jun; Zhu, Tianhui; Chen, Wenjie] Jinan Univ, Shenzhen Eye Hosp, Shenzhen Key Lab Ophthalmol, Shenzhen, Guangdong, Peoples R China. [Zhao, Jun] Shenzhen Univ, Sch Ophthalmol & Optometry, Shenzhen, Guangdong, Peoples R China. [Fan, Bao Jian] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [He, Liumei; Yang, Baocheng; Deng, Zhihui] Shenzhen Blood Ctr, Immunogenet Lab, Shenzhen, Guangdong, Peoples R China. RP Zhao, J (reprint author), Jinan Univ, Shenzhen Eye Hosp, Shenzhen Key Lab Ophthalmol, Shenzhen, Guangdong, Peoples R China. EM doctorzhaojun@163.com; zhihui_deng@aliyun.com FU Shenzhen Science & Technology Project, People's Republic of China [201102188]; Guangdong Nature Science Foundation, People's Republic of China [S2013010013464] FX The funders, Shenzhen Science & Technology Project, People's Republic of China (No. 201102188) and Guangdong Nature Science Foundation, People's Republic of China (No. S2013010013464), had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JZ is the author who received the funding. NR 29 TC 0 Z9 1 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2015 VL 10 IS 7 AR e0132179 DI 10.1371/journal.pone.0132179 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1FD UT WOS:000358162300102 PM 26161794 ER PT J AU Rybin, D Doros, G Pencina, MJ Fava, M AF Rybin, Denis Doros, Gheorghe Pencina, Michael J. Fava, Maurizio TI Placebo non-response measure in sequential parallel comparison design studies SO STATISTICS IN MEDICINE LA English DT Article DE SPCD; repeated measures; placebo effect ID PSYCHIATRIC CLINICAL-TRIALS AB The Sequential Parallel Comparison Design (SPCD) is one of the novel approaches addressing placebo response. The analysis of SPCD data typically classifies subjects as placebo responders' or placebo non-responders'. Most current methods employed for analysis of SPCD data utilize only a part of the data collected during the trial. A repeated measures model was proposed for analysis of continuous outcomes that permitted the inclusion of information from all subjects into the treatment effect estimation. We describe here a new approach using a weighted repeated measures model that further improves the utilization of data collected during the trial, allowing the incorporation of information that is relevant to the placebo response, and dealing with the problem of possible misclassification of subjects. Our simulations show that when compared to the unweighted repeated measures model method, our approach performs as well or, under certain conditions, better, in preserving the type I error, achieving adequate power and minimizing the mean squared error. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Rybin, Denis; Doros, Gheorghe] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Doros, Gheorghe] HCRI, Boston, MA 02215 USA. [Pencina, Michael J.] Duke Univ, Biostat & Bioinformat, DCRI, Durham, NC 27705 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rybin, D (reprint author), Boston Univ, Dept Biostat, 801 Massachusetts Ave, Boston, MA 02118 USA. EM drybine@bu.edu OI Rybin, Denis/0000-0002-3657-4829 NR 14 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUL 10 PY 2015 VL 34 IS 15 BP 2281 EP 2293 DI 10.1002/sim.6494 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CJ8FC UT WOS:000355734600001 PM 25865181 ER PT J AU McClanahan, F Riches, JC Miller, S Day, WP Kotsiou, E Neuberg, D Croce, CM Capasso, M Gribben, JG AF McClanahan, Fabienne Riches, John C. Miller, Shaun Day, William P. Kotsiou, Eleni Neuberg, Donna Croce, Carlo M. Capasso, Melania Gribben, John G. TI Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the E mu-TCL1 CLL mouse model SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CHRONIC VIRAL-INFECTION; CLINICAL-SIGNIFICANCE; DISEASE PROGRESSION; SUB-POPULATIONS; PD-1; EXHAUSTION; EXPRESSION; CANCER; MICROENVIRONMENT AB T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the E mu-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity. C1 [McClanahan, Fabienne; Riches, John C.; Miller, Shaun; Day, William P.; Kotsiou, Eleni; Gribben, John G.] Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, London EC1M 6BQ, England. [McClanahan, Fabienne] German Canc Res Ctr, Dept Mol Genet, Heidelberg, Germany. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Croce, Carlo M.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Capasso, Melania] Queen Mary Univ London, Barts Canc Inst, Ctr Canc & Inflammat, London EC1M 6BQ, England. RP Gribben, JG (reprint author), Queen Mary Univ London, Barts Canc Inst, 3rd Floor John Vane Sci Ctr,Charterhouse Sq, London EC1M 6BQ, England. EM j.gribben@qmul.ac.uk FU Deutsche Krebshilfe by the Helmholtz Virtual Institute; National Institutes of Health, National Cancer Institute for the CLL Research Consortium [P01 CA95426] FX This work was supported by grants from Deutsche Krebshilfe (F.M.) by the Helmholtz Virtual Institute (J.G.G., F.M.), and from the National Institutes of Health, National Cancer Institute for the CLL Research Consortium (grant P01 CA95426) (J.G.G., D.N., C.M.C.). NR 56 TC 16 Z9 16 U1 0 U2 5 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 JUL 9 PY 2015 VL 126 IS 2 BP 212 EP 221 DI 10.1182/blood-2015-02-626754 PG 10 WC Hematology SC Hematology GA CO0TP UT WOS:000358866400016 PM 25979947 ER PT J AU Etulain, J Martinod, K Wong, SL Cifuni, SM Schattner, M Wagner, DD AF Etulain, Julia Martinod, Kimberly Wong, Siu Ling Cifuni, Stephen M. Schattner, Mirta Wagner, Denisa D. TI P-selectin promotes neutrophil extracellular trap formation in mice SO BLOOD LA English DT Article ID ACTIVATED PLATELETS; LEUKOCYTE INTERACTION; ELEVATED LEVELS; BLOOD; ATHEROSCLEROSIS; INFLAMMATION; THROMBOSIS; ADHESION; MICROPARTICLES; CD11B/CD18 AB Neutrophil extracellular traps (NETs) can be released in the vasculature. In addition to trapping microbes, they promote inflammatory and thrombotic diseases. Considering that P-selectin induces prothrombotic and proinflammatory signaling, we studied the role of this selectin in NET formation. NET formation(NETosis) was induced by thrombin-activated platelets rosetting with neutrophils and was inhibited by anti-P-selectin aptamer or anti-P-selectin glycoprotein ligand-1 (PSGL-1) inhibitory antibody but was not induced by platelets from P-selectin(-/-) mice. Moreover, NETosis was also promoted by P-selectin-immunoglobulin fusion protein but not by control immunoglobulin. We isolated neutrophils from mice engineered to overproduce soluble P-selectin (P-selectin(Delta CT/Delta CT) mice). Although the levels of circulating DNA and nucleosomes (indicative of spontaneous NETosis) were normal in these mice, basal neutrophil histone citrullination and presence of P-selectin on circulating neutrophils were elevated. NET formation after stimulation with platelet activating factor, ionomycin, orphorbol 12-myristate 13-acetate was significantly enhanced, indicating that the P-selectin(Delta CT/Delta CT) neutrophils were primed for NETosis. In summary, P-selectin, cellular or soluble, through binding to PSGL-1, promotes NETosis, suggesting that this pathway is a potential therapeutic target for NET-related diseases. C1 [Etulain, Julia; Schattner, Mirta] Natl Acad Med, Natl Sci & Tech Res Council, Inst Expt Med, Lab Expt Thrombosis, Buenos Aires, DF, Argentina. [Etulain, Julia; Martinod, Kimberly; Wong, Siu Ling; Cifuni, Stephen M.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Martinod, Kimberly; Wong, Siu Ling; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Martinod, Kimberly] Harvard Univ, Sch Med, Grad Program Immunol, Boston, MA USA. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Wagner, DD (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, 3 Blackfan Circle,Third Floor, Boston, MA 02115 USA. EM denisa.wagner@childrens.harvard.edu OI Martinod, Kimberly/0000-0002-1026-6107 FU National Institutes of Health National Heart, Lung, and Blood Institute [R01HL102101]; International Society on Thrombosis and Haemostasis FX This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute grant R01HL102101 ( D.D.W.). J.E. was the recipient of a Reach-the-World Fellowship from the International Society on Thrombosis and Haemostasis. NR 27 TC 39 Z9 40 U1 0 U2 13 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 JUL 9 PY 2015 VL 126 IS 2 BP 242 EP 246 DI 10.1182/blood-2015-01-624023 PG 5 WC Hematology SC Hematology GA CO0TP UT WOS:000358866400019 PM 25979951 ER PT J AU Brahmer, J Reckamp, KL Baas, P Crino, L Eberhardt, WEE Poddubskaya, E Antonia, S Pluzanski, A Vokes, EE Holgado, E Waterhouse, D Ready, N Gainor, J Frontera, OA Havel, L Steins, M Garassino, MC Aerts, JG Domine, M Paz-Ares, L Reck, M Baudelet, C Harbison, CT Lestini, B Spigel, DR AF Brahmer, Julie Reckamp, Karen L. Baas, Paul Crino, Lucio Eberhardt, Wilfried E. E. Poddubskaya, Elena Antonia, Scott Pluzanski, Adam Vokes, Everett E. Holgado, Esther Waterhouse, David Ready, Neal Gainor, Justin Aren Frontera, Osvaldo Havel, Libor Steins, Martin Garassino, Marina C. Aerts, Joachim G. Domine, Manuel Paz-Ares, Luis Reck, Martin Baudelet, Christine Harbison, Christopher T. Lestini, Brian Spigel, David R. TI Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PHASE-III TRIAL; LIGAND-1 EXPRESSION; ANTI-PD-1 ANTIBODY; SAFETY; CHEMOTHERAPY; BLOCKADE AB BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. C1 [Brahmer, Julie] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Reckamp, Karen L.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Baas, Paul] Netherlands Canc Inst, Amsterdam, Netherlands. [Baas, Paul] Antoni van Leeuwenhoek Hosp, Amsterdam, Netherlands. [Aerts, Joachim G.] Erasmus MC Canc Inst, Rotterdam, Netherlands. [Aerts, Joachim G.] Ziekenhuis Amphia, Breda, Netherlands. [Crino, Lucio] Univ Hosp Perugia, Perugia, Italy. [Garassino, Marina C.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Eberhardt, Wilfried E. E.] Univ Duisburg Essen, Univ Klinikum Essen, West German Canc Ctr, Dept Med Oncol, Essen, Germany. [Eberhardt, Wilfried E. E.] Univ Duisburg Essen, Ruhrlandklin, Essen, Germany. [Steins, Martin] Univ Heidelberg Hosp, Thoraxklin, Heidelberg, Germany. [Reck, Martin] LungenClin Grosshansdorf, Grosshansdorf, Germany. [Poddubskaya, Elena] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Antonia, Scott] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Pluzanski, Adam] Inst Marii Sklodowskiej Curie, Ctr Onkol, Warsaw, Poland. [Vokes, Everett E.] Univ Chicago Med & Biol Sci, Chicago, IL USA. [Holgado, Esther] Hosp Madrid Norte Sanchinarro, Madrid, Spain. [Domine, Manuel] Hosp Univ Fdn Jimenez Diaz, Madrid, Spain. [Paz-Ares, Luis] Hosp Univ Virgen Rocio, Seville, Spain. [Waterhouse, David] Oncol Hematol Care, Cincinnati, OH USA. [Ready, Neal] Duke Univ, Med Ctr, Durham, NC USA. [Gainor, Justin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Aren Frontera, Osvaldo] Ctr Int Estudios Clin, Santiago, Chile. [Havel, Libor] Nemocnice Bulovce, Prague, Czech Republic. [Baudelet, Christine; Harbison, Christopher T.; Lestini, Brian] Bristol Myers Squibb Co, Princeton, NJ USA. [Spigel, David R.] Sarah Cannon Res Inst, Nashville, TN USA. [Spigel, David R.] Tennessee Oncol, Nashville, TN USA. RP Brahmer, J (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Bunting Blaustein Canc Res Bldg,1650 Orleans St, Baltimore, MD 21287 USA. EM brahmju@jhmi.edu RI IBIS, NUEVAS TERAPIA/P-3415-2015; Garassino, Marina/D-7128-2017; OI Garassino, Marina/0000-0002-3821-5598; Reckamp, Karen/0000-0002-9213-0325 FU Bristol-Myers Squibb FX Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004. NR 22 TC 861 Z9 904 U1 38 U2 112 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 JUL 9 PY 2015 VL 373 IS 2 BP 123 EP 135 DI 10.1056/NEJMoa1504627 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA CM3QP UT WOS:000357598600005 PM 26028407 ER PT J AU Rosenfield, K Jaff, MR White, CJ Rocha-Singh, K Mena-Hurtado, C Metzger, DC Brodmann, M Pilger, E Zeller, T Krishnan, P Gammon, R Muller-Hulsbeck, S Nehler, MR Benenati, JF Scheinert, D AF Rosenfield, Kenneth Jaff, Michael R. White, Christopher J. Rocha-Singh, Krishna Mena-Hurtado, Carlos Metzger, D. Christopher Brodmann, Marianne Pilger, Ernst Zeller, Thomas Krishnan, Prakash Gammon, Roger Mueller-Huelsbeck, Stefan Nehler, Mark R. Benenati, James F. Scheinert, Dierk CA Levant 2 Investigators TI Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUPERFICIAL FEMORAL-ARTERY; NITINOL STENT IMPLANTATION; RESILIENT RANDOMIZED-TRIAL; POPLITEAL ARTERIES; ELUTING STENTS; FOLLOW-UP; LESIONS; ANGIOPLASTY; RESTENOSIS; FRACTURES AB BACKGROUND The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2: 1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. C1 [Rosenfield, Kenneth; Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Christopher J.] Ochsner Med Ctr, New Orleans, LA USA. [Rocha-Singh, Krishna] St Johns Hosp, Prairie Heart Inst, Springfield, IL USA. [Mena-Hurtado, Carlos] Yale Univ, Sch Med, New Haven, CT USA. [Metzger, D. Christopher] Wellmont Cardiovasc Associates Heart Inst, Kingsport, TN USA. [Brodmann, Marianne; Pilger, Ernst] Med Univ Graz, Graz, Austria. [Zeller, Thomas] Univ Heart Ctr Freiburg Bad Krozingen, Bad Krozingen, Germany. [Mueller-Huelsbeck, Stefan] Diakonissenanstalt Flensburg, Flensburg, Germany. [Scheinert, Dierk] Park Krankenhaus Leipzig, Leipzig, Germany. [Scheinert, Dierk] Univ Klinikum Leipzig, Leipzig, Germany. [Krishnan, Prakash] Mt Sinai Med Ctr, New York, NY 10029 USA. [Gammon, Roger] Austin Heart, Austin, TX USA. [Nehler, Mark R.] Univ Colorado, Med Ctr, Denver, CO 80202 USA. [Benenati, James F.] Baptist Cardiac & Vasc Inst, Miami, FL USA. RP Rosenfield, K (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM krosenfield1@partners.org RI White, Christopher/J-6686-2012; Ketelsen, Dominik/A-1143-2012 OI White, Christopher/0000-0001-8618-7539; Ketelsen, Dominik/0000-0002-7333-8024 FU Lutonix-Bard FX Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541. NR 24 TC 76 Z9 83 U1 2 U2 9 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 JUL 9 PY 2015 VL 373 IS 2 BP 145 EP 153 DI 10.1056/NEJMoa1406235 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CM3QP UT WOS:000357598600007 PM 26106946 ER PT J AU Gharib, SD Berger, DL Choy, G Huck, AE AF Gharib, Soheyla D. Berger, David L. Choy, Garry Huck, Amelia E. TI Case 21-2015: A 37-Year-Old American Man Living in Vietnam, with Fever and Bacteremia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PYOGENIC LIVER-ABSCESS C1 [Gharib, Soheyla D.] Harvard Univ Hlth Serv, Dept Med, Cambridge, MA 02138 USA. [Berger, David L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Choy, Garry] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Huck, Amelia E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gharib, Soheyla D.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Berger, David L.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Choy, Garry] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Huck, Amelia E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Gharib, SD (reprint author), Harvard Univ Hlth Serv, Dept Med, Cambridge, MA 02138 USA. NR 8 TC 2 Z9 2 U1 0 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 JUL 9 PY 2015 VL 373 IS 2 BP 174 EP 183 DI 10.1056/NEJMcpc1411439 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CM3QP UT WOS:000357598600012 PM 26154791 ER PT J AU Adragna, NC Ravilla, NB Lauf, PK Begum, G Khanna, AR Sun, D Kahle, KT AF Adragna, Norma C. Ravilla, Nagendra B. Lauf, Peter K. Begum, Gulnaz Khanna, Arjun R. Sun, Dandan Kahle, Kristopher T. TI Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE K-Cl cotransporters; KCC3; NKCC1; SPAK; cell volume homeostasis; regulatory volume decrease; cerebral edema; neurodegeneration ID SMOOTH-MUSCLE-CELLS; CATION-CHLORIDE COTRANSPORTERS; VASCULAR ENDOTHELIAL-CELLS; PROTEIN-KINASE-G; RED-BLOOD-CELLS; ION-TRANSPORT; N-ETHYLMALEIMIDE; KCL COTRANSPORT; DEPENDENT K; ERYTHROCYTES AB The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K+ and Cl- efflux via activation of K+ channels, volume-regulated anion channels (VRACs), and the K+-Cl- cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na+-K+-2Cl(-) cotransporter isoform 1 (NKCC1). This results in a rapid (<10 min) and significant (>90%) reduction in intracellular K+ content (K-i) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, K-i homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD. C1 [Adragna, Norma C.; Ravilla, Nagendra B.; Lauf, Peter K.] Wright State Univ, Boonshoft Sch Med, Dept Pharmacol & Toxicol, Dayton, OH 45435 USA. [Lauf, Peter K.] Wright State Univ, Boonshoft Sch Med, Dept Pathol, Dayton, OH 45435 USA. [Begum, Gulnaz; Sun, Dandan] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Khanna, Arjun R.; Kahle, Kristopher T.] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA. [Khanna, Arjun R.; Kahle, Kristopher T.] Harvard Univ, Harvard Med Sch, Boston, MA USA. [Sun, Dandan] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Kahle, Kristopher T.] Harvard Univ, Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. RP Adragna, NC (reprint author), Wright State Univ, Boonshoft Sch Med, Dept Pharmacol & Toxicol, Math & Microbiol 002D, Bldg 3640 Col Glenn Hwy, Dayton, OH 45435 USA. EM norma.adragna@wright.edu; kkahle@enders.tch.harvard.edu FU Pharmacology and Toxicology Master in Science Program; Wright State University Foundation; NIH [R01 NS38118, R01 NS075995]; Manton Center for Orphan Disease Research; Harvard-MIT Basic Neuroscience Grant FX We thank Kathy Leonard who trained NBR in the essentials of our long established ion flux techniques. We also thank David Clapham (Harvard) for his critical insights and comments on this manuscript. This work has been presented in part as abstracts and posters at the EB 2013 meeting in Boston, MA, and at the Lake Cumberland Biological Transport Conference in June 2013. This work has been supported, in part, by the Pharmacology and Toxicology Master in Science Program (NBR) and Wright State University Foundation; NIH R01 NS38118 and R01 NS075995 (DS); the Manton Center for Orphan Disease Research (KK), and a Harvard-MIT Basic Neuroscience Grant. NR 61 TC 5 Z9 5 U1 3 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUL 9 PY 2015 VL 9 AR 255 DI 10.3389/fncel.2015.00255 PG 13 WC Neurosciences SC Neurosciences & Neurology GA CM4SZ UT WOS:000357676300001 PM 26217182 ER PT J AU Stein, LD Knoppers, BM Campbell, P Getz, G Korbel, JO AF Stein, Lincoln D. Knoppers, Bartha M. Campbell, Peter Getz, Gad Korbel, Jan O. TI Create a cloud commons SO NATURE LA English DT Editorial Material C1 [Stein, Lincoln D.] Ontario Inst Canc Res, Informat & Biocomp, Toronto, ON, Canada. [Knoppers, Bartha M.] McGill Univ, Ctr Genom & Policy, Montreal, PQ, Canada. [Campbell, Peter] Wellcome Trust Sanger Inst, Canc Genom, Hinxton, Cambs, England. [Getz, Gad] Broad Inst MIT & Harvard, Canc Genome Computat Anal Grp, Cambridge, MA USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Bioinformat, Boston, MA USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Korbel, Jan O.] European Mol Biol Lab, Genome Biol, D-69012 Heidelberg, Germany. RP Stein, LD (reprint author), Ontario Inst Canc Res, Informat & Biocomp, Toronto, ON, Canada. EM lincoln.stein@gmail.com NR 6 TC 18 Z9 18 U1 1 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 JUL 9 PY 2015 VL 523 IS 7559 BP 149 EP 151 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM4ZO UT WOS:000357695900011 PM 26156357 ER PT J AU Joung, JK AF Joung, J. Keith TI Standards needed for gene-editing errors SO NATURE LA English DT Letter C1 Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Joung, JK (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM jjoung@partners.org NR 1 TC 4 Z9 4 U1 0 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 JUL 9 PY 2015 VL 523 IS 7559 BP 158 EP 158 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM4ZO UT WOS:000357695900015 PM 26156364 ER PT J AU Gagliani, N Vesely, MCA Iseppon, A Brockmann, L Xu, H Palm, NW de Zoete, MR Licona-Limon, P Paiva, RS Ching, T Weaver, C Zi, XY Pan, XH Fan, R Garmire, LX Cotton, MJ Drier, Y Bernstein, B Geginat, J Stockinger, B Esplugues, E Huber, S Flavell, RA AF Gagliani, Nicola Vesely, Maria Carolina Amezcua Iseppon, Andrea Brockmann, Leonie Xu, Hao Palm, Noah W. de Zoete, Marcel R. Licona-Limon, Paula Paiva, Ricardo S. Ching, Travers Weaver, Casey Zi, Xiaoyuan Pan, Xinghua Fan, Rong Garmire, Lana X. Cotton, Matthew J. Drier, Yotam Bernstein, Bradley Geginat, Jens Stockinger, Brigitta Esplugues, Enric Huber, Samuel Flavell, Richard A. TI TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation SO NATURE LA English DT Article ID PATHOGENIC T(H)17 CELLS; TGF-BETA; DIFFERENTIATION; INTERLEUKIN-10; RESPONSES; FOXP3(+); RECEPTOR; EXPRESSION; INTESTINE; ABSENCE AB Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The TH17 lineage of T helper (TH) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A)(1) and plasticity (they can start expressing cytokines typical of other lineages)(1,2) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion TH17 cells ex vivo during immune responses. Thus, it is unknown whether TH17 cell plasticity merely reflects change in expression of a few cytokines, or if TH17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation(3,4). Furthermore, although TH17 cell instability/plasticity has been associated with pathogenicity(1,2,5), it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic TH17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track TH17 cells during immune responses to show that CD4(+) T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of TH17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre-and post-conversion TH17 cells also revealed a role for canonical TGF-beta signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, TH17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that TH17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases. C1 [Gagliani, Nicola; Vesely, Maria Carolina Amezcua; Iseppon, Andrea; Xu, Hao; Palm, Noah W.; de Zoete, Marcel R.; Licona-Limon, Paula; Paiva, Ricardo S.; Flavell, Richard A.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Brockmann, Leonie; Huber, Samuel] Univ Klinikum Hamburg Eppendorf, Med Klin & Poliklin, D-20246 Hamburg, Germany. [de Zoete, Marcel R.; Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA. [Ching, Travers; Garmire, Lana X.] Univ Hawaii, Ctr Canc, Manoa, HI 96813 USA. [Weaver, Casey] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Zi, Xiaoyuan; Fan, Rong] Yale Univ, Dept Biomed Engn, New Haven, CT 06520 USA. [Pan, Xinghua] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Cotton, Matthew J.; Drier, Yotam; Bernstein, Bradley] Howard Hughes Med Inst, Boston, MA 02114 USA. [Cotton, Matthew J.; Drier, Yotam; Bernstein, Bradley] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cotton, Matthew J.; Drier, Yotam; Bernstein, Bradley] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Geginat, Jens] Ist Nazl Genet Mol Romeo & Enrica Invernizzi, I-20122 Milan, Italy. [Stockinger, Brigitta] MRCNat Inst Med Res, Div Mol Immunol, London NW7 1AA, England. [Esplugues, Enric] Icahn Sch Med Mt Sinai, Mt Sinai Sch Med, Immunol Inst, New York, NY 10029 USA. RP Flavell, RA (reprint author), Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA. EM s.huber@uke.de; richard.flavell@yale.edu RI Drier, Yotam/K-5208-2012; OI Drier, Yotam/0000-0003-1725-2995; Esplugues, Enric/0000-0002-8130-0413 FU NIH/BD2K [K01ES025434]; NIH/NIGMS [P20 COBRE GM103457]; DFG [EXC 257 NeuroCure, SFB633, HU1714/3]; Crohn's & Colitis Foundation of America [311143]; Dr. Keith Landesman Memorial Fellowship of the Cancer Research Institute; Ernst Jung-Stiftung Hamburg; Howard Hughes Medical Institute; Cariplo foundation [2013-0937]; AbbVie-Yale Collaboration; Francis Crick Institute FX The authors would like to thank C. Lieber, P. Musco, E. Hughes-Picard and J. Alderman for expert administrative assistance. J. Stein, L. Evangelisti and C. Hughes for generating the IL-17A IRES-eGFP-CRE-ERT2 constructs, embryonic stem cells and chimaeric mice, respectively. We thank E. Baiocchi for remote key support. LXG is supported by grants K01ES025434 from NIH/BD2K and P20 COBRE GM103457 from NIH/NIGMS. E. E. was supported by the DFG (EXC 257 NeuroCure and SFB633) and by the Crohn's & Colitis Foundation of America (#311143). N.G. is supported by the Dr. Keith Landesman Memorial Fellowship of the Cancer Research Institute. S.H. is supported by the DFG (HU1714/3) and by Ernst Jung-Stiftung Hamburg and has an endowed Hofschneider-Professorship from the Stiftung Experimentelle Biomedizin. This work was supported, by the Howard Hughes Medical Institute, by Cariplo foundation (2013-0937 to J.G. and R.A.F.), by the AbbVie-Yale Collaboration (R.A.F.) and by the Francis Crick Institute (B.S.). NR 38 TC 94 Z9 98 U1 8 U2 47 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 JUL 9 PY 2015 VL 523 IS 7559 BP 221 EP U225 DI 10.1038/nature14452 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM4ZO UT WOS:000357695900037 PM 25924064 ER PT J AU Weisbart, RH Chan, G Jordaan, G Noble, PW Liu, YF Glazer, PM Nishimura, RN Hansen, JE AF Weisbart, Richard H. Chan, Grace Jordaan, Gwen Noble, Philip W. Liu, Yanfeng Glazer, Peter M. Nishimura, Robert N. Hansen, James E. TI DNA-dependent targeting of cell nuclei by a lupus autoantibody SO SCIENTIFIC REPORTS LA English DT Article AB A nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has been found to inhibit DNA repair and selectively kill certain cancer cells that are highly vulnerable to DNA damage. In addition, a 3E10 single chain variable fragment (scFv) has been developed for use as a delivery vehicle to carry therapeutic cargo proteins into cell nuclei. A greater understanding of the mechanism by which 3E10 penetrates cell nuclei is needed to help determine the scope of its potential therapeutic applications. Here we show that the presence of extracellular DNA significantly enhances the nuclear uptake of 3E10 scFv. In addition, we find that 3E10 scFv preferentially localizes into tumor cell nuclei in vivo, likely due to increased DNA in the local environment released from ischemic and necrotic regions of tumor. These data provide insight into the mechanism of nuclear penetration by 3E10 and demonstrate the potential for use of 3E10 in therapeutic approaches to diseases ranging from malignancy to ischemic conditions such as stroke. C1 [Weisbart, Richard H.; Chan, Grace; Jordaan, Gwen; Nishimura, Robert N.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Res, Sepulveda, CA 91343 USA. [Noble, Philip W.; Liu, Yanfeng; Glazer, Peter M.; Hansen, James E.] Yale Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Glazer, Peter M.] Yale Sch Med, Dept Genet, New Haven, CT 06520 USA. [Glazer, Peter M.; Hansen, James E.] Yale Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. [Nishimura, Robert N.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. RP Weisbart, RH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Res, Sepulveda, CA 91343 USA. EM rweisbar@ucla.edu; james.e.hansen@yale.edu FU Veterans Affairs Merit Review Grant; Yale Center for Clinical Investigation CTSA Scholar Award; National Center for Advancing Translational Science (NCATS) of the National Institutes of Health (NIH) [UL1 TR000142]; NIH roadmap for Medical Research FX Veterans Affairs Merit Review Grant (RHW). Yale Center for Clinical Investigation CTSA Scholar Award (JEH). This publication was made possible by CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. NR 13 TC 4 Z9 4 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 JUL 9 PY 2015 VL 5 AR 12022 DI 10.1038/srep12022 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V46JC UT WOS:000209879500001 PM 26156563 ER PT J AU Xi, M Fung, SJ Yamuy, J Chase, MH AF Xi, M. Fung, S. J. Yamuy, J. Chase, M. H. TI INTERACTIONS BETWEEN HYPOCRETINERGIC AND GABAERGIC SYSTEMS IN THE CONTROL OF ACTIVITY OF NEURONS IN THE CAT PONTINE RETICULAR FORMATION SO NEUROSCIENCE LA English DT Article DE REM sleep; orexin; inhibition; electrical stimulation; intracellular recording ID EYE-MOVEMENT SLEEP; INDUCED MOTOR INHIBITION; LUMBAR MOTONEURONS; REM-SLEEP; POSTSYNAPTIC POTENTIALS; MASSETER MOTONEURONS; CENTRAL NUCLEUS; GABA(A) RECEPTORS; OREXIN RECEPTORS; FEEDING-BEHAVIOR AB Anatomical studies have demonstrated that hypocretinergic and GABAergic neurons innervate cells in the nucleus pontis oralis (NPO), a nucleus responsible for the generation of active (rapid eye movement (REM)) sleep (AS) and wakefulness (W). Behavioral and electrophysiological studies have shown that hypocretinergic and GABAergic processes in the NPO are involved in the generation of AS as well as W. An increase in hypocretin in the NPO is associated with both AS and W, whereas GABA levels in the NPO are elevated during W. We therefore examined the manner in which GABA modulates NPO neuronal responses to hypocretin. We hypothesized that interactions between the hypocretinergic and GABAergic systems in the NPO play an important role in determining the occurrence of AS or W. To determine the veracity of this hypothesis, we examined the effects of the juxtacellular application of hypocretin-1 and GABA on the activity of NPO neurons, which were recorded intracellularly, in chloralose-anesthetized cats. The juxtacellular application of hypocretin-1 significantly increased the mean amplitude of spontaneous EPSPs and the frequency of discharge of NPO neurons; in contrast, the juxtacellular microinjection of GABA produced the opposite effects, i.e., there was a significant reduction in the mean amplitude of spontaneous EPSPs and a decrease in the discharge of these cells. When hypocretin-1 and GABA were applied simultaneously, the inhibitory effect of GABA on the activity of NPO neurons was reduced or completely blocked. In addition, hypocretin-1 also blocked GABAergic inhibition of EPSPs evoked by stimulation of the laterodorsal tegmental nucleus. These data indicate that hypocretin and GABA function within the context of a neuronal gate that controls the activity of AS-on neurons. Therefore, we suggest that the occurrence of either AS or W depends upon interactions between hypocretinergic and GABAergic processes as well as inputs from other sites that project to AS-on neurons in the NPO. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Xi, M.; Fung, S. J.; Chase, M. H.] Websci Int, Los Angeles, CA 90024 USA. [Xi, M.; Fung, S. J.; Yamuy, J.; Chase, M. H.] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Yamuy, J.; Chase, M. H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. RP Xi, M (reprint author), Websci Int, 1251 Westwood Blvd, Los Angeles, CA 90024 USA. EM mxi@websciences.org FU U.S. Public Health Service [MH 43362] FX This work was supported by the following grant from the U.S. Public Health Service: MH 43362. We thank Mr. Oscar Ramos, Mr. Trent Wenzel, Ms. Ricki-Leigh Malaguti and Ms. Emi Koda for their excellent technical assistance. NR 75 TC 1 Z9 1 U1 0 U2 7 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 JUL 9 PY 2015 VL 298 BP 190 EP 199 DI 10.1016/j.neuroscience.2015.04.022 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CI5GT UT WOS:000354783300018 PM 25892701 ER PT J AU Evans, TM Jaramillo, CA Sataranatarajan, K Watts, L Sabia, M Qi, W Van Remmen, H AF Evans, T. M. Jaramillo, C. A. Sataranatarajan, K. Watts, L. Sabia, M. Qi, W. Van Remmen, H. TI THE EFFECT OF MILD TRAUMATIC BRAIN INJURY ON PERIPHERAL NERVOUS SYSTEM PATHOLOGY IN WILD-TYPE MICE AND THE G93A MUTANT MOUSE MODEL OF MOTOR NEURON DISEASE SO NEUROSCIENCE LA English DT Article DE TBI; amyotrophic lateral sclerosis; mouse model; oxidative stress; spinal cord ID AMYOTROPHIC-LATERAL-SCLEROSIS; SPINAL-CORD-INJURY; OXIDATIVE STRESS; SKELETAL-MUSCLE; HEAD-INJURY; ANTIOXIDANT THERAPIES; SUPEROXIDE-DISMUTASE; LIPID-PEROXIDATION; TRANSGENIC MODEL; HIGH-SCHOOL AB Traumatic brain injury (TBI) is associated with a risk of neurodegenerative disease. Some suggest a link between TBI and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). To investigate the potential mechanisms linking TBI to MND, we measured motor function and neuropathology following mild-TBI in wild-type and a transgenic model of ALS, G93A mutant mice. Mild-TBI did not alter the lifespan of G93A mice or age of onset; however, rotarod performance was impaired in G93A verses wild-type mice. Grip strength was reduced only in G93A mice after mild-TBI. Increased electromyography (EMG) abnormalities and markers of denervation (AchR, Runx1) indicate that mild-TBI may result in peripheral effects that are exaggerated in G93A mice. Markers of inflammation (cell edema, astrogliosis and microgliosis) were detected at 24 and 72 h in the brain and spinal cord in wild-type and G93A mice. Levels of F2-isoprostanes, a marker of oxidative stress, were increased in the spinal cord 24 h post mild-TBI in wild-type mice but were not affected by TBI in G93A mice. In summary, our data demonstrate that mild-TBI induces inflammation and oxidative stress and negatively impacts muscle denervation and motor performance, suggesting mild-TBI can potentiate motor neuron pathology and influence the development of MND in mice. Published by Elsevier Ltd. on behalf of IBRO. C1 [Evans, T. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Watts, L.; Van Remmen, H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Watts, L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Watts, L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Res, Imaging Inst, San Antonio, TX 78229 USA. [Jaramillo, C. A.] Polytrauma Rehabil Ctr, San Antonio, TX USA. [Jaramillo, C. A.; Sabia, M.; Qi, W.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Jaramillo, C. A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Rehabil Med, San Antonio, TX 78229 USA. [Sataranatarajan, K.; Van Remmen, H.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Sataranatarajan, K.; Van Remmen, H.] Oklahoma City VA Med Ctr, Oklahoma City, OK USA. RP Van Remmen, H (reprint author), Oklahoma Med Res Fdn, Free Rad Biol & Aging Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM EvansTM@uthscsa.edu; jaramilloc3@uthscsa.edu; Kavithalakshmi-Sataranatarajan@omrf.org; wattsl@uthscsa.edu; sabia@uthscsa.edu; Qi@uthscsa.edu; holly-vanremmen@omrf.org FU independent National Research Service Award, National Institute for Neurological Diseases and Stroke [1F31NS080508-01]; Hartford Foundation/American Federation for Aging Research Scholars in Geriatric Medicine Program; VA Merit Review grant FX This research was funded in part by an independent National Research Service Award, National Institute for Neurological Diseases and Stroke (1F31NS080508-01; Evans TM) and the Hartford Foundation/American Federation for Aging Research Scholars in Geriatric Medicine Program (Jaramillo CA) and a VA Merit Review grant to Dr. Van Remmen. We also acknowledge the assistance of Vivian Diaz and the Nathan Shock Center in animal care and maintenance and collection of body weight and body composition data. We would also like to acknowledge the help and guidance of Shane Sprague and the Neurosurgery Department Brain Injury Core for their support in establishing our TBI procedures. NR 54 TC 2 Z9 2 U1 1 U2 2 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 JUL 9 PY 2015 VL 298 BP 410 EP 423 DI 10.1016/j.neuroscience.2015.04.041 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CI5GT UT WOS:000354783300032 PM 25921732 ER PT J AU Muehlenkamp, JJ Hilt, LM Ehlinger, PP McMillan, T AF Muehlenkamp, Jennifer J. Hilt, Lori M. Ehlinger, Peter P. McMillan, Taylor TI Nonsuicidal self-injury in sexual minority college students: a test of theoretical integration SO CHILD AND ADOLESCENT PSYCHIATRY AND MENTAL HEALTH LA English DT Article DE Sexual minority; Youth; NSSI; Suicide; Self-injury; Self-harm; College; Minority stress; Burdensomeness ID PSYCHOMETRIC PROPERTIES; BISEXUAL POPULATIONS; YOUNG-ADULTS; PERCEIVED BURDENSOMENESS; THWARTED BELONGINGNESS; INTERPERSONAL THEORY; CONSTRUCT-VALIDITY; SUICIDAL BEHAVIORS; MENTAL-HEALTH; UNITED-STATES AB Background: Individuals identifying as a sexual minority report engaging in nonsuicidal self-injury (NSSI) at substantially higher rates compared to their heterosexual peers. Given that NSSI is a known risk factor for suicide, it is important to understand the processes unique to being a sexual minority that increases risk for NSSI so that adequate prevention efforts can be established. The current study integrated Minority Stress Theory and the Interpersonal Theory of Suicide to test a model of NSSI and suicide risk. Methods: A total of 137 college students who identified as a sexual minority completed an anonymous on-line study assessing NSSI, suicidal thoughts/behaviors, and constructs of the minority stress and interpersonal theories. Two linear regressions using bootstrapping analyses were conducted to test our hypotheses. Results: Minority stress was directly associated with NSSI and via perceived burdensomeness, explaining 27 % of the variance. NSSI was associated with increased risk for suicide thoughts/behaviors directly, and through acquired capability, explaining 45 % of the variance. Conclusions: These findings provide evidence that unique stressors individuals face as a result of their sexual minority status increases risk for self-harm by influencing cognitive and emotional processes such as burdensomeness and acquired capability. Implications for prevention, intervention, and future research are briefly discussed. C1 [Muehlenkamp, Jennifer J.] Univ Wisconsin, Dept Psychol, 105 Garfield Ave, Eau Claire, WI 54702 USA. [Hilt, Lori M.] Lawrence Univ, Dept Psychol, Appleton, WI 54911 USA. [Ehlinger, Peter P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [McMillan, Taylor] Eastern Illinois Univ, Charleston, IL 61920 USA. RP Muehlenkamp, JJ (reprint author), Univ Wisconsin, Dept Psychol, 105 Garfield Ave, Eau Claire, WI 54702 USA. EM muehlejj@uwec.edu NR 56 TC 0 Z9 0 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 1753-2000 J9 CHILD ADOL PSYCH MEN JI Child Adolesc. Psychiatry Ment. Health PD JUL 8 PY 2015 VL 9 AR 16 DI 10.1186/s13034-015-0050-y PG 8 WC Pediatrics; Psychiatry SC Pediatrics; Psychiatry GA DE9EL UT WOS:000370938600001 PM 26157477 ER PT J AU Jodar, M Sendler, E Moskovtsev, SI Librach, CL Goodrich, R Swanson, S Hauser, R Diamond, MP Krawetz, SA AF Jodar, Meritxell Sendler, Edward Moskovtsev, Sergey I. Librach, Clifford L. Goodrich, Robert Swanson, Sonja Hauser, Russ Diamond, Michael P. Krawetz, Stephen A. TI Absence of sperm RNA elements correlates with idiopathic male infertility SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ASSISTED REPRODUCTION; SEMEN QUALITY; CLINICAL-USE; GENOME-WIDE; SPERMATOZOA; CHROMATIN; SEQ; IDENTIFICATION; MORPHOLOGY; FERTILITY AB Semen parameters are typically used to diagnose male infertility and specify clinical interventions. In idiopathic infertile couples, an unknown male factor could be the cause of infertility even when the semen parameters are normal. Next-generation sequencing of spermatozoal RNAs can provide an objective measure of the paternal contribution and may help guide the care of these couples. We assessed spermatozoal RNAs from 96 couples presenting with idiopathic infertility and identified the final reproductive outcome and sperm RNA elements (SREs) reflective of fecundity status. The absence of required SREs reduced the probability of achieving live birth by timed intercourse or intrauterine insemination from 73 to 27%. However, the absence of these same SREs does not appear to be critical when using assisted reproductive technologies such as in vitro fertilization with or without intracytoplasmic sperm injection. About 30% of the idiopathic infertile couples presented an incomplete set of required SREs, suggesting a male component as the cause of their infertility. Conversely, analysis of couples that failed to achieve a live birth despite presenting with a complete set of SREs suggested that a female factor may have been involved, and this was confirmed by their diagnosis. The data in this study suggest that SRE analysis has the potential to predict the individual success rate of different fertility treatments and reduce the time to achieve live birth. C1 [Jodar, Meritxell; Sendler, Edward; Goodrich, Robert; Krawetz, Stephen A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Jodar, Meritxell; Sendler, Edward; Goodrich, Robert; Krawetz, Stephen A.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Moskovtsev, Sergey I.; Librach, Clifford L.; Swanson, Sonja] CReATe Fertil Ctr, Toronto, ON M5G 1N8, Canada. [Moskovtsev, Sergey I.; Librach, Clifford L.] Univ Toronto, Dept Obstet & Gynaecol, Ottawa, ON M5G 1E2, Canada. [Librach, Clifford L.] Womens Coll Hosp, Dept Obstet & Gynecol, Toronto, ON M5G 1B1, Canada. [Hauser, Russ] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Mem Obstet & Gynecol Serv, Boston, MA 02114 USA. [Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA 30912 USA. RP Krawetz, SA (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. EM steve@compbio.med.wayne.edu OI Diamond, Michael/0000-0001-6353-4489 FU Collaborative Translational Research Project grant from EMD Serono; funds to S.A.K. through Charlotte B. Failing Professorship; NIH [ES017285, ES009718] FX The work was supported by a Collaborative Translational Research Project grant from EMD Serono to S.A.K. and M.P.D., funds to S.A.K. through Charlotte B. Failing Professorship, and NIH grants ES017285 and ES009718 to R.H. NR 43 TC 9 Z9 9 U1 3 U2 16 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 JUL 8 PY 2015 VL 7 IS 295 DI 10.1126/scitranslmed.aab1287 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CN8ZY UT WOS:000358736400006 ER PT J AU Taubert, J Van Belle, G Vanduffel, W Rossion, B Vogels, R AF Taubert, Jessica Van Belle, Goedele Vanduffel, Wim Rossion, Bruno Vogels, Rufin TI Neural Correlate of the Thatcher Face Illusion in a Monkey Face-Selective Patch SO JOURNAL OF NEUROSCIENCE LA English DT Article DE electrophysiology; face perception; fMRI; visual illusion ID MACAQUE TEMPORAL-LOBE; INVERTED FACES; REGIONS; FMRI; ERP; INVERSION; CONTRAST; NEURONS; SYSTEM; CELL AB Compelling evidence that our sensitivity to facial structure is conserved across the primate order comes from studies of the "Thatcher face illusion": humans and monkeys notice changes in the orientation of facial features (e.g., the eyes) only when faces are upright, not when faces are upside down. Although it is presumed that face perception in primates depends on face-selective neurons in the inferior temporal (IT) cortex, it is not known whether these neurons respond differentially to upright faces with inverted features. Using micro-electrodes guided by functional MRI mapping, we recorded cell responses in three regions of monkey IT cortex. We report an interaction in the middle lateral face patch (ML) between the global orientation of a face and the local orientation of its eyes, a response profile consistent with the perception of the Thatcher illusion. This increased sensitivity to eye orientation in upright faces resisted changes in screen location and was not found among face-selective neurons in other areas of IT cortex, including neurons in another face-selective region, the anterior lateral face patch. We conclude that the Thatcher face illusion is correlated with a pattern of activity in the ML that encodes faces according to a flexible holistic template. C1 [Taubert, Jessica; Van Belle, Goedele; Rossion, Bruno] Univ Louvain, Face Categorizat Lab, B-1348 Louvain La Neuve, Belgium. [Taubert, Jessica; Vanduffel, Wim; Vogels, Rufin] Katholieke Univ Leuven, Lab Neuro & Psychophysiol, B-3000 Leuven, Belgium. [Vanduffel, Wim] Massachusetts Gen Hosp, Martinos Ctr, Charlestown, MA 02129 USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Taubert, J (reprint author), Lab Neuro & Psychofysiol, Campus Gasthuisberg,Herestr 49 Bus 1021, BE-3000 Leuven, Belgium. EM jessica.taubert@kuleuven.be FU Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Geconcerteerde Onderzoeksactie [GOA/10/019]; Interuniversitaire Attractiepool and Programma Financiering [PF 10/008]; Fonds de la Recherche Scientifique [FRSM 3.4601.12] FX This study was supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Geconcerteerde Onderzoeksactie (GOA/10/019), Interuniversitaire Attractiepool and Programma Financiering (PF 10/008), and Fonds de la Recherche Scientifique (FRSM 3.4601.12). We extend our gratitude to M. Docx, I. Puttemans, C. Ulens, P. Kayenbergh, G. Meulemans, W. Depuydt, S. Verstraeten, and M. De Paep for technical support. NR 23 TC 4 Z9 4 U1 17 U2 62 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 8 PY 2015 VL 35 IS 27 BP 9872 EP 9878 DI 10.1523/JNEUROSCI.0446-15.2015 PG 7 WC Neurosciences SC Neurosciences & Neurology GA CN2LT UT WOS:000358253400008 PM 26156988 ER PT J AU Lillis, KP Wang, ZM Mail, M Zhao, GQ Berdichevsky, Y Bacskai, B Staley, KJ AF Lillis, Kyle P. Wang, Zemin Mail, Michelle Zhao, Grace Q. Berdichevsky, Yevgeny Bacskai, Brian Staley, Kevin J. TI Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium imaging; homeostasis; network; two-photon ID TEMPORAL-LOBE EPILEPSY; HIPPOCAMPAL SLICE CULTURES; INDUCED STATUS EPILEPTICUS; TRAUMATIC BRAIN-INJURY; SMALL-WORLD NETWORKS; FUNCTIONAL CONNECTIVITY; POSTTRAUMATIC EPILEPSY; PYRAMIDAL CELLS; OPTICAL ELECTROPHYSIOLOGY; ORGANOTYPIC CULTURE AB In secondary epilepsy, a seizure-prone neural network evolves during the latent period between brain injury and the onset of spontaneous seizures. The nature of the evolution is largely unknown, and even its completeness at the onset of seizures has recently been challenged by measures of gradually decreasing intervals between subsequent seizures. Sequential calcium imaging of neuronal activity, in the pyramidal cell layer of mouse hippocampal in vitro preparations, during early post-traumatic epileptogenesis demonstrated rapid increases in the fraction of neurons that participate in interictal activity. This was followed by more gradual increases in the rate at which individual neurons join each developing seizure, the pairwise correlation of neuronal activities as a function of the distance separating the pair, and network-wide measures of functional connectivity. These data support the continued evolution of synaptic connectivity in epileptic networks beyond the latent period: early seizures occur when recurrent excitatory pathways are largely polysynaptic, while ongoing synaptic remodeling after the onset of epilepsy enhances intranetwork connectivity as well as the onset and spread of seizure activity. C1 [Lillis, Kyle P.; Wang, Zemin; Mail, Michelle; Bacskai, Brian; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lillis, Kyle P.; Wang, Zemin; Mail, Michelle; Bacskai, Brian; Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhao, Grace Q.] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA. [Berdichevsky, Yevgeny] Lehigh Univ, Dept Elect & Comp Engn, Bethlehem, PA 18015 USA. RP Staley, KJ (reprint author), 114 16th St,2600, Charlestown, MA 02129 USA. EM staley.kevin@mgh.harvard.edu FU National Institutes of Health [NS034700, NS074772, NS077908, EB000768] FX This work was supported by the National Institutes of Health grants NS034700, NS074772, and NS077908 (to K.S.), and EB000768 (to B.B.). NR 95 TC 7 Z9 7 U1 3 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 8 PY 2015 VL 35 IS 27 BP 9920 EP 9934 DI 10.1523/JNEUROSCI.4007-14.2015 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CN2LT UT WOS:000358253400013 PM 26156993 ER PT J AU Lynn, SK Wormwood, JB Barrett, LF Quigley, KS AF Lynn, Spencer K. Wormwood, Jolie B. Barrett, Lisa F. Quigley, Karen S. TI Decision making from economic and signal detection perspectives: development of an integrated framework SO FRONTIERS IN PSYCHOLOGY LA English DT Article ID SUSTAINED INATTENTIONAL BLINDNESS; ORBITOFRONTAL CORTEX; PARIETAL CORTEX; CAUDATE-NUCLEUS; RESPONSE BIAS; VISUAL-DISCRIMINATION; NEURAL REPRESENTATION; PROSPECT-THEORY; HUMAN BRAIN; REWARD AB Behavior is comprised of decisions made from moment to moment (i.e., to respond one way or another). Often, the decision maker cannot be certain of the value to be accrued from the decision (i.e., the outcome value). Decisions made under outcome value uncertainty form the basis of the economic framework of decision making. Behavior is also based on perception perception of the external physical world and of the internal bodily milieu, which both provide cues that guide decision making. These perceptual signals are also often uncertain: another person's scowling facial expression may indicate threat or intense concentration, alternatives that require different responses from the perceiver. Decisions made under perceptual uncertainty form the basis of the signals framework of decision making. Traditional behavioral economic approaches to decision making focus on the uncertainty that comes from variability in possible outcome values, and typically ignore the influence of perceptual uncertainty. Conversely, traditional signal detection approaches to decision making focus on the uncertainty that arises from variability in perceptual signals and typically ignore the influence of outcome value uncertainty. Here, we compare and contrast the economic and signals frameworks that guide research in decision making, with the aim of promoting their integration. We show that an integrated framework can expand our ability to understand a wider variety of decision-making behaviors, in particular the complexly determined real-world decisions we all make every day. C1 [Lynn, Spencer K.; Wormwood, Jolie B.; Barrett, Lisa F.; Quigley, Karen S.] Northeastern Univ, Dept Psychol, Interdisciplinary Affect Sci Lab, Boston, MA 02115 USA. [Barrett, Lisa F.] Massachusetts Gen Hosp, Dept Psychiat, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Quigley, Karen S.] Edith Nourse Rogers Mem Vet Adm Hosp, Bedford, MA 01730 USA. RP Lynn, SK (reprint author), Northeastern Univ, Psychol NI 125, 360 Huntington Ave, Boston, MA 02115 USA. EM s.lynn@neu.edu FU U.S. Army Research Institute for the Behavioral and Social Sciences [W5J9CQ-12-C-0028, W5J9CQ-12-C-0049]; National Institutes of Health [R01MH093394, DP1OD003312] FX We thank Elizabeth Clark-Polner and Anna Neumann for helpful discussion and reviews. Preparation of this article was supported by the U.S. Army Research Institute for the Behavioral and Social Sciences (Contract W5J9CQ-12-C-0028 to SL; Contract W5J9CQ-12-C-0049 to LB) and the National Institutes of Health (Grant R01MH093394 to SL, Grant DP1OD003312 to LB). The views, opinions, and findings contained in this article are those of the authors and should not be construed as an official Department of the Army or National Institutes of Health position, policy, or decision, unless so designated by other documents. NR 80 TC 0 Z9 0 U1 2 U2 13 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 8 PY 2015 VL 6 AR 962 DI 10.3389/fpsyg.2015.00952 PG 14 WC Psychology, Multidisciplinary SC Psychology GA CM4BU UT WOS:000357630000001 ER PT J AU Xu, X Choi, SH Hu, TC Tiyanont, K Habets, R Groot, AJ Vooijs, M Aster, JC Chopra, R Fryer, C Blacklow, SC AF Xu, Xiang Choi, Sung Hee Hu, Tiancen Tiyanont, Kittichoat Habets, Roger Groot, Arjan J. Vooijs, Marc Aster, Jon C. Chopra, Rajiv Fryer, Christy Blacklow, Stephen C. TI Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region SO STRUCTURE LA English DT Article ID PROTEOLYTIC ACTIVATION; MUTATIONS; LIGAND; RECEPTORS; HETERODIMERIZATION; TRANSCRIPTION; COMPLEXES; LEUKEMIA; REPEATS; DISEASE AB Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors. C1 [Xu, Xiang; Choi, Sung Hee; Tiyanont, Kittichoat; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Xu, Xiang; Choi, Sung Hee; Tiyanont, Kittichoat; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Hu, Tiancen; Chopra, Rajiv; Fryer, Christy] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Habets, Roger; Groot, Arjan J.; Vooijs, Marc] Maastricht Univ, Dept Radiotherapy MAASTRO, GROW Sch Dev Biol & Oncol, NL-6229 Maastricht, Netherlands. [Aster, Jon C.; Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Aster, Jon C.; Blacklow, Stephen C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Blacklow, SC (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM stephen_blacklow@hms.harvard.edu FU NIH [R01 CA092433, P01 CA119070]; European Research Council ERC grants [208259, 334987]; Dana Farber - Novartis Drug Discovery Program FX This work was supported by NIH grant R01 CA092433 (to S.C.B.), and P01 CA119070 (to J.C.A. and S.C.B.). M.V., A.J., and R.H. are supported by European Research Council ERC grants 208259 and 334987. T.H., R.C., and C.F. are employees of Novartis, and this work was supported in part by the Dana Farber - Novartis Drug Discovery Program. NR 33 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 7 PY 2015 VL 23 IS 7 BP 1227 EP 1235 DI 10.1016/j.str.2015.05.001 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CQ0UG UT WOS:000360312200010 PM 26051713 ER PT J AU Nakamura, K Bechis, MZ Yee, AJ Dudzinski, DM AF Nakamura, Kenta Bechis, Mary Z. Yee, Andrew J. Dudzinski, David M. TI Progressive Onset of Extracardiac and Myocardial Symptoms Right Heart Failure and Cor Pulmonale in a Young Man With Debilitating Polyneuropathy and Monoclonal Gammopathy SO CIRCULATION LA English DT Article DE heart failure; hypertension; pulmonary; paraneoplastic syndromes; pericardial effusion; polyneuropathies; pulmonary heart disease ID ENDOTHELIAL GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; POEMS-SYNDROME; UNDETERMINED SIGNIFICANCE; BEVACIZUMAB THERAPY; HYPERTENSION; VEGF; LENALIDOMIDE; AMYLOIDOSIS; PATIENT C1 [Nakamura, Kenta; Bechis, Mary Z.; Dudzinski, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Yee, Andrew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Oncol,Dept Med, Boston, MA USA. RP Nakamura, K (reprint author), Massachusetts Gen Hosp, Corrigan Minehan Heart Ctr, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM nakamura@mgh.harvard.edu NR 37 TC 2 Z9 2 U1 0 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 JUL 7 PY 2015 VL 132 IS 1 BP 59 EP 67 DI 10.1161/CIRCULATIONAHA.115.016524 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CM2GO UT WOS:000357498100008 PM 26149427 ER PT J AU Neufer, PD Bamman, MM Muoio, DM Bouchard, C Cooper, DM Goodpaster, BH Booth, FW Kohrt, WM Gerszten, RE Mattson, MP Hepple, RT Kraus, WE Reid, MB Bodine, SC Jakicic, JM Fleg, JL Williams, JP Joseph, L Evans, M Maruvada, P Rodgers, M Roary, M Boyce, AT Drugan, JK Koenig, JI Ingraham, RH Krotoski, D Garcia-Cazarin, M McGowan, JA Laughlin, MR AF Neufer, P. Darrell Bamman, Marcas M. Muoio, Deborah M. Bouchard, Claude Cooper, Dan M. Goodpaster, Bret H. Booth, Frank W. Kohrt, Wendy M. Gerszten, Robert E. Mattson, Mark P. Hepple, Russell T. Kraus, William E. Reid, Michael B. Bodine, Sue C. Jakicic, John M. Fleg, Jerome L. Williams, John P. Joseph, Lyndon Evans, Mary Maruvada, Padma Rodgers, Mary Roary, Mary Boyce, Amanda T. Drugan, Jonelle K. Koenig, James I. Ingraham, Richard H. Krotoski, Danuta Garcia-Cazarin, Mary McGowan, Joan A. Laughlin, Maren R. TI Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits SO CELL METABOLISM LA English DT Review ID HUMAN SKELETAL-MUSCLE; MESSENGER-RNA EXPRESSION; MITOCHONDRIAL BIOGENESIS; CARDIOVASCULAR-DISEASE; RESISTANCE EXERCISE; METABOLIC SYNDROME; MODERATE EXERCISE; GENE-EXPRESSION; ADIPOSE-TISSUE; CLINICAL-TRIAL AB The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.'' Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying "-omics'' technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine. C1 [Neufer, P. Darrell] E Carolina Univ, Brody Sch Med, Dept Physiol, East Carolina Diabet & Obes Inst, Greenville, NC 27834 USA. [Neufer, P. Darrell] E Carolina Univ, Brody Sch Med, Dept Kinesiol, East Carolina Diabet & Obes Inst, Greenville, NC 27834 USA. [Bamman, Marcas M.] Univ Alabama Birmingham, UAB Ctr Exercise Med, Birmingham, AL 35294 USA. [Bamman, Marcas M.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Muoio, Deborah M.; Kraus, William E.] Duke Univ, Sch Med, Duke Mol Physiol, Durham, NC 27701 USA. [Bouchard, Claude] Louisiana State Univ, Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Cooper, Dan M.] Univ Calif Irvine, UC Irvine Inst Clin & Translat Sci, Irvine, CA 92697 USA. [Cooper, Dan M.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92697 USA. [Goodpaster, Bret H.] Florida Hosp, Sanford Burnham Med Res Inst, Translat Res Inst Metab & Diabet, Orlando, FL 32804 USA. [Booth, Frank W.] Univ Missouri, Dept Biomed Sci, Columbia, MO 65211 USA. [Booth, Frank W.] Univ Missouri, Dept Med Pharmacol & Physiol, Columbia, MO 65211 USA. [Booth, Frank W.] Univ Missouri, Dept Nutr & Exercise Physiol, Columbia, MO 65211 USA. [Kohrt, Wendy M.] Univ Colorado, Sch Med, Div Geriatr Med, Aurora, CO 80045 USA. [Gerszten, Robert E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Hepple, Russell T.] McGill Univ, Ctr Hlth, Dept Kinesiol, Montreal, PQ H2W 1S4, Canada. [Reid, Michael B.] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL 32611 USA. [Bodine, Sue C.] Univ Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Phys Act & Weight Management Res Ctr, Pittsburgh, PA 15261 USA. [Fleg, Jerome L.] NHLBI, NIH, Bethesda, MD 20892 USA. [Williams, John P.; Joseph, Lyndon] NIA, NIH, Bethesda, MD 20892 USA. [Evans, Mary; Maruvada, Padma; Laughlin, Maren R.] NIDDK, NIH, Bethesda, MD 20892 USA. [Rodgers, Mary] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Roary, Mary] NINR, NIH, Bethesda, MD 20892 USA. [Boyce, Amanda T.; Drugan, Jonelle K.; McGowan, Joan A.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Koenig, James I.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Ingraham, Richard H.] NIH, Ctr Sci Review, Bethesda, MD 20892 USA. [Krotoski, Danuta] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Garcia-Cazarin, Mary] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Neufer, PD (reprint author), E Carolina Univ, Brody Sch Med, Dept Physiol, East Carolina Diabet & Obes Inst, Greenville, NC 27834 USA. EM neuferp@ecu.edu RI Bouchard, Claude/A-7637-2009 FU NIH Common Fund FX We gratefully acknowledge financial support from the NIH Common Fund and the following individuals that participated in webinars and conference calls leading up to the workshop: Shannon Bailey, Robert Balaban, Charles Burant, Richard Casaburi, Shulin Cheng, Charlene Chu, Roger Fielding, Monika Fleshner, Jacob Friedman, Paige Geiger, John Holloszy, Lee Jones, Gabrielle Kardon, Christiaan Leeuwenburgh, Gregory Lewis, Wendy Lynch, Paul MacLean, Sreekumaran Nair, Robert O'Doherty, Charlotte Peterson, Orian Shirihai, Kathleen Sluka, Bruce Spiegelman, Russel Swerdlow, John Thyfault, James Tidball, Rick Vega, Eric Verdin, Douglas Wallace, Zhen Yan, Juleen Zierath, and Michael Zigmond. We also gratefully acknowledge additional members of the NIH Working Group: D. Lee Alekel, Catherine Alfano, Josephine E. Boyington, Rosalind A. Breslow, Carole Christian, Wilson Compton, Lawton Cooper, Augusto Diana, Luigi Ferrucci, Katrina Gwinn, Lynda Hardy, Tamara B. Harris, Lynne Haverkos, Mary Kautz, Partap Khalsa, Delvin Knight, Frank Perna, Barry Portnoy, Xenia Tigno, Richard Troiano, Elizabeth Wilder, Lois Winsky, Pamela Wolters, and Steve Zullo. The views expressed are those of the authors and do not necessarily reflect those of the NIH or the Department of Health and Human Services of the United States. NR 57 TC 39 Z9 39 U1 3 U2 37 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 JUL 7 PY 2015 VL 22 IS 1 BP 4 EP 11 DI 10.1016/j.cmet.2015.05.011 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CM4LU UT WOS:000357656900003 PM 26073496 ER PT J AU Egerman, MA Cadena, SM Gilbert, JA Meyer, A Nelson, HN Swalley, SE Mallozzi, C Jacobi, C Jennings, LL Clay, I Laurent, G Ma, SL Brachat, S Lach-Trifilieff, E Shavlakadze, T Trendelenburg, AU Brack, AS Glass, DJ AF Egerman, Marc A. Cadena, Samuel M. Gilbert, Jason A. Meyer, Angelika Nelson, Hallie N. Swalley, Susanne E. Mallozzi, Carolyn Jacobi, Carsten Jennings, Lori L. Clay, Ieuan Laurent, Gaelle Ma, Shenglin Brachat, Sophie Lach-Trifilieff, Estelle Shavlakadze, Tea Trendelenburg, Anne-Ulrike Brack, Andrew S. Glass, David J. TI GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration SO CELL METABOLISM LA English DT Article ID GROWTH/DIFFERENTIATION FACTOR 11; TRANSFORMING-GROWTH-FACTOR; MYOGENIC DIFFERENTIATION; MYOBLAST DIFFERENTIATION; SIGNALING PATHWAY; BETA SUPERFAMILY; MYOSTATIN; ACTIVIN; MASS; FOLLISTATIN AB Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-beta molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia. C1 [Egerman, Marc A.; Cadena, Samuel M.; Gilbert, Jason A.; Swalley, Susanne E.; Mallozzi, Carolyn; Jennings, Lori L.; Laurent, Gaelle; Ma, Shenglin; Shavlakadze, Tea; Trendelenburg, Anne-Ulrike; Glass, David J.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Nelson, Hallie N.; Brack, Andrew S.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Meyer, Angelika; Jacobi, Carsten; Clay, Ieuan; Brachat, Sophie; Lach-Trifilieff, Estelle] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland. RP Glass, DJ (reprint author), Novartis Inst Biomed Res, 100 Technol Sq, Cambridge, MA 02139 USA. EM david.glass@novartis.com OI MALLOZZI, CINZIA/0000-0002-6126-9500 FU NIH [R01 AR060868, R01 AR061002] FX Thank you to Jiang Zhu for additional bioinformatics analysis, to Hua Li for help in processing tissues, and to Bo Guo for help with the SOMAmer binding assay. We thank the Muscle Diseases Group and the Aging Pathways Group at the Novartis Institutes for Biomedical Research (NIBR) for their enthusiastic support, along with the rest of the NIBR community. The portion of the work done by A.S.B. was supported by NIH grants R01 AR060868 and R01 AR061002. All authors except for H.N.N. and A.S.B. are employees of Novartis, and some are also stockholders of Novartis. H.N.N. and A.S.B. declare no conflicts. NR 32 TC 90 Z9 94 U1 13 U2 61 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 JUL 7 PY 2015 VL 22 IS 1 BP 164 EP 174 DI 10.1016/j.cmet.2015.05.010 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CM4LU UT WOS:000357656900020 PM 26001423 ER PT J AU Mainero, C Louapre, C AF Mainero, Caterina Louapre, Celine TI Meningeal inflammation in multiple sclerosis The key to the origin of cortical lesions? SO NEUROLOGY LA English DT Editorial Material ID PATHOLOGY; GRADIENT C1 [Mainero, Caterina; Louapre, Celine] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Mainero, Caterina; Louapre, Celine] Harvard Univ, Sch Med, Boston, MA USA. RP Mainero, C (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM caterina@nmr.mgh.harvard.edu NR 10 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 7 PY 2015 VL 85 IS 1 BP 12 EP 13 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CM2AQ UT WOS:000357482300002 PM 25888561 ER PT J AU Gidicsin, CM Maye, JE Locascio, JJ Pepin, LC Philiossaint, M Becker, JA Younger, AP Dekhtyar, M Schultz, AP Amariglio, RE Marshall, GA Rentz, DM Hedden, T Sperling, RA Johnson, KA AF Gidicsin, Christopher M. Maye, Jacqueline E. Locascio, Joseph J. Pepin, Lesley C. Philiossaint, Marlie Becker, J. Alex Younger, Alayna P. Dekhtyar, Maria Schultz, Aaron P. Amariglio, Rebecca E. Marshall, Gad A. Rentz, Dorene M. Hedden, Trey Sperling, Reisa A. Johnson, Keith A. TI Cognitive activity relates to cognitive performance but not to Alzheimer disease biomarkers SO NEUROLOGY LA English DT Article ID HUMAN CEREBRAL-CORTEX; NORMAL OLDER-ADULTS; PHYSICAL-ACTIVITY; LEISURE ACTIVITIES; AMYLOID BURDEN; SOCIOECONOMIC-STATUS; APOE GENOTYPE; LIFE-STYLE; RISK; IMPAIRMENT AB Objective: We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. Methods: In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 +/- 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater F-18-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. Results: Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, contrary to hypotheses, we did not find evidence of an association of Pittsburgh compound B retention, F-18-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, or with current physical activity. Conclusions: We conclude that a history of lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain beta-amyloid burden, brain glucose metabolism, or hippocampal volume. C1 [Gidicsin, Christopher M.; Maye, Jacqueline E.; Pepin, Lesley C.; Philiossaint, Marlie; Becker, J. Alex; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Locascio, Joseph J.; Schultz, Aaron P.; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Younger, Alayna P.; Schultz, Aaron P.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hedden, Trey; Johnson, Keith A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Younger, Alayna P.; Schultz, Aaron P.; Hedden, Trey; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Dekhtyar, Maria; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment,Dept Neurol, Boston, MA 02115 USA. RP Johnson, KA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. EM kajohnson@pet.mgh.harvard.edu FU National Institute on Aging [P01 AG036694, R01 AG034556, R01 AG037497, K01 AG040197]; Alzheimer's Association Zenith Award; National Institute of Biomedical Imaging and Bioengineering, NIH [P41EB015896]; NIH Shared Instrumentation Grant Program; High-End Instrumentation Grant Program [1S10RR023401, 1S10RR019307, 1S10RR023043, S10RR019254] FX Supported by National Institute on Aging grants P01 AG036694, R01 AG034556, R01 AG037497, and K01 AG040197 and an Alzheimer's Association Zenith Award. This research was performed in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource grant supported by the National Institute of Biomedical Imaging and Bioengineering, NIH. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant numbers 1S10RR023401, 1S10RR019307, 1S10RR023043, and S10RR019254. NR 40 TC 3 Z9 3 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 7 PY 2015 VL 85 IS 1 BP 48 EP 55 DI 10.1212/WNL.0000000000001704 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CM2AQ UT WOS:000357482300008 PM 26062627 ER PT J AU Amariglio, RE Mormino, EC Pietras, AC Marshall, GA Vannini, P Johnson, KA Sperling, RA Rentz, DM AF Amariglio, Rebecca E. Mormino, Elizabeth C. Pietras, Alison C. Marshall, Gad A. Vannini, Patrizia Johnson, Keith A. Sperling, Reisa A. Rentz, Dorene M. TI Subjective cognitive concerns, amyloid-beta, and neurodegeneration in clinically normal elderly SO NEUROLOGY LA English DT Article ID PRECLINICAL ALZHEIMER-DISEASE; NORMAL OLDER INDIVIDUALS; MEMORY COMPLAINTS; ENTORHINAL CORTEX; DECLINE; BURDEN; ADULTS; HIPPOCAMPAL; IMPAIRMENT; VALIDATION AB Objective: To determine whether neuroimaging biomarkers of amyloid-beta (A beta) and neurodegeneration (ND) are associated with greater self-reported subjective cognitive concerns (SCC) in clinically normal older individuals. Methods: A total of 257 participants underwent Pittsburgh compound B PET, PET with fluorodeoxyglucose F-18, and structural MRI, as well as a battery of neuropsychological measures including several questionnaires regarding SCC. Individuals were classified into 4 biomarker groups: biomarker negative (A beta-/ND-), amyloidosis alone (A beta+/ND-), amyloidosis plus ND (A beta+/ND+), and ND alone (A beta-/ND+). Results: Both A beta and ND were independently associated with greater SCC controlling for objective memory performance. By contrast, neither A beta nor ND was associated with objective memory performance controlling for SCC. Further examination revealed greater SCC in individuals with A beta or ND positivity compared to biomarker-negative individuals. In addition, greater SCC predicted A beta positivity when controlling for ND status. Conclusions: When individuals were grouped by biomarker status, those who were positive on A beta or ND had the highest report of SCC compared to biomarker-negative individuals. Findings were consistent when SCC was used to predict A beta positivity. Taken together, results suggest that both A beta and ND are associated with SCC, independent of objective memory performance. Enrichment of individuals with SCC may increase likelihood of A beta and ND markers in potential participants for secondary prevention trials. C1 [Amariglio, Rebecca E.; Pietras, Alison C.; Marshall, Gad A.; Vannini, Patrizia; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Amariglio, Rebecca E.; Mormino, Elizabeth C.; Marshall, Gad A.; Vannini, Patrizia; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Amariglio, RE (reprint author), Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA. EM ramariglio@partners.org FU Alzheimer's Association [NIRG-12-243012]; NIH [K23AG044431, F32AG044054, K23 AG033634, 8KL2TR000168-05, R01EB014894, R21 AG038994, R01 AG026484]; Halloran Consulting Group; Grifols; Bayer; Biogen Idec; Bristol-Myers Squibb; GE Healthcare; Isis Pharmaceuticals Inc.; Janssen Alzheimer's Immunotherapy; Piramal; Siemens Medical Solutions; Genzyme; GEHC; Lundbeck; Pfizer; Eisai; Janssen Alzheimer Immunotherapy; Merck; Roche; Eli Lilly; Fidelity Investigator-Initiated grant; Alzheimer Association [SGCOG-13-282201]; The NIH [R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, R01 AG037497, U01 AG032438, U01 AG024904, K24 AG035007, P50 AG005134, U19 AG010483, R01 MH090291] FX R. Amariglio was supported by Alzheimer's Association NIRG-12-243012 and NIH grant K23AG044431. She is coinvestigator for Eisai, Eli Lilly, and Merck. E. Mormino received funding from NIH grant F32AG044054. A. Pietras reports no disclosures relevant to the manuscript. G. Marshall has served as paid consultant for Halloran Consulting Group and Grifols. He is a site principal investigator coinvestigator for Janssen Alzheimer Immunotherapy, Wyeth/Pfizer Pharmaceuticals, Eisai Inc., Eli Lilly and Company, Avid Radiopharmaceuticals, Bristol-Myers-Squibb, Merck, and Navidea clinical trials. These relationships are not related to the content in the manuscript. G. Marshall receives research support for NIH grant K23 AG033634. P. Vannini received funding from NIH grant 8KL2TR000168-05. K. Johnson has served as paid consultant for Bayer, Biogen Idec, Bristol-Myers Squibb, GE Healthcare, Isis Pharmaceuticals Inc., Janssen Alzheimer's Immunotherapy, Piramal, Siemens Medical Solutions, and Genzyme. He is a site principal investigator or coinvestigator for Lilly/Avid, Biogen Idec, Bristol-Myers Squibb, Eisai, Pfizer, Janssen Alzheimer Immunotherapy, Merck, and Navidea clinical trials. He has spoken at symposia sponsored by Janssen Alzheimer's Immunotherapy, GEHC, Lundbeck, and Pfizer. These relationships are not related to the content in the manuscript. K. Johnson receives research support from NIH grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497. R. Sperling has served as a paid consultant for Bristol-Myers Squibb, Eisai, Janssen Alzheimer Immunotherapy, Pfizer, Merck, and Roche, and as an unpaid consultant to Avid and Eli Lilly. She is a site principal investigator or coinvestigator for Avid, Bristol-Myers Squibb, Pfizer, and Janssen Alzheimer Immunotherapy clinical trials. She has spoken at symposia sponsored by Eli Lilly, Pfizer, and Janssen Alzheimer Immunotherapy. These relationships are not related to the content in the manuscript. R. Sperling receives research support for NIH grants U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, and P01 AG036694. D. Rentz received research support from the NIH grants P01 AG036694, R01 MH090291, U01 AG024904, R01 AG027435, R01 AG037497, and P50 AG005134, a Fidelity Investigator-Initiated grant, and Alzheimer Association grant SGCOG-13-282201. She is coinvestigator for Eli Lilly. Go to Neurology.org for full disclosures. NR 40 TC 8 Z9 8 U1 3 U2 10 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 JUL 7 PY 2015 VL 85 IS 1 BP 56 EP 62 DI 10.1212/WNL.0000000000001712 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CM2AQ UT WOS:000357482300009 PM 26048028 ER PT J AU Lobritz, MA Belenky, P Porter, CBM Gutierrez, A Yang, JH Schwarz, EG Dwyer, DJ Khalil, AS Collins, JJ AF Lobritz, Michael A. Belenky, Peter Porter, Caroline B. M. Gutierrez, Arnaud Yang, Jason H. Schwarz, Eric G. Dwyer, Daniel J. Khalil, Ahmad S. Collins, James J. TI Antibiotic efficacy is linked to bacterial cellular respiration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE E. coli; S. aureus; antibiotics; cellular respiration; metabolomics ID BETA-LACTAM ANTIBIOTICS; MULTICENTER COLLABORATIVE EVALUATION; ESCHERICHIA-COLI; STAPHYLOCOCCUS-AUREUS; MYCOBACTERIUM-TUBERCULOSIS; NALIDIXIC-ACID; ATP SYNTHASE; ANTAGONISM; CHLORAMPHENICOL; DEATH AB Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes-the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy. C1 [Lobritz, Michael A.; Khalil, Ahmad S.; Collins, James J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Lobritz, Michael A.; Porter, Caroline B. M.; Gutierrez, Arnaud; Yang, Jason H.; Collins, James J.] Harvard Univ, Inst Med Engn & Sci, Dept Biol Engn, Cambridge, MA 02139 USA. [Lobritz, Michael A.; Porter, Caroline B. M.; Gutierrez, Arnaud; Yang, Jason H.; Collins, James J.] Harvard Univ, Synthet Biol Ctr, Cambridge, MA 02139 USA. [Lobritz, Michael A.; Porter, Caroline B. M.; Gutierrez, Arnaud; Yang, Jason H.; Collins, James J.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Lobritz, Michael A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lobritz, Michael A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Belenky, Peter] Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. [Schwarz, Eric G.; Khalil, Ahmad S.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Khalil, Ahmad S.] Boston Univ, Biol Design Ctr, Boston, MA 02215 USA. [Dwyer, Daniel J.] Univ Maryland, Dept Cell Biol & Mol Genet, Inst Phys Sci & Technol, Dept Biomed Engn, College Pk, MD 20742 USA. [Dwyer, Daniel J.] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Collins, James J.] Harvard MIT Program Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Lobritz, MA (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. EM mlobritz@mgh.harvard.edu; akhalil@bu.edu; jimjc@mit.edu FU Howard Hughes Medical Institute; National Institutes of Health [DP1 OD003644]; Merieux Research Grant from the Institut Merieux; Wyss Institute at Harvard University FX This work was supported by the Howard Hughes Medical Institute (J.J.C.), National Institutes of Health Director's Pioneer Award DP1 OD003644 (to J.J.C.), and a Merieux Research Grant from the Institut Merieux (to A.S.K. and J.J.C.). M.A.L. is supported in part by the Clinical Fellows program from the Wyss Institute at Harvard University. NR 56 TC 39 Z9 41 U1 12 U2 67 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 JUL 7 PY 2015 VL 112 IS 27 BP 8173 EP 8180 DI 10.1073/pnas.1509743112 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM2QU UT WOS:000357527600033 PM 26100898 ER PT J AU Mallis, RJ Bai, K Arthanari, H Hussey, RE Handley, M Li, ZH Chingozha, L Duke-Cohan, JS Lu, H Wang, JH Zhu, C Wagner, G Reinherz, EL AF Mallis, Robert J. Bai, Ke Arthanari, Haribabu Hussey, Rebecca E. Handley, Maris Li, Zhenhai Chingozha, Loice Duke-Cohan, Jonathan S. Lu, Hang Wang, Jia-Huai Zhu, Cheng Wagner, Gerhard Reinherz, Ellis L. TI Pre-TCR ligand binding impacts thymocyte development before alpha beta TCR expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pre-T-cell receptor; NMR spectroscopy; biomembrane force probe; thymic development; repertoire selection ID T-CELL-RECEPTOR; CRYSTAL-STRUCTURE; PEPTIDE-MHC; POSITIVE SELECTION; ANTIGEN RECEPTOR; STRUCTURAL BASIS; KINETICS; COMPLEX; DIFFERENTIATION; MIGRATION AB Adaptive cellular immunity requires accurate self-vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of alpha beta T-cell receptors (alpha beta TCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pT alpha-beta heterodimer appearing before alpha beta TCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligand-independent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the beta-subunit binds pMHC using V beta complementarity-determining regions as well as an exposed hydrophobic V beta patch characteristic of the preTCR. Force-regulated single bonds akin to those of alpha beta TCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential beta- and then, alpha beta-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for beta-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction. C1 [Mallis, Robert J.; Arthanari, Haribabu; Wang, Jia-Huai; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Bai, Ke; Li, Zhenhai; Zhu, Cheng] Georgia Inst Technol, Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Hussey, Rebecca E.; Handley, Maris; Duke-Cohan, Jonathan S.; Wang, Jia-Huai; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA. [Chingozha, Loice; Lu, Hang] Georgia Inst Technol, Sch Chem & Biomol Engn, Atlanta, GA 30332 USA. [Duke-Cohan, Jonathan S.; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wang, Jia-Huai] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu FU NIH [R01AI088023, R01AI044902, P01GM04746, R01AI37581, R01AI19807, R01AI100643]; National Science Foundation [CBET 0954578] FX We thank Juan Carlos Zuniga-Pflucker for OP9 and OP9-DL4 cell lines; the NIH Tetramer Core Facility at Emory University for providing biotinylated peptides bound to MHC molecules monomers; Rafael A. Irizarry for statistical consultation; Bo Zhao, Jingang Gui, Baoyu Liu, and Wei Chen for assistance with preliminary experiments; and Matthew J. Lang (M.J.L.) for discussion. This work was supported by NIH Grants R01AI088023 (to H.L.), R01AI044902 (to C.Z.), P01GM04746 (to G.W.), R01AI37581 (to G.W.), R01AI19807 (to E.L.R.), and R01AI100643 (to M.J.L. and E.L.R.) and National Science Foundation Grant CBET 0954578 (to H.L.). NR 49 TC 6 Z9 6 U1 0 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 JUL 7 PY 2015 VL 112 IS 27 BP 8373 EP 8378 DI 10.1073/pnas.1504971112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM2QU UT WOS:000357527600067 PM 26056289 ER PT J AU Duda, DG Heist, RS Sahani, DV Stylianopoulos, T Engelman, JA Jain, RK AF Duda, Dan G. Heist, Rebecca S. Sahani, Dushyant V. Stylianopoulos, Triantafyllos Engelman, Jeffrey A. Jain, Rakesh K. TI Reply to Ciccolini et al.: Using mathematical modeling to predict response to antiangiogenic therapy in cancer patients SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Duda, Dan G.; Stylianopoulos, Triantafyllos; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Duda, Dan G.; Heist, Rebecca S.; Sahani, Dushyant V.; Stylianopoulos, Triantafyllos; Engelman, Jeffrey A.; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Heist, Rebecca S.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu OI Stylianopoulos, Triantafyllos/0000-0002-3093-1696 FU NCI NIH HHS [P01 CA080124, R01 CA159258] NR 6 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 JUL 7 PY 2015 VL 112 IS 27 BP E3454 EP E3454 DI 10.1073/pnas.1507225112 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM2QU UT WOS:000357527600002 PM 26080434 ER PT J AU Kim, JH Park, JM Roh, YJ Kim, IW Hasan, T Choi, MG AF Kim, Ju Hee Park, Jae Myung Roh, Yoon Jin Kim, In-Wook Hasan, Tayyaba Choi, Myung-Gyu TI Enhanced efficacy of photodynamic therapy by inhibiting ABCG2 in colon cancers SO BMC CANCER LA English DT Article DE Photodynamic therapy; Colon cancer; Protoporphyrin; ATP-binding cassette transporters; Photosensitizing agents ID IN-VITRO; SCUTELLARIA-BARBATA; PHEOPHORBIDE; RESISTANCE; APOPTOSIS; CELLS; TRANSPORTERS; EXPRESSION; SURVIVAL; MOUSE AB Background: Photodynamic therapy (PDT) contains a photosensitizing process, which includes cellular uptake of photosensitizer and delivery of light to the target. ATP-binding cassette subfamily G2 (ABCG2) regulates endogenous protoporphyrin levels. In human colon cancers, it is not fully examined the role of ABCG2 in porphyrin-based photodynamic therapy. Methods: SW480 and HT29 cells were selected because they showed low and high ABCG2 expression levels, respectively. Pyropheophorbid-a (PPa) was used as a photosensitizer. Cells were exposed to a 670 nm diod laser. Cell viability and necrosi apoptosis was examined. Production level of singlet oxygen was detected with the photomultiplier-tube s/ -based singlet oxygen detection system. Results: SW480 cells, which expressed lower level of ABCG2, showed the higher uptake of PPa than HT-29 cells. The uptake level of PPa was significantly correlated with the decreased cell viability after PDT. Pretreatment with a ABCG2 inhibitor, Ko-143, significantly enhanced the PDT efficacy in HT29 cells compared to vehicle-pretreated cells. To confirm the ABCG2 effect on PDT, we established ABCG2 over-expressing stable cells in SW480 cells (SW480/ABCG2). Furthermore, SW480/ABCG2 cells showed significantly decreased PDT effect compared to the control cells. The increased or decreased cell survival was significantly correlated with the production level of singlet oxygen after PDT. Conclusion: ABCG2 plays an important role in determining the PDT efficacy by controlling the photosensitizer efflux rate. This implies the control of ABCG2 expression may be a potential solution to enhance photosensitivity. C1 [Kim, Ju Hee; Park, Jae Myung; Roh, Yoon Jin; Kim, In-Wook; Choi, Myung-Gyu] Catholic Univ Korea, Catholic Res Inst Med Sci, Seoul 137071, South Korea. [Hasan, Tayyaba] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA USA. [Park, Jae Myung] Catholic Univ Korea, Seoul St Marys Hosp, Div Gastroenterol, Dept Internal Med, Seoul 137071, South Korea. RP Park, JM (reprint author), Catholic Univ Korea, Catholic Res Inst Med Sci, Seoul 137071, South Korea. EM parkjerry@catholic.ac.kr OI Park, Jae Myung/0000-0002-1534-7467 FU Global Research and Development Center through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and Future Planning [NRF-2011-0031644] FX This research was supported by program of Global Research and Development Center through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2011-0031644). NR 27 TC 4 Z9 4 U1 6 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 7 PY 2015 VL 15 AR 504 DI 10.1186/s12885-015-1514-4 PG 9 WC Oncology SC Oncology GA CM0MM UT WOS:000357372100003 PM 26149077 ER PT J AU Kalim, S Clish, CB Deferio, JJ Ortiz, G Moffet, AS Gerszten, RE Thadhani, R Rhee, EP AF Kalim, Sahir Clish, Clary B. Deferio, Joseph J. Ortiz, Guillermo Moffet, Alexander S. Gerszten, Robert E. Thadhani, Ravi Rhee, Eugene P. TI Cross-sectional examination of metabolites and metabolic phenotypes in uremia SO BMC NEPHROLOGY LA English DT Article DE Dialysis; Metabolism; Metabolomics; Uremic toxins ID MAINTENANCE HEMODIALYSIS-PATIENTS; DIALYSIS PATIENTS; REVERSE EPIDEMIOLOGY; INSULIN-RESISTANCE; BLOOD-PRESSURE; RISK-FACTORS; BILE-ACIDS; MORTALITY; SURVIVAL; TOXINS AB Background: Although metabolomic approaches have begun to document numerous changes that arise in end stage renal disease (ESRD), how these alterations relate to established metabolic phenotypes in uremia is unknown. Methods: In 200 incident hemodialysis patients we used partial least squares discriminant analysis to identify which among 166 metabolites could best discriminate individuals with or without diabetes, and across tertiles of body mass index, serum albumin, total cholesterol, and systolic blood pressure. Results: Our data do not recapitulate metabolomic signatures of diabetes and obesity identified among individuals with normal renal function (e.g. elevations in branched chain and aromatic amino acids) and highlight several potential markers of diabetes status specific to ESRD, including xanthosine-5-phosphate and vanillylmandelic acid. Further, our data identify significant associations between elevated tryptophan and long-chain acylcarnitine levels and both decreased total cholesterol and systolic blood pressure in ESRD. Higher tryptophan levels were also associated with higher serum albumin levels, but this may reflect tryptophan's significant albumin binding. Finally, an examination of the uremic retention solutes captured by our platform in relation to 24 clinical phenotypes provides a framework for investigating mechanisms of uremic toxicity. Conclusions: In sum, these studies leveraging metabolomic and metabolic phenotype data acquired in a well-characterized ESRD cohort demonstrate striking differences from metabolomics studies in the general population, and may provide clues to novel functional pathways in the ESRD population. C1 [Kalim, Sahir; Deferio, Joseph J.; Ortiz, Guillermo; Moffet, Alexander S.; Thadhani, Ravi; Rhee, Eugene P.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Clish, Clary B.; Gerszten, Robert E.; Rhee, Eugene P.] Broad Inst, Cambridge, MA USA. [Gerszten, Robert E.] MGH, Div Cardiol, Boston, MA USA. [Gerszten, Robert E.] MGH, Cardiovasc Res Ctr, Boston, MA USA. RP Kalim, S (reprint author), Massachusetts Gen Hosp, Div Nephrol, 165 Cambridge St,Suite 302, Boston, MA 02114 USA. EM skalim@mgh.harvard.edu FU National Kidney Foundation Young Investigator award; NIH [KL2TR001100, K08-DK-090142, 2R01DK081572, 1R01 HL098280, K24 DK094872]; Extramural Grant Program by Satellite Healthcare FX SK received support from the National Kidney Foundation Young Investigator award and NIH award KL2TR001100; EPR was supported by the Extramural Grant Program by Satellite Healthcare, a not-for-profit renal care provider, and NIH grant K08-DK-090142. REG received support from NIH 2R01DK081572 and NIH 1R01 HL098280; RT received support from NIH award K24 DK094872. NR 52 TC 0 Z9 0 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 7 PY 2015 VL 16 AR 98 DI 10.1186/s12882-015-0100-y PG 13 WC Urology & Nephrology SC Urology & Nephrology GA CM0JZ UT WOS:000357365500004 PM 26149577 ER PT J AU Friedman, MJ AF Friedman, Matthew J. TI Suicide Among US Military Personnel Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, White River Jct, VT 05009 USA. RP Friedman, MJ (reprint author), US Dept Vet Affairs, Dept Vet Affairs, Natl Ctr PTSD, 215 N Main St, White River Jct, VT 05009 USA. EM matthew.friedman@dartmouth.edu NR 1 TC 1 Z9 1 U1 0 U2 1 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 JUL 7 PY 2015 VL 314 IS 1 BP 84 EP 85 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CM1QR UT WOS:000357455900024 PM 26151276 ER PT J AU Mendez, JR Perl, J Schuemann, J Shin, J Paganetti, H Faddegon, B AF Mendez, J. Ramos Perl, J. Schuemann, J. Shin, J. Paganetti, H. Faddegon, B. TI Improved efficiency in Monte Carlo simulation for passive-scattering proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Monte Carlo Techniques in Medical Physics CY JUN 17-20, 2014 CL Univ Laval, Quebec City, CANADA HO Univ Laval DE Monte Carlo; variance reduction; proton therapy; TOPAS; treatment head ID TREATMENT PLANNING SYSTEM; DOSE CALCULATION; CLINICAL IMPLEMENTATION; ELECTRON-BEAMS; GEANT4; DISTRIBUTIONS; REDUCTION; VARIANCE; FACILITY; HISTORY AB The aim of this work was to improve the computational efficiency of Monte Carlo simulations when tracking protons through a proton therapy treatment head. Two proton therapy facilities were considered, the Francis H Burr Proton Therapy Center (FHBPTC) at the Massachusetts General Hospital and the Crocker Lab eye treatment facility used by University of California at San Francisco (UCSFETF). The computational efficiency was evaluated for phase space files scored at the exit of the treatment head to determine optimal parameters to improve efficiency while maintaining accuracy in the dose calculation. For FHBPTC, particles were split by a factor of 8 upstream of the second scatterer and upstream of the aperture. The radius of the region for Russian roulette was set to 2.5 or 1.5 times the radius of the aperture and a secondary particle production cut (PC) of 50 mm was applied. For UCSFETF, particles were split a factor of 16 upstream of a water absorber column and upstream of the aperture. Here, the radius of the region for Russian roulette was set to 4 times the radius of the aperture and a PC of 0.05 mm was applied. In both setups, the cylindrical symmetry of the proton beam was exploited to position the split particles randomly spaced around the beam axis. When simulating a phase space for subsequent water phantom simulations, efficiency gains between a factor of 19.9 +/- 0.1 and 52.21 +/- 0.04 for the FHTPC setups and 57.3 +/- 0.5 for the UCSFETF setups were obtained. For a phase space used as input for simulations in a patient geometry, the gain was a factor of 78.6 +/- 7.5. Lateral-dose curves in water were within the accepted clinical tolerance of 2%, with statistical uncertainties of 0.5% for the two facilities. For the patient geometry and by considering the 2% and 2mm criteria, 98.4% of the voxels showed a gamma index lower than unity. An analysis of the dose distribution resulted in systematic deviations below of 0.88% for 20% of the voxels with dose of 20% of the maximum or more. C1 [Mendez, J. Ramos; Faddegon, B.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. [Perl, J.] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA. [Schuemann, J.; Paganetti, H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Schuemann, J.; Paganetti, H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Shin, J.] St Jude Childrens Res Hosp, Dept Radiol Sci, Memphis, TN 38105 USA. RP Mendez, JR (reprint author), Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. EM joserm84@gmail.com FU National Cancer Institute Grant [R01CA140735] FX This work was supported by National Cancer Institute Grant R01CA140735. NR 31 TC 0 Z9 0 U1 1 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2015 VL 60 IS 13 BP 5019 EP 5035 DI 10.1088/0031-9155/60/13/5019 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CL3SX UT WOS:000356872000007 PM 26061457 ER PT J AU Ramos-Mendez, J Perl, J Schumann, J Shin, J Paganetti, H Faddegon, B AF Ramos-Mendez, J. Perl, J. Schuemann, J. Shin, J. Paganetti, H. Faddegon, B. TI A framework for implementation of organ effect models in TOPAS with benchmarks extended to proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Monte Carlo Techniques in Medical Physics CY JUN 17-20, 2014 CL Univ Laval, Quebec City, CANADA HO Univ Laval DE organ effect; proton therapy; Monte Carlo; TOPAS ID MONTE-CARLO SIMULATIONS; TISSUE COMPLICATION PROBABILITY; DOSE-VOLUME HISTOGRAMS; RADIOTHERAPY; RADIATION; BEAM; OPTIMIZATION; NTCP; TOOL AB The aim of this work was to develop a framework for modeling organ effects within TOPAS (TOol for PArticle Simulation), a wrapper of the Geant4 Monte Carlo toolkit that facilitates particle therapy simulation. The DICOM interface for TOPAS was extended to permit contour input, used to assign voxels to organs. The following dose response models were implemented: The Lyman-Kutcher-Burman model, the critical element model, the population based critical volume model, the parallel-serial model, a sigmoid-based model of Niemierko for normal tissue complication probability and tumor control probability (TCP), and a Poisson-based model for TCP. The framework allows easy manipulation of the parameters of these models and the implementation of other models. As part of the verification, results for the parallel-serial and Poisson model for x-ray irradiation of a water phantom were compared to data from the AAPM Task Group 166. When using the task group dose-volume histograms (DVHs), results were found to be sensitive to the number of points in the DVH, with differences up to 2.4%, some of which are attributable to differences between the implemented models. New results are given with the point spacing specified. When using Monte Carlo calculations with TOPAS, despite the relatively good match to the published DVH's, differences up to 9% were found for the parallel-serial model (for a maximum DVH difference of 2%) and up to 0.5% for the Poisson model (for a maximum DVH difference of 0.5%). However, differences of 74.5% (in Rectangle1), 34.8% (in PTV) and 52.1% (in Triangle) for the critical element, critical volume and the sigmoid-based models were found respectively. We propose a new benchmark for verification of organ effect models in proton therapy. The benchmark consists of customized structures in the spread out Bragg peak plateau, normal tissue, tumor, penumbra and in the distal region. The DVH's, DVH point spacing, and results of the organ effect models are provided. The models were used to calculate dose response for a Head and Neck patient to demonstrate functionality of the new framework and indicate the degree of variability between the models in proton therapy. C1 [Ramos-Mendez, J.; Faddegon, B.] Univ Calif San Francisco, Deparment Radiat Oncol, San Francisco, CA 94143 USA. [Perl, J.] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA. [Schuemann, J.; Paganetti, H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Schuemann, J.; Paganetti, H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Shin, J.] St Jude Childrens Res Hosp, Radiobiol Sci Dept, Memphis, TN 38105 USA. RP Ramos-Mendez, J (reprint author), Univ Calif San Francisco, Deparment Radiat Oncol, San Francisco, CA 94143 USA. EM joserm84@gmail.com FU National Cancer Institute Grant [R01CA140735] FX We would like to thank Dr J Chen at the University of California San Francisco for help with the Pinnacle treatment planning system. This work was supported by National Cancer Institute Grant R01CA140735. NR 30 TC 1 Z9 1 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2015 VL 60 IS 13 BP 5037 EP 5052 DI 10.1088/0031-9155/60/13/5037 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CL3SX UT WOS:000356872000008 PM 26061583 ER PT J AU Polster, L Schuemann, J Rinaldi, I Burigo, L McNamara, AL Stewart, RD Attili, A Carlson, DJ Sato, T Mendez, JR Faddegon, B Perl, J Paganetti, H AF Polster, Lisa Schuemann, Jan Rinaldi, Ilaria Burigo, Lucas McNamara, Aimee L. Stewart, Robert D. Attili, Andrea Carlson, David J. Sato, Tatsuhiko Mendez, Jose Ramos Faddegon, Bruce Perl, Joseph Paganetti, Harald TI Extension of TOPAS for the simulation of proton radiation effects considering molecular and cellular endpoints SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Monte Carlo Techniques in Medical Physics CY JUN 17-20, 2014 CL Univ Laval, Quebec City, CANADA HO Univ Laval DE Monte Carlo; simulation; proton therapy; relative biological effectiveness ID RELATIVE BIOLOGICAL EFFECTIVENESS; LINEAR-ENERGY-TRANSFER; MICRODOSIMETRIC-KINETIC-MODEL; EFFECTIVENESS RBE VALUES; MONTE-CARLO SIMULATIONS; HEAVY-ION BOMBARDMENT; TRACK STRUCTURE; DNA-DAMAGE; CLINICAL-APPLICATIONS; THERAPY AB The aim of this work is to extend a widely used proton Monte Carlo tool, TOPAS, towards the modeling of relative biological effect (RBE) distributions in experimental arrangements as well as patients. TOPAS provides a software core which users configure by writing parameter files to, for instance, define application specific geometries and scoring conditions. Expert users may further extend TOPAS scoring capabilities by plugging in their own additional C++ code. This structure was utilized for the implementation of eight biophysical models suited to calculate proton RBE. As far as physics parameters are concerned, four of these models are based on the proton linear energy transfer, while the others are based on DNA double strand break induction and the frequency-mean specific energy, lineal energy, or delta electron generated track structure. The biological input parameters for all models are typically inferred from fits of the models to radiobiological experiments. The model structures have been implemented in a coherent way within the TOPAS architecture. Their performance was validated against measured experimental data on proton RBE in a spread-out Bragg peak using V79 Chinese Hamster cells. This work is an important step in bringing biologically optimized treatment planning for proton therapy closer to the clinical practice as it will allow researchers to refine and compare pre-defined as well as user-defined models. C1 [Polster, Lisa; Schuemann, Jan; Rinaldi, Ilaria; McNamara, Aimee L.; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Polster, Lisa] Heidelberg Univ, Med Fac Mannheim, Expt Radiat Oncol, D-68167 Mannheim, Germany. [Schuemann, Jan; McNamara, Aimee L.] Harvard Univ, Dept Radiat Oncol, Sch Med, Boston, MA 02114 USA. [Rinaldi, Ilaria] Univ Heidelberg Hosp, D-69120 Heidelberg, Germany. [Rinaldi, Ilaria] Univ Munich, Fac Phys, Chair Expt Phys Med Phys, D-80539 Munich, Germany. [Burigo, Lucas] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany. [Burigo, Lucas] Goethe Univ Frankfurt, Inst Theoret Phys, D-60438 Frankfurt, Germany. [Stewart, Robert D.] Univ Washington, Med Ctr, Dept Radiat Oncol, Seattle, WA 98195 USA. [Attili, Andrea] Ist Nazl Fis Nucl, Dipartimento Fis, I-10125 Turin, Italy. [Carlson, David J.] Yale Univ, Dept Therapeut Radiol, Sch Med, New Haven, CT 06520 USA. [Sato, Tatsuhiko] Japan Atom Energy Agcy, Nucl Sci & Engn Ctr, Tokai, Ibaraki 3191195, Japan. [Mendez, Jose Ramos; Faddegon, Bruce] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Perl, Joseph; Paganetti, Harald] SLAC Natl Accelerator Lab, Menlo Pk, CA 94025 USA. RP Polster, L (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@mgh.harvard.edu RI McNamara, Aimee/C-9432-2009; Stewart, Robert/A-3609-2013 OI McNamara, Aimee/0000-0001-8792-0464; Stewart, Robert/0000-0001-5946-0595 FU NCI ('TOPAS: Fast and easy to use Monte Carlo system for proton therapy') [R01 CA 140735]; NCI ('Proton Therapy Research') [U19CA021239]; NCI Federal Share of program income earned by Massachusetts General Hospital ('Advanced Monte Carlo dose calculation for proton therapy') [C06 CA059267]; Medical Faculty Mannheim of Heidelberg University; Siemens AG; Konrad Adenauer Foundation; Helmholtz Graduate School for Hadron and Ion Research; German Academic Exchange Service (DAAD) FX This work was supported by NCI R01 CA 140735 ('TOPAS: Fast and easy to use Monte Carlo system for proton therapy') (HP, JS, JP, BF), NCI U19CA021239 ('Proton Therapy Research') (HP), NCI C06 CA059267 Federal Share of program income earned by Massachusetts General Hospital ('Advanced Monte Carlo dose calculation for proton therapy') (AM), the Medical Faculty Mannheim of Heidelberg University (LP), the Siemens AG (LP), the Konrad Adenauer Foundation (LP) the Helmholtz Graduate School for Hadron and Ion Research (LB), and a fellowship within the Postdoc-Program of the German Academic Exchange Service (DAAD) (IR). NR 48 TC 9 Z9 9 U1 2 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2015 VL 60 IS 13 BP 5053 EP 5070 DI 10.1088/0031-9155/60/13/5053 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CL3SX UT WOS:000356872000009 PM 26061666 ER PT J AU Fekete, CAC Doolan, P Dias, MF Beaulieu, L Seco, J AF Fekete, Charles-Antoine Collins Doolan, Paul Dias, Marta F. Beaulieu, Luc Seco, Joao TI Developing a phenomenological model of the proton trajectory within a heterogeneous medium required for proton imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Monte Carlo Techniques in Medical Physics CY JUN 17-20, 2014 CL Univ Laval, Quebec City, CANADA HO Univ Laval DE proton imaging; proton path estimate; proton CT; cubic spline trajectories; multiple Coulomb scattering; proton radiography; most likely path ID COMPUTED-TOMOGRAPHY; MONTE-CARLO; SPATIAL-RESOLUTION; PATH; SCATTERING AB To develop an accurate phenomenological model of the cubic spline path estimate of the proton path, accounting for the initial proton energy and water equivalent thickness (WET) traversed. Monte Carlo (MC) simulations were used to calculate the path of protons crossing various WET (10-30 cm) of different material (LN300, water and CB2-50% CaCO3) for a range of initial energies (180-330 MeV). For each MC trajectory, cubic spline trajectories (CST) were constructed based on the entrance and exit information of the protons and compared with the MC using the root mean square (RMS) metric. The CST path is dependent on the direction vector magnitudes (\P-0,P-1\). First, \P-0,P-1\ is set to the proton path length (with factor Lambda(Norm)(0,1) = 1.0). Then, two optimal factor Lambda(0,1) are introduced in \P-0,P-1\. The factors are varied to minimize the RMS difference with MC paths for every configuration. A set of Lambda(opt)(0,1) factors, function of WET/water equivalent path length (WEPL), that minimizes the RMS are presented. MTF analysis is then performed on proton radiographs of a line-pair phantom reconstructed using the CST trajectories. Lambda(opt)(0,1) was fitted to the WET/WEPL ratio using a quadratic function (Y = A + BX2 where A = 1.01,0.99, B = 0.43,-0.46 respectively for Lambda(opt)(0), Lambda(opt)(1)). The RMS deviation calculated along the path, between the CST and the MC, increases with the WET. The increase is larger when using Lambda(Norm)(0,1) than Lambda(opt)(0,1) (difference of 5.0% with WET/WEPL = 0.66). For 230/330 MeV protons, the MTF10% was found to increase by 40/16% respectively for a thin phantom (15 cm) when using the Lambda(opt)(0,1) model compared to the Lambda(Norm)(0,1) model. Calculation times for Lambda(opt)(0,1) are scaled down compared to MLP and RMS deviation are similar within standard deviation. Based on the results of this study, using CST with the Lambda(opt)(0,1) factors reduces the RMS deviation and increases the spatial resolution when reconstructing proton trajectories. C1 [Fekete, Charles-Antoine Collins; Beaulieu, Luc] Univ Laval, Dept Phys Genie Phys & Opt, Quebec City, PQ, Canada. [Fekete, Charles-Antoine Collins; Beaulieu, Luc] Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada. [Fekete, Charles-Antoine Collins; Beaulieu, Luc] CHU Quebec, Dept Radiooncol, Quebec City, PQ, Canada. [Fekete, Charles-Antoine Collins; Beaulieu, Luc] CHU Quebec, CRCHU Quebec, Quebec City, PQ, Canada. [Fekete, Charles-Antoine Collins; Dias, Marta F.; Seco, Joao] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Doolan, Paul] UCL, Dept Med Phys & Bioengn, London, England. [Dias, Marta F.] Politecn Milan, DEIB, Milan, Italy. RP Fekete, CAC (reprint author), Univ Laval, Dept Phys Genie Phys & Opt, Quebec City, PQ, Canada. EM charles-antoine.collins-fekete.1@ulaval.ca FU Fonds de Recherche Quebecois-Nature et technologies; CREATE Medical Physics Research Training Network grant of Natural Sciences and Engineering Research Council [432290]; Canada Foundation for Innovation (CFI); Nano-Quebec; RMGA; Fonds de Recherche du Quebec-Nature et Technologies (FRQ-NT) FX Charles-Antoine Collins-Fekete is supported by a scholarship from Fonds de Recherche Quebecois-Nature et technologies. CACF acknowledges partial support by the CREATE Medical Physics Research Training Network grant of the Natural Sciences and Engineering Research Council (Grant number: 432290). Computations were made on the supercomputer Colosse from Universite Laval, managed by Calcul Quebec and Compute Canada. The operation of this supercomputer is funded by the Canada Foundation for Innovation (CFI), Nano-Quebec, RMGA and the Fonds de Recherche du Quebec - Nature et Technologies (FRQ-NT). NR 15 TC 1 Z9 1 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2015 VL 60 IS 13 BP 5071 EP 5082 DI 10.1088/0031-9155/60/13/5071 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CL3SX UT WOS:000356872000010 PM 26061775 ER PT J AU Papp, D Bortfeld, T Unkelbach, J AF Papp, David Bortfeld, Thomas Unkelbach, Jan TI A modular approach to intensity-modulated arc therapy optimization with noncoplanar trajectories SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Monte Carlo Techniques in Medical Physics CY JUN 17-20, 2014 CL Univ Laval, Quebec City, CANADA HO Univ Laval DE arc therapy (VMAT); optimization; noncoplanar radiotherapy; 4pi; treatment planning ID BEAM ANGLE SELECTION; RADIATION-THERAPY; ORIENTATION OPTIMIZATION; RADIOTHERAPY; IMRT; ALGORITHM; COLLISION; PREVENTION; ROTATION; HEAD AB Utilizing noncoplanar beam angles in volumetric modulated arc therapy (VMAT) has the potential to combine the benefits of arc therapy, such as short treatment times, with the benefits of noncoplanar intensity modulated radiotherapy (IMRT) plans, such as improved organ sparing. Recently, vendors introduced treatment machines that allow for simultaneous couch and gantry motion during beam delivery to make noncoplanar VMAT treatments possible. Our aim is to provide a reliable optimization method for noncoplanar isocentric arc therapy plan optimization. The proposed solution is modular in the sense that it can incorporate different existing beam angle selection and coplanar arc therapy optimization methods. Treatment planning is performed in three steps. First, a number of promising noncoplanar beam directions are selected using an iterative beam selection heuristic; these beams serve as anchor points of the arc therapy trajectory. In the second step, continuous gantry/couch angle trajectories are optimized using a simple combinatorial optimization model to define a beam trajectory that efficiently visits each of the anchor points. Treatment time is controlled by limiting the time the beam needs to trace the prescribed trajectory. In the third and final step, an optimal arc therapy plan is found along the prescribed beam trajectory. In principle any existing arc therapy optimization method could be incorporated into this step; for this work we use a sliding window VMAT algorithm. The approach is demonstrated using two particularly challenging cases. The first one is a lung SBRT patient whose planning goals could not be satisfied with fewer than nine noncoplanar IMRT fields when the patient was treated in the clinic. The second one is a brain tumor patient, where the target volume overlaps with the optic nerves and the chiasm and it is directly adjacent to the brainstem. Both cases illustrate that the large number of angles utilized by isocentric noncoplanar VMAT plans can help improve dose conformity, homogeneity, and organ sparing simultaneously using the same beam trajectory length and delivery time as a coplanar VMAT plan. C1 [Papp, David] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Papp, David; Bortfeld, Thomas; Unkelbach, Jan] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Bortfeld, Thomas; Unkelbach, Jan] Harvard Univ, Sch Med, Boston, MA USA. RP Papp, D (reprint author), N Carolina State Univ, Dept Math, Box 8205, Raleigh, NC 27695 USA. EM dpapp@ncsu.edu; tbortfeld@mgh.harvard.edu; junkelbach@mgh.harvard.edu FU Philips Radiation Oncology Systems FX The research was partially supported by Philips Radiation Oncology Systems. The authors are also grateful to the anonymous referees for the numerous constructive comments that helped improve the manuscript. NR 38 TC 4 Z9 4 U1 1 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2015 VL 60 IS 13 BP 5179 EP 5198 DI 10.1088/0031-9155/60/13/5179 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CL3SX UT WOS:000356872000016 PM 26083759 ER PT J AU Li, XY Pietschke, C Fraune, S Altrock, PM Bosch, TCG Traulsen, A AF Li, Xiang-Yi Pietschke, Cleo Fraune, Sebastian Altrock, Philipp M. Bosch, Thomas C. G. Traulsen, Arne TI Which games are growing bacterial populations playing? SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE bacterial interactions; frequency-dependent selection; Lotka-Volterra equations; nonlinear dynamics; population dynamics ID AKAIKE INFORMATION CRITERION; SEA HYDROTHERMAL VENTS; HUMAN GUT MICROBIOME; INTESTINAL MICROBIOTA; MODEL SELECTION; DEEP-SEA; LOGISTIC GROWTH; IMMUNE-SYSTEM; COLONIZATION; EVOLUTION AB Microbial communities display complex population dynamics, both in frequency and absolute density. Evolutionary game theory provides a natural approach to analyse and model this complexity by studying the detailed interactions among players, including competition and conflict, cooperation and coexistence. Classic evolutionary game theory models typically assume constant population size, which often does not hold for microbial populations. Here, we explicitly take into account population growth with frequency-dependent growth parameters, as observed in our experimental system. We study the in vitro population dynamics of the two commensal bacteria (Curvibacter sp. (AEP1.3) and Duganella sp. (C1.2)) that synergistically protect the metazoan host Hydra vulgaris (AEP) from fungal infection. The frequency-dependent, nonlinear growth rates observed in our experiments indicate that the interactions among bacteria in co-culture are beyond the simple case of direct competition or, equivalently, pairwise games. This is in agreement, with the synergistic effect of anti-fungal activity observed in vivo. Our analysis provides new insight into the minimal degree of complexity needed to appropriately understand and predict coexistence or extinction events in this kind of microbial community dynamics. Our approach extends the understanding of microbial communities and points to novel experiments. C1 [Li, Xiang-Yi; Pietschke, Cleo; Traulsen, Arne] Max Planck Inst Evolut Biol, Dept Evolutionary Theory, D-24306 Plon, Germany. [Pietschke, Cleo; Fraune, Sebastian; Bosch, Thomas C. G.] Univ Kiel, Inst Zool, D-24098 Kiel, Germany. [Altrock, Philipp M.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Altrock, Philipp M.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Altrock, Philipp M.] Harvard Univ, Program Evolutionary Dynam, Cambridge, MA 02138 USA. RP Traulsen, A (reprint author), Max Planck Inst Evolut Biol, Dept Evolutionary Theory, August Thienemannstr 2, D-24306 Plon, Germany. EM traulsen@evolbio.mpg.de RI Fraune, Sebastian/B-7970-2010; Traulsen, Arne/A-4955-2009; Bosch, Thomas/D-5218-2011; OI Traulsen, Arne/0000-0002-0669-5267; Li, Xiang-Yi/0000-0001-8662-0865 FU International Max Planck Research School for Evolutionary Biology; DFG [Bo 848/17-2, FR 3041/2-1]; Deutsche Akademie der Naturforscher Leopoldina [LPDS 2012-12]; Clusters of Excellence 'The Future Ocean' and 'Inflammation at Interfaces' FX We acknowledge support from the International Max Planck Research School for Evolutionary Biology (XL.), the DFG (C.P., grant no. FR 3041/2-1 and grant no. Bo 848/17-2) and Deutsche Akademie der Naturforscher Leopoldina (P.M.A., grant no. LPDS 2012-12). This work was supported by the DFG and the Clusters of Excellence 'The Future Ocean' and 'Inflammation at Interfaces'. NR 74 TC 7 Z9 7 U1 2 U2 29 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JUL 6 PY 2015 VL 12 IS 108 AR 20150121 DI 10.1098/rsif.2015.0121 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CO0FD UT WOS:000358824600010 PM 26236827 ER PT J AU Kenny, JD Taylor, NE Brown, EN Solt, K AF Kenny, Jonathan D. Taylor, Norman E. Brown, Emery N. Solt, Ken TI Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence SO PLOS ONE LA English DT Article ID ISOFLURANE ANESTHESIA; PROPOFOL ANESTHESIA; RATS; METHYLPHENIDATE; CHILDREN; POTENCY; MAC; REQUIREMENTS; AMPHETAMINE; SEVOFLURANE AB Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from delta (0.1-4 Hz) to theta (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes significant neurophysiological changes, but does not promote behavioral arousal during general anesthesia. We hypothesize that dextroamphetamine is more likely than atomoxetine to be clinically useful for restoring consciousness in anesthetized patients, mainly due to its stimulation of dopaminergic neurotransmission. C1 [Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Taylor, Norman E.; Brown, Emery N.; Solt, Ken] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Solt, K (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM ksolt@mgh.harvard.edu OI Kenny, Jonathan/0000-0003-3745-3217; Solt, Ken/0000-0001-5328-2062 FU National Institute of General Medical Sciences [TR01-GM104948, K08-GM094394]; Mentored Research Training Grant (NET) from the Foundation for Anesthesia Education and Research FX This research was supported by grants TR01-GM104948 (KS and ENB) and K08-GM094394 (KS) from the National Institute of General Medical Sciences (www.nigms.nih.gov), and a Mentored Research Training Grant (NET) from the Foundation for Anesthesia Education and Research (www.faer.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 5 Z9 5 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 6 PY 2015 VL 10 IS 7 AR e0131914 DI 10.1371/journal.pone.0131914 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1DQ UT WOS:000358157600165 PM 26148114 ER PT J AU Rice, WL Li, W Mamuya, F McKee, M Paunescu, TG Lu, HAJ AF Rice, William L. Li, Wei Mamuya, Fahmy McKee, Mary Paunescu, Teodor G. Lu, Hua A. Jenny TI Polarized Trafficking of AQP2 Revealed in Three Dimensional Epithelial Culture SO PLOS ONE LA English DT Article ID AQUAPORIN-2 WATER CHANNEL; CANINE KIDNEY-CELLS; COLLECTING DUCT; PLASMA-MEMBRANE; RAT-KIDNEY; BRATTLEBORO RATS; APICAL MEMBRANE; MDCK CYSTS; PHOSPHORYLATION; VASOPRESSIN AB In renal collecting duct (CD) principal cells (PCs), vasopressin (VP) acts through its receptor, V2R, to increase intracellular cAMP leading to phosphorylation and apical membrane accumulation of the water channel aquaporin 2 (AQP2). The trafficking and function of basolaterally located AQP2 is, however, poorly understood. Here we report the successful application of a 3-dimensional Madin-Darby canine kidney (MDCK) epithelial model to study polarized AQP2 trafficking. This model recapitulates the luminal architecture of the CD and bi-polarized distribution of AQP2 as seen in kidney. Without stimulation, AQP2 is located in the subapical and basolateral regions. Treatment with VP, forskolin (FK), or 8-(4-Chlorophenylthio)-20-O-methyladenosine 30,50-cyclic monophosphate monosodium hydrate (CPT-cAMP) leads to translocation of cytosolic AQP2 to the apical membrane, but not to the basolateral membrane. Treating cells with methyl-beta-cyclodextrin (m beta CD) to acutely block endocytosis causes accumulation of AQP2 on the basolateral membrane, but not on the apical membrane. Our data suggest that AQP2 may traffic differently at the apical and basolateral domains in this 3D epithelial model. In addition, application of a panel of phosphorylation specific AQP2 antibodies reveals the polarized, subcellular localization of differentially phosphorylated AQP2 at S256, S261, S264 and S269 in the 3D culture model, which is consistent with observations made in the CDs of VP treated animals, suggesting the preservation of phosphorylation dependent regulatory mechanism of AQP2 trafficking in this model. Therefore we have established a 3D culture model for the study of trafficking and regulation of both the apical and basolaterally targeted AQP2. The new model will enable further characterization of the complex mechanism regulating bi-polarized trafficking of AQP2 in vitro. C1 [Lu, Hua A. Jenny] Massachusetts Gen Hosp, Dept Med, Ctr Syst Biol, Program Membrane Biol,Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lu, HAJ (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Syst Biol, Program Membrane Biol,Div Nephrol, Boston, MA 02114 USA. EM Halu@partners.org FU National Institutes of Health [NIH 5T32 DK007540-24]; NIH [R01 DK096015, R01 DK38452, R01 DK096586]; Gottschalk research grant from the American Society of Nephrology (ASN); Nephcure Foundation grant; Boston Area Diabetes and Endocrinology Research Center [NIH DK-57521]; Center for the Study of Inflammatory Bowel Disease [NIH DK-43351] FX WL Rice is supported by an National Institutes of Health training grant (NIH 5T32 DK007540-24). HAJ Lu is supported by an NIH R01 DK096015 and a Gottschalk research grant from the American Society of Nephrology (ASN) and the Nephcure Foundation grant. Additional material support was from NIH grant R01 DK38452 (D. Brown) and R01 DK096586 (D. Brown). The Microscopy Core Facility of the Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (NIH DK-57521) and from the Center for the Study of Inflammatory Bowel Disease (NIH DK-43351). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 3 Z9 3 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 JUL 6 PY 2015 VL 10 IS 7 AR e0131719 DI 10.1371/journal.pone.0131719 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1DQ UT WOS:000358157600135 PM 26147297 ER PT J AU Garrett, WS AF Garrett, Wendy S. TI From cell biology to the microbiome: An intentional infinite loop SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID NUCLEAR RESPONSES; RHO GTPASES; CDC42 AB Cell biology is the study of the structure and function of the unit or units of living organisms. Enabled by current and evolving technologies, cell biologists today are embracing new scientific challenges that span many disciplines. The eclectic nature of cell biology is core to its future and remains its enduring legacy. C1 [Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 6 PY 2015 VL 210 IS 1 BP 7 EP 8 DI 10.1083/jcb.201506019 PG 2 WC Cell Biology SC Cell Biology GA CM5XZ UT WOS:000357763600003 PM 26150386 ER PT J AU Siedner, MJ Santorino, D Lankowski, AJ Kanyesigye, M Bwana, MB Haberer, JE Bangsberg, DR AF Siedner, Mark J. Santorino, Data Lankowski, Alexander J. Kanyesigye, Michael Bwana, Mwebesa B. Haberer, Jessica E. Bangsberg, David R. TI A combination SMS and transportation reimbursement intervention to improve HIV care following abnormal CD4 test results in rural Uganda: a prospective observational cohort study SO BMC MEDICINE LA English DT Article DE HIV/AIDS; Sub-Saharan Africa; Clinical trial; Short message service; Financial incentive; Antiretroviral therapy ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL TREATMENT PROGRAMS; RESOURCE-LIMITED SETTINGS; EARLY MORTALITY; MIXED METHODS; SOUTH-AFRICA; 1ST YEAR; THERAPY; HIV/AIDS; METAANALYSIS AB Background: Up to 50 % of HIV-infected persons in sub-Saharan Africa are lost from care between HIV diagnosis and antiretroviral therapy (ART) initiation. Structural barriers, including cost of transportation to clinic and poor communication systems, are major contributors. Methods: We conducted a prospective, pragmatic, before-and-after clinical trial to evaluate a combination mobile health and transportation reimbursement intervention to improve care at a publicly operated HIV clinic in Uganda. Patients undergoing CD4 count testing were enrolled, and clinicians selected a result threshold that would prompt early return for ART initiation or further care. Participants enrolled in the pre-intervention period (January-August 2012) served as a control group. Participants in the intervention period (September 2012-November 2013) were randomized to receive daily short message service (SMS) messages for up to seven days in one of three formats: 1) messages reporting an abnormal result directly, 2) personal identification number-protected messages reporting an abnormal result, or 3) messages reading "ABCDEFG" to confidentially convey an abnormal result. Participants returning within seven days of their first message received transportation reimbursements (about $6USD). Our primary outcomes of interest were time to return to clinic and time to ART initiation. Results: There were 45 participants in the pre-intervention period and 138 participants in the intervention period (46, 49, and 43 in the direct, PIN, and coded groups, respectively) with low CD4 count results. Median time to clinic return was 33 days (IQR 11-49) in the pre-intervention period and 6 days (IQR 3-16) in the intervention period (P < 0.001); and median time to ART initiation was 47 days (IQR 11-75) versus 12 days (IQR 5-19), (P < 0.001). In multivariable models, participants in the intervention period had earlier return to clinic (AHR 2.32, 95 % CI 1.53 to 3.51) and earlier time to ART initiation (AHR 2.27, 95 % CI 1.38 to 3.72). All three randomized message formats improved time to return to clinic and time to ART initiation (P < 0.01 for all comparisons versus the pre-intervention period). Conclusions: A combination of an SMS laboratory result communication system and transportation reimbursements significantly decreased time to clinic return and time to ART initiation after abnormal CD4 test results. C1 [Siedner, Mark J.; Bangsberg, David R.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Siedner, Mark J.; Lankowski, Alexander J.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Santorino, Data; Kanyesigye, Michael; Bwana, Mwebesa B.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Lankowski, Alexander J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haberer, Jessica E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haberer, Jessica E.] Harvard Univ, Sch Publ Hlth, Boston, MA 02114 USA. RP Siedner, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM msiedner@mgh.harvard.edu FU National Institutes of Health [R24 TW007988, T32 AI007433, K23 MH099916]; Harvard Global Health Institute FX All authors report no conflicts of interest. This study was funded by the National Institutes of Health (R24 TW007988, T32 AI007433, K23 MH099916), and the Harvard Global Health Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 9 Z9 9 U1 5 U2 8 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 JUL 6 PY 2015 VL 13 AR 160 DI 10.1186/s12916-015-0397-1 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CM5EW UT WOS:000357710600001 PM 26149722 ER PT J AU Seok, J Xu, WH Davis, RW Xiao, WZ AF Seok, Junhee Xu, Weihong Davis, Ronald W. Xiao, Wenzhong TI RASA: Robust Alternative Splicing Analysis for Human Transcriptome Arrays SO SCIENTIFIC REPORTS LA English DT Article ID CELL-DIFFERENTIATION; GENE-EXPRESSION; EXON ARRAYS; RNA-SEQ; MICROARRAYS; DISEASE; CANCER; DISCOVERY; INSIGHTS; BRAIN AB Human transcriptome arrays (HTA) have recently been developed for high-throughput alternative splicing analysis by measuring signals not only from exons but also from exon-exon junctions. Effective use of these rich signals requires the development of computational methods for better gene and alternative splicing analyses. In this work, we introduce a computational method, Robust Alternative Splicing Analysis (RASA), for the analysis of the new transcriptome arrays by effective integration of the exon and junction signals. To increase robustness, RASA calculates the expression of each gene by selecting exons classified as not alternatively spliced. It then identifies alternatively spliced exons that are supported by both exon and junction signals to reduce the false positives. Finally, it detects additional alternative splicing candidates that are supported by only exon signals because the signals from the corresponding junctions are not well detected. RASA was demonstrated with Affymetrix HTAs and its performance was evaluated with mRNA-Seq and RT-PCR. The validation rate is 52.4%, which is a 60% increase when compared with previous methods that do not use selected exons for gene expression calculation and junction signals for splicing detection. These results suggest that RASA significantly improves alternative splicing analyses on HTA platforms. C1 [Seok, Junhee] Korea Univ, Sch Elect Engn, Seoul 136701, South Korea. [Xu, Weihong; Davis, Ronald W.; Xiao, Wenzhong] Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Xiao, Wenzhong] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Xiao, Wenzhong] Shriners Hosp Children, Boston, MA 02114 USA. RP Seok, J (reprint author), Korea Univ, Sch Elect Engn, Seoul 136701, South Korea. EM jseok14@korea.ac.kr; wenzhong.xiao@mgh.harvard.edu FU National Research Foundation of Korea (NRF) - Korea government [NRF-2014R1A1A2A16050527]; Korea University; NIH [U54-GM62119, P01-HG00205, R01-GM101401]; Shriners Research Grant [85500-BOS] FX We thank Ms. Julie Wilhelmy and Dr. Michael Mindrinos for help on RT-PCR experiments. This work was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (No. NRF-2014R1A1A2A16050527). It was also funded by the Korea University Grant, NIH (U54-GM62119, P01-HG00205, R01-GM101401) and Shriners Research Grant (85500-BOS). NR 32 TC 1 Z9 1 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 6 PY 2015 VL 5 AR 11917 DI 10.1038/srep11917 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CM0NP UT WOS:000357375300001 PM 26145443 ER PT J AU Caplan, D Michaud, J Hufford, R AF Caplan, David Michaud, Jennifer Hufford, Rebecca TI Mechanisms underlying syntactic comprehension deficits in vascular aphasia: new evidence from self-paced listening SO COGNITIVE NEUROPSYCHOLOGY LA English DT Article DE syntactic comprehension disorders; aphasia; on-line measures ID REAL-TIME COMPREHENSION; MOVING-WINDOW TECHNIQUE; SENTENCE COMPREHENSION; AGRAMMATIC APHASIA; LANGUAGE COMPREHENSION; WORKING-MEMORY; EYE-MOVEMENTS; PERFORMANCE; DETERMINANTS; EYETRACKING AB Sixty-one people with aphasia (pwa) and 41 matched controls were tested for the ability to understand sentences that required the ability to process particular syntactic elements and assign particular syntactic structures. Participants paced themselves word-by-word through 20 examples of 11 spoken sentence types and indicated which of two pictures corresponded to the meaning of each sentence. Sentences were developed in pairs such that comprehension of the experimental version of a pair required an aspect of syntactic processing not required in the corresponding baseline sentence. The need for the syntactic operations required only in the experimental version was triggered at a critical word in the experimental sentence. Listening times for critical words in experimental sentences were compared to those for corresponding words in the corresponding baseline sentences. The results were consistent with several models of syntactic comprehension deficits in pwa: resource reduction, slowed lexical and/or syntactic processing, abnormal susceptibility to interference from thematic roles generated non-syntactically. They suggest that a previously unidentified disturbance limiting the duration of parsing and interpretation may lead to these deficits, and that this mechanism may lead to structure-specific deficits in pwa. The results thus point to more than one mechanism underlying syntactic comprehension disorders both across and within pwa. C1 [Caplan, David; Michaud, Jennifer; Hufford, Rebecca] Massachusetts Gen Hosp, Dept Neurol, Neuropsychol Lab, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neuropsychol Lab, 175 Cambridge St,Suite 340,Fruit St, Boston, MA 02114 USA. EM dcaplan@partners.org FU National Institute of Deafness and Communication Disorders (NIDCD) [DC00942] FX This research was supported by National Institute of Deafness and Communication Disorders (NIDCD) [grant number DC00942] to David Caplan. NR 64 TC 1 Z9 1 U1 4 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0264-3294 EI 1464-0627 J9 COGN NEUROPSYCHOL JI Cogn. Neuropsychol. PD JUL 4 PY 2015 VL 32 IS 5 BP 283 EP 313 DI 10.1080/02643294.2015.1058253 PG 31 WC Psychology; Psychology, Experimental SC Psychology GA CR7IA UT WOS:000361521100003 PM 26165856 ER PT J AU Logue, E Marceaux, J Balldin, V Hilsabeck, RC AF Logue, Erin Marceaux, Janice Balldin, Valerie Hilsabeck, Robin C. TI Further Validation of the Pillbox Test in a Mixed Clinical Sample SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article DE Medication management; IADLs; Executive functioning.; Cognitive impairment/dementia; Validity ID COGNITIVE FUNCTION; PERFORMANCE AB Objective: The purpose of this research was to provide further criterion and construct validation of the Pillbox Test, a brief, ecologically valid measure designed to assess executive functioning(EF). Method: Participants were 179 older male veterans who completed the Pillbox Test as part of a neuropsychological evaluation. Results: Performance on the Pillbox Test differed significantly between patients with and without dementia, with total error scores of >= 5 and >= 7 showing similar levels of sensitivity and specificity at 67% and at or near 70%, respectively. Hierarchical multiple regression analysis revealed that measures of EF predicted performance on the Pillbox Test above and beyond measures of processing speed, but not above and beyond measures in other cognitive domains. Conclusions: Findings suggest the Pillbox Test is a promising new performance-based measure of executive functioning that can discriminate between patients with and without dementia. C1 [Logue, Erin; Marceaux, Janice; Balldin, Valerie; Hilsabeck, Robin C.] South Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. [Hilsabeck, Robin C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. RP Hilsabeck, RC (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. EM hilsabeck@uthscsa.edu NR 34 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 1385-4046 EI 1744-4144 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PD JUL 4 PY 2015 VL 29 IS 5 BP 611 EP 623 DI 10.1080/13854046.2015.1061054 PG 13 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA CR3DU UT WOS:000361211600003 PM 26133227 ER PT J AU Fan, KH Jiang, JB Wang, ZR Yin, W Sun, YG Li, HQ AF Fan, Kuohai Jiang, Junbing Wang, Zhirui Yin, Wei Sun, Yaogui Li, Hongquan TI Expression and purification of the recombinant murine REG3 alpha protein in Pichia pastoris and characterization of its antimicrobial and antitumour efficacy SO BIOTECHNOLOGY & BIOTECHNOLOGICAL EQUIPMENT LA English DT Article DE REG3; expression; purification; Pichia pastori; antimicrobial; anticancer ID PRIMARY LIVER-CANCER; REG FAMILY GENE; CHROMOSOMAL LOCALIZATION; MOLECULAR-CLONING; INJURY; PANCREATITIS; LECTIN AB Regenerating islet-derived 3-alpha (REG3) is a secreted intestinal antimicrobial protein, which shows antibacterial, anti-inflammatory and anti-apoptotic activities. It could significantly promote internal tissue regeneration and wound repair. In the present study, we expressed the codon-optimized murine REG3 in the yeast Pichia pastoris system. The secreted murine REG3 was captured using ProteinIsoTM Ni-NTA resin and further purified using a strong anion exchange resin Poros (R) 50 HQ. The final protein yield was 20 mg/L. The antibacterial activity and the anticancer efficacy of the recombinant REG3 were assessed using liquid growth inhibition assay, killing kinetics and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The results showed that the recombinant murine REG3 possessed antimicrobial activity against Escherichia coli, Salmonella paratyphi A, Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Bacillus pumilus and Micrococcus luteus. Moreover, 100% killing against E. coli and S. aureus was observed after 30 min. The recombinant murine REG3 had a potent antitumour activity in a time-dependent and dose-dependent manner and had a negligible haemolysis activity against human erythrocytes. Taken together, P. pastoris is an efficient expression system for producing large quantities of antibacterial active REG3 for further research studies and clinical applications. C1 [Fan, Kuohai; Jiang, Junbing; Yin, Wei; Sun, Yaogui; Li, Hongquan] Shanxi Agr Univ, Dept Clin Med, Coll Anim Sci & Technol, Taigu, Shanxi, Peoples R China. [Wang, Zhirui] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Wang, Zhirui] MGH DF HCC Recombinant Prot Express & Purificat C, Boston, MA USA. RP Li, HQ (reprint author), Shanxi Agr Univ, Dept Clin Med, Coll Anim Sci & Technol, Taigu, Shanxi, Peoples R China. EM livets@sxau.edu.cn FU Key Scientific and Technological Project of Shanxi Province [20100312016]; Graduate Excellent Innovation Project of Shanxi Province [20123048] FX Key Scientific and Technological Project of Shanxi Province [grant number 20100312016]; Graduate Excellent Innovation Project of Shanxi Province [grant number 20123048]. NR 31 TC 0 Z9 0 U1 2 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1310-2818 EI 1314-3530 J9 BIOTECHNOL BIOTEC EQ JI Biotechnol. Biotechnol. Equip. PD JUL 4 PY 2015 VL 29 IS 4 BP 740 EP 745 DI 10.1080/13102818.2015.1037794 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA CL4XK UT WOS:000356960300018 ER PT J AU Ortiz, VE Kwo, J AF Ortiz, Vilma E. Kwo, Jean TI Obesity: physiologic changes and implications for preoperative management SO BMC ANESTHESIOLOGY LA English DT Review DE Obesity; Morbid obesity; Preoperative evaluation; Metabolic syndrome; Obstructive sleep apnea (OSA); Bariatric; Body mass index; Insulin resistance ID OBSTRUCTIVE SLEEP-APNEA; NONALCOHOLIC FATTY LIVER; BODY-MASS INDEX; HELICOBACTER-PYLORI INFECTION; BARIATRIC SURGICAL-PROCEDURES; AMERICAN-HEART-ASSOCIATION; MAJOR NONCARDIAC SURGERY; CORONARY-ARTERY-DISEASE; VISCERAL ADIPOSE-TISSUE; COLLEGE-OF-CARDIOLOGY AB The proportion of patients defined as obese continues to grow in many westernized nations, particularly the United States (USA). This trend has shifted the perioperative management of obese patients into the realm of routine care. As obese patients present for all types of procedures, it is crucial for anesthesiologists, surgeons, internists, and perioperative health care providers alike to have a firm understanding of their altered multi-organ physiology in order to safely prepare the obese patient for an operation. A careful preoperative evaluation may also serve to identify risk factors for postoperative adverse events. Subsequently, preoperative measures may be implemented to mitigate these complications. In this manuscript we address the major considerations for the preoperative evaluation of the severely obese patient. C1 [Ortiz, Vilma E.; Kwo, Jean] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Ortiz, VE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM vortiz@mgh.harvard.edu NR 124 TC 6 Z9 7 U1 3 U2 3 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 JUL 4 PY 2015 VL 15 AR 97 DI 10.1186/s12871-015-0079-8 PG 12 WC Anesthesiology SC Anesthesiology GA CM0JY UT WOS:000357365400001 PM 26141622 ER PT J AU Medina, J Hopkins, L Powers, M Baird, SO Smits, J AF Medina, Johnna Hopkins, Lindsey Powers, Mark Baird, Scarlett O. Smits, Jasper TI The Effects of a Hatha Yoga Intervention on Facets of Distress Tolerance SO COGNITIVE BEHAVIOUR THERAPY LA English DT Article DE exercise; intervention; distress tolerance; Hatha yoga ID OBSESSIVE-COMPULSIVE DISORDER; ANXIETY SENSITIVITY; PERCEIVED STRESS; YOUNG-ADULTS; CANNABIS USE; SAMPLE-SIZE; EARLY-LAPSE; INTOLERANCE; MINDFULNESS; MEDIATION AB Individuals with low distress tolerance (DT) experience negative emotion as particularly threatening and are highly motivated to reduce or avoid such affective experiences. Consequently, these individuals have difficulty regulating emotions and tend to engage in maladaptive strategies, such as overeating, as a means to reduce or avoid distress. Hatha yoga encourages one to implement present-centered awareness and non-reaction in the face of physical and psychological discomfort and, thus, emerges as a potential strategy for increasing DT. To test whether a hatha yoga intervention can enhance DT, a transdiagnostic risk and maintenance factor, this study randomly assigned females high in emotional eating in response to stress (N=52) either to an 8-week, twice-weekly hatha (Bikram) yoga intervention or to a waitlist control condition. Self-reported DT and emotional eating were measured at baseline, weekly during treatment, and 1-week post-treatment. Consistent with prediction, participants in the yoga condition reported greater increases in DT over the course of the intervention relative to waitlist participants (Cohen's d=.82). Also consistent with prediction, the reduction in emotional eating was greater for the yoga condition than the waitlist condition (Cohen's d=.92). Importantly, reductions distress absorption, a specific sub-facet of DT, accounted for 15% of the variance in emotional eating, a hallmark behavior of eating pathology and risk factor for obesity. C1 [Medina, Johnna; Powers, Mark; Baird, Scarlett O.; Smits, Jasper] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Hopkins, Lindsey] San Francisco VA Med Ctr, San Francisco, CA USA. RP Medina, J (reprint author), Univ Texas Austin, Dept Psychol, 108 E Dean Keeton Stop A8000, Austin, TX 78712 USA. EM johnnam@utexas.edu RI Hopkins, Lindsey/D-4408-2015 OI Hopkins, Lindsey/0000-0002-0577-2961 FU National Institute on Drug Addiction [R01 DA027533, K01 DA035930] FX Portions of this research were funded by grants from the National Institute on Drug Addiction, R01 DA027533 & K01 DA035930. NR 69 TC 1 Z9 1 U1 6 U2 24 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1650-6073 EI 1651-2316 J9 COGN BEHAV THERAPY JI Cogn. Behav. Ther. PD JUL 4 PY 2015 VL 44 IS 4 SI SI BP 288 EP 300 DI 10.1080/16506073.2015.1028433 PG 13 WC Behavioral Sciences; Psychology, Clinical SC Behavioral Sciences; Psychology GA CJ9HB UT WOS:000355812000006 PM 25952547 ER PT J AU Huffman, JC Moore, SV DuBois, CM Mastromauro, CA Suarez, L Park, ER AF Huffman, Jeff C. Moore, Shannon V. DuBois, Christina M. Mastromauro, Carol A. Suarez, Laura Park, Elyse R. TI An exploratory mixed methods analysis of adherence predictors following acute coronary syndrome SO PSYCHOLOGY HEALTH & MEDICINE LA English DT Article DE health behavior; mixed methods; acute coronary syndrome; positive affect; optimism ID HEART-DISEASE; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; EXERCISE; LIFE; RECOMMENDATIONS; OPTIMISM; REHABILITATION; ASSOCIATION; VALIDATION AB Adherence to cardiac health behaviors is a critical predictor of prognosis in the months following an acute coronary syndrome (ACS). However, there has been minimal concomitant study of multiple nonadherence risk factors, as assessed via record review, structured assessments, and qualitative interviews, among hospitalized ACS patients. Accordingly, we completed an exploratory mixed methods study with 22 individuals who were admitted for ACS and had suboptimal pre-ACS adherence to physical activity, heart-healthy diet, and/or medications, defined by a Medical Outcomes Study Specific Adherence Scale (MOS SAS) score <15/18. During hospitalization, participants underwent quantitative assessments of sociodemographic, medical, and psychological variables, followed by in-depth semi-structured interviews to explore intentions, plans, and perceived barriers related to post-discharge health behavior changes. The MOS SAS was readministered at 3months and participants were designated as persistently nonadherent (MOS SAS n=9) or newly adherent (n=13). Interviews were transcribed and coded by trained raters via content analysis, and quantitative variables were compared between groups using chi-square analysis and independent-samples t-tests. On our primary qualitative analysis, we found that participants with vaguely described intentions/plans regarding health behavior change, and those who focused on barriers to change that were perceived as static, were more likely to be persistently nonadherent. On exploratory quantitative analyses, greater medical burden, diabetes, depressive symptoms, and low optimism/positive affect at baseline were associated with subsequent post-ACS nonadherence (all p<.05). In conclusion, this appears to be the first study to prospectively examine all of these constructs in hospitalized ACS patients, and we found that specific factors were associated with nonadherence to key health behaviors 3months later. Therefore it may be possible to predict future nonadherence in ACS patients, even during hospitalization, and specific interventions during admission may be indicated to prevent adverse outcomes among patients at highest risk for post-ACS nonadherence. C1 [Huffman, Jeff C.; Moore, Shannon V.; DuBois, Christina M.; Mastromauro, Carol A.; Suarez, Laura; Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Huffman, Jeff C.; Suarez, Laura; Park, Elyse R.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Park, Elyse R.] Benson Henry Inst Mind Body Med, Boston, MA USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St Blake 11, Boston, MA 02114 USA. EM jhuffman@partners.org FU National Institutes of Health - National Heart, Lung, and Blood Institute [R01HL113272] FX This work was supported by the National Institutes of Health - National Heart, Lung, and Blood Institute [grant number R01HL113272]. NR 36 TC 2 Z9 2 U1 1 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1354-8506 EI 1465-3966 J9 PSYCHOL HEALTH MED JI Psychol. Health Med. PD JUL 4 PY 2015 VL 20 IS 5 BP 541 EP 550 DI 10.1080/13548506.2014.989531 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH5ZF UT WOS:000354114200004 PM 25495864 ER PT J AU Rozenman, M Johnson, OE Chang, SW Woods, DW Walkup, JT Wilhelm, S Peterson, A Scahill, L Piacentini, J AF Rozenman, Michelle Johnson, Olivia E. Chang, Susanna W. Woods, Douglas W. Walkup, John T. Wilhelm, Sabine Peterson, Alan Scahill, Lawrence Piacentini, John TI Relationships Between Premonitory Urge and Anxiety in Youth With Chronic Tic Disorders SO CHILDRENS HEALTH CARE LA English DT Article ID OBSESSIVE-COMPULSIVE SCALE; TOURETTE-SYNDROME; INTERVIEW SCHEDULE; SENSITIVITY INDEX; BEHAVIOR-THERAPY; PARENT VERSIONS; DSM-IV; CHILD; RELIABILITY; VALIDITY AB Tourette's Disorder and other chronic tic disorders are common neurodevelopmental conditions. One characteristic of tic disorders is the premonitory urge, an aversive or unpleasant sensory phenomenon that may precede tics. Initial examination of premonitory urge in pediatric tic disorders suggests that awareness and experience of sensations preceding tics may be related to anxiety and OCD. However, it may be possible that specific anxiety-related symptoms, such as anxious physiologic arousal, are particularly relevant to the experience of premonitory urge. The current study examines relationships between tic-related premonitory urge and anxiety-related symptom clusters in treatment-seeking youths with a primary diagnosis of Tourette's or other chronic tic disorder. The sample consisted of 124 youth, ages 9 to 17, who participated in the multi-site Comprehensive Behavioral Intervention for Tics randomized controlled trial (CBIT; Piacentini et al., 2010). Specific anxiety-related subtypes, including generalized worry, separation, social, and panic/somatic symptoms, as well as severity of obsessions and compulsions, were assessed as potential correlates of premonitory urge. Findings indicated that age, global tic-related impairment, and specific panic/somatic symptoms accounted for a substantial proportion of variance in youth report of premonitory urge. These findings provide information about the characteristics of premonitory urge in pediatric tic disorders and have implications for the treatment of pediatric tic syndromes. C1 [Rozenman, Michelle; Johnson, Olivia E.; Chang, Susanna W.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Div Child & Adolescent Psychiat, Los Angeles, CA 90095 USA. [Woods, Douglas W.] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Walkup, John T.] Weill Cornell Med Coll, Div Child & Adolescent Psychiat, New York, NY USA. [Wilhelm, Sabine] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Peterson, Alan] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Scahill, Lawrence] Emory Univ, Sch Med, Atlanta, GA USA. [Scahill, Lawrence] Marcus Autism Ctr, Atlanta, GA USA. [Rozenman, Michelle; Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. RP Rozenman, M (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,67-455, Los Angeles, CA 90095 USA. EM mrozenman@mednet.ucla.edu FU National Institute of Mental Health [R01MH070802]; Yale University Clinical and Translational Sciences Award from the National Center for Research Resources (NCRR), National Institutes of Health (NIH) [UL1 RR024139] FX This work was supported by grant R01MH070802 from the National Institute of Mental Health to Dr. Piacentini with subcontracts to Drs. Walkup, Woods, Scahill, Wilhelm, and Peterson. Drs. Scahill & Dziura also received support from the Yale University Clinical and Translational Sciences Award: Grant UL1 RR024139 from the National Center for Research Resources (NCRR), National Institutes of Health (NIH). NR 28 TC 1 Z9 1 U1 2 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0273-9615 EI 1532-6888 J9 CHILD HEALTH CARE JI Child. Health Care PD JUL 3 PY 2015 VL 44 IS 3 SI SI BP 235 EP 248 DI 10.1080/02739615.2014.986328 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CW4HF UT WOS:000364951400004 PM 27110050 ER PT J AU Ramanujam, K Himle, MB Hayes, LP Woods, DW Scahill, L Sukhodolsky, DG Wilhelm, S Deckersbach, T Peterson, AL Specht, M Walkup, JT Chang, SW Piacentini, J AF Ramanujam, Krishnapriya Himle, Michael B. Hayes, Loran P. Woods, Douglas W. Scahill, Lawrence Sukhodolsky, Denis G. Wilhelm, Sabine Deckersbach, Thilo Peterson, Alan L. Specht, Matt Walkup, John T. Chang, Susanna W. Piacentini, John TI Clinical Correlates and Predictors of Caregiver Strain in Children With Chronic Tic Disorders SO CHILDRENS HEALTH CARE LA English DT Article ID SCALE-PARENT VERSION; FUNCTIONAL IMPAIRMENT; ANXIETY DISORDERS; DISRUPTIVE BEHAVIOR; INTERVIEW SCHEDULE; TOURETTES-SYNDROME; SEVERITY-SCALE; DSM-IV; IMPACT; VALIDITY AB Although tics are the defining feature of chronic tic disorders (CTD), many children experience comorbid internalizing and externalizing problems that contribute to impairment across several domains, including family functioning. The current study examined clinical correlates and predictors of caregiver strain in parents of children with CTD. Participants were 123 children and adolescents diagnosed with a CTD who participated in a randomized-controlled trial of behavior therapy for reducing tics. Results showed that a combination of disruptive behavior, inattention/hyperactivity, and tic intensity best explained objective strain, and a combination of inattention/hyperactivity and tic intensity were the best predictors of subjective caregiver strain. Implications of these findings for care providers are discussed. C1 [Ramanujam, Krishnapriya; Himle, Michael B.; Hayes, Loran P.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Woods, Douglas W.] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Scahill, Lawrence] Emory Univ, Emory Sch Med, Marcus Autism Ctr, Atlanta, GA USA. [Sukhodolsky, Denis G.] Yale Univ, Sch Med, Yale Child Studies Ctr, New Haven, CT USA. [Wilhelm, Sabine; Deckersbach, Thilo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Specht, Matt; Walkup, John T.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Walkup, John T.] Cornell Univ, Weill Cornell Med Sch, New York, NY 10021 USA. [Chang, Susanna W.; Piacentini, John] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. RP Himle, MB (reprint author), Univ Utah, Dept Psychol, 380 S 1530 E,Rm 502, Salt Lake City, UT 84112 USA. EM michael.himle@utah.edu OI Sukhodolsky, Denis/0000-0002-5401-792X FU National Institute of Mental Health [R01MH070802]; Yale University Clinical and Translational Sciences Award from the National Center for Research Resources, NIH [UL1 RR024139] FX This research was supported by grant R01MH070802 from the National Institute of Mental Health to the Tourette Syndrome Association, Inc. (PI: Dr. John Piacentini), with subcontracts to Drs. Douglas Woods, Larry Scahill, Sabine Wilhelm, Alan Peterson, and John Walkup. Dr Scahill received support from the Yale University Clinical and Translational Sciences Award grant UL1 RR024139 from the National Center for Research Resources, NIH. NR 29 TC 0 Z9 0 U1 2 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0273-9615 EI 1532-6888 J9 CHILD HEALTH CARE JI Child. Health Care PD JUL 3 PY 2015 VL 44 IS 3 SI SI BP 249 EP 263 DI 10.1080/02739615.2014.948166 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CW4HF UT WOS:000364951400005 PM 26855465 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI Snapshot: painters and photography, Bonnard to Vuillard SO EARLY POPULAR VISUAL CULTURE LA English DT Book Review C1 [Mifflin, Jeffrey] Massachusetts Gen Hosp, Arch & Special Collect, Boston, MA 02114 USA. RP Mifflin, J (reprint author), Massachusetts Gen Hosp, Arch & Special Collect, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1746-0654 EI 1746-0662 J9 EARLY POPUL VIS CULT JI Early Popul. Vis. Cult. PD JUL 3 PY 2015 VL 13 IS 3 BP 242 EP 243 DI 10.1080/17460654.2015.1036526 PG 2 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA CS8QP UT WOS:000362353600006 ER PT J AU Gordon, AJ Haibach, J AF Gordon, Adam J. Haibach, Jeffrey TI Screening and Intervening on Alcohol and Other Drug Use in General Wellness Programs: Challenges and Opportunities SO SUBSTANCE ABUSE LA English DT Editorial Material C1 [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Sect Treatment Res & Educ Addict Med, Pittsburgh, PA USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Gordon, Adam J.; Haibach, Jeffrey] VA Pittsburgh Healthcare Syst, VA Pittsburghs Interdisciplinary Addict Program E, Pittsburgh, PA 15240 USA. RP Gordon, AJ (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr C,Bldg 30,Mailcode 151-C, Pittsburgh, PA 15240 USA. EM gordona@medschool.pitt.edu NR 17 TC 1 Z9 1 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PD JUL 3 PY 2015 VL 36 IS 3 BP 255 EP 256 DI 10.1080/08897077.2015.1073975 PG 2 WC Substance Abuse SC Substance Abuse GA CQ0OA UT WOS:000360294600001 PM 26275177 ER PT J AU Wakeman, SE Rich, JD AF Wakeman, Sarah E. Rich, Josiah D. TI Addiction Treatment Within U.S. Correctional Facilities: Bridging the Gap Between Current Practice and Evidence-Based Care SO JOURNAL OF ADDICTIVE DISEASES LA English DT Article DE buprenorphine; methadone; substance use; naltrexone; Incarceration; prison; jail; opioid; addiction ID RANDOMIZED CLINICAL-TRIAL; METHADONE-MAINTENANCE; ASSISTED TREATMENT; DEPENDENT INMATES; RELEASE; PRISON; INCARCERATION; BUPRENORPHINE; DETOXIFICATION; POSTRELEASE AB The United States leads the world in creating prisoners. This epidemic of incarceration is largely due to the "War on Drugs," which has resulted in criminalization of the disease of addiction. Half of prisoners have an active substance use disorder yet a minority receives formal treatment. Opioid agonist maintenance is among the most effective treatments for opioid use disorder. Maintenance treatment reduces illicit opioid use, crime, recidivism, and cost, yet few correctional facilities provide this lifesaving treatment. Increased access to opioid agonist maintenance as well as reexamination of drug policy is necessary to address this costly and morbid incarceration epidemic. C1 [Wakeman, Sarah E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Wakeman, Sarah E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wakeman, Sarah E.; Rich, Josiah D.] Ctr Prisoner Hlth & Human Rights, Providence, RI USA. [Rich, Josiah D.] Brown Univ, Dept Med & Epidemiol, Warren Alpert Med Sch, Providence, RI 02912 USA. [Rich, Josiah D.] Miriam Hosp, Div Infect Dis, Providence, RI 02906 USA. RP Wakeman, SE (reprint author), 55 Fruit St,Founders 883, Boston, MA 02114 USA. EM swakeman@partners.org FU NIDA NIH HHS [K24 DA022112] NR 37 TC 1 Z9 1 U1 8 U2 25 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1055-0887 EI 1545-0848 J9 J ADDICT DIS JI J. Addict. Dis. PD JUL 3 PY 2015 VL 34 IS 2-3 SI SI BP 220 EP 225 DI 10.1080/10550887.2015.1059217 PG 6 WC Substance Abuse SC Substance Abuse GA CQ1PC UT WOS:000360368900010 PM 26076211 ER PT J AU Thomas, ML Brown, GG Gur, RC Moore, TM Patt, VM Nock, MK Naifeh, JA Heeringa, S Ursano, RJ Stein, MB AF Thomas, Michael L. Brown, Gregory G. Gur, Ruben C. Moore, Tyler M. Patt, Virginie M. Nock, Matthew K. Naifeh, James A. Heeringa, Steven Ursano, Robert J. Stein, Murray B. CA Army STARRS Collaborators TI Measurement of latent cognitive abilities involved in concept identification learning SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article DE Neuropsychology; Concept identification learning; Item response theory; Penn Conditional Exclusion Test; Army STARRS; Latent variable measurement ID SERVICEMEMBERS ARMY STARRS; ITEM RESPONSE THEORY; FRONTAL-LOBE DAMAGE; ASSESS RISK; CONSTRUCT-VALIDITY; INDIVIDUAL-DIFFERENCES; PARKINSONS-DISEASE; SUICIDAL IDEATION; RESILIENCE; MODEL AB Introduction: We used cognitive and psychometric modeling techniques to evaluate the construct validity and measurement precision of latent cognitive abilities measured by a test of concept identification learning: the Penn Conditional Exclusion Test (PCET). Method: Item response theory parameters were embedded within classic associative- and hypothesis-based Markov learning models and were fitted to 35,553 Army soldiers' PCET data from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). Results: Data were consistent with a hypothesis-testing model with multiple latent abilities-abstraction and set shifting. Latent abstraction ability was positively correlated with number of concepts learned, and latent set-shifting ability was negatively correlated with number of perseverative errors, supporting the construct validity of the two parameters. Abstraction was most precisely assessed for participants with abilities ranging from 1.5 standard deviations below the mean to the mean itself. Measurement of set shifting was acceptably precise only for participants making a high number of perseverative errors. Conclusions: The PCET precisely measures latent abstraction ability in the Army STARRS sample, especially within the range of mildly impaired to average ability. This precision pattern is ideal for a test developed to measure cognitive impairment as opposed to cognitive strength. The PCET also measures latent set-shifting ability, but reliable assessment is limited to the impaired range of ability, reflecting that perseverative errors are rare among cognitively healthy adults. Integrating cognitive and psychometric models can provide information about construct validity and measurement precision within a single analytical framework. C1 [Thomas, Michael L.; Brown, Gregory G.; Patt, Virginie M.; Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Brown, Gregory G.] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Gur, Ruben C.; Moore, Tyler M.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gur, Ruben C.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Naifeh, James A.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Heeringa, Steven] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. RP Brown, GG (reprint author), VA San Diego Healthcare Syst, Psychol Serv 116B, 3350 La Jolla Village Dr, San Diego, CA 92161 USA. EM gbrown@ucsd.edu FU Department of the Army; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981] FX Army STARRS was sponsored by the Department of the Army and funded with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [cooperative agreement number U01MH087981]. The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. NR 78 TC 0 Z9 0 U1 3 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1380-3395 EI 1744-411X J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD JUL 3 PY 2015 VL 37 IS 6 BP 653 EP 669 DI 10.1080/13803395.2015.1042358 PG 17 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA CM8GZ UT WOS:000357938300009 PM 26147832 ER PT J AU Spatz, JM Wein, MN Gooi, JH Qu, YL Garr, JL Liu, S Barry, KJ Uda, Y Lai, F Dedic, C Balcells-Camps, M Kronenberg, HM Babij, P Pajevic, PD AF Spatz, Jordan M. Wein, Marc N. Gooi, Jonathan H. Qu, Yili Garr, Jenna L. Liu, Shawn Barry, Kevin J. Uda, Yuhei Lai, Forest Dedic, Christopher Balcells-Camps, Mercedes Kronenberg, Henry M. Babij, Philip Pajevic, Paola Divieti TI The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOST DOWN-REGULATION; SPINAL-CORD-INJURY; PARATHYROID-HORMONE; BONE-FORMATION; BED REST; TARGETED ABLATION; SERUM SCLEROSTIN; RANKL EXPRESSION; GENE-EXPRESSION; SPACE-FLIGHT AB Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 +/- 1.9-fold, p< 0.001), sclerostin (4.7 +/- 0.1-fold, p< 0.001), and the receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) (2.5 +/- 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone. C1 [Spatz, Jordan M.; Wein, Marc N.; Qu, Yili; Garr, Jenna L.; Liu, Shawn; Barry, Kevin J.; Uda, Yuhei; Lai, Forest; Dedic, Christopher; Kronenberg, Henry M.; Pajevic, Paola Divieti] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Spatz, Jordan M.; Wein, Marc N.; Qu, Yili; Garr, Jenna L.; Liu, Shawn; Barry, Kevin J.; Uda, Yuhei; Lai, Forest; Dedic, Christopher; Kronenberg, Henry M.; Pajevic, Paola Divieti] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Spatz, Jordan M.; Balcells-Camps, Mercedes] MIT, Harvard MIT Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Balcells-Camps, Mercedes] Ramon Llull Univ, Inst Quim Sarria, Bioengn Dept, Barcelona 08017, Spain. [Gooi, Jonathan H.] Univ Melbourne, NorthWest Acad Ctr, St Albans, Vic 3065, Australia. [Babij, Philip] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Pajevic, PD (reprint author), Boston Univ, Goldman Sch Dent Med, Mol & Cell Biol, 700 Albany St, Boston, MA 02118 USA. EM pdivieti@bu.edu RI Gooi, Jonathan/M-2407-2016 FU National Institutes of Health from the NIAMS [AR059655]; National Institutes of Health from NIDDK [DK011794, DK100215]; Northrop Grumman Aerospace Systems Ph.D. training fellowship; Massachusetts Institute of Technology Hugh Hampton Young fellowship; National Space Biomedical Research Institute through NASA [NCC 9-58]; United States Army Institute for Environmental Medicine Oak Ridge Science Institute for Science and Education fellowship program; Spain's Ministerio de Economia e Innovacion [SAF2013-43302-R]; Posimat; Fundacio Empreses Institut Quimic de Sarria FX This work was supported, in whole or in part, by National Institutes of Health Grants AR059655 from the NIAMS (to P. D. P.) and DK011794 (to H. M. K.) and DK100215 (to M. N. W.) from the NIDDK. P. Babij was employed by Amgen Inc. and received Amgen stock.; Supported by a Northrop Grumman Aerospace Systems Ph.D. training fellowship, a Massachusetts Institute of Technology Hugh Hampton Young fellowship, the National Space Biomedical Research Institute through NASA Grant NCC 9-58, and the United States Army Institute for Environmental Medicine Oak Ridge Science Institute for Science and Education fellowship program.; Supported by Spain's Ministerio de Economia e Innovacion (Grant SAF2013-43302-R), Posimat, and Fundacio Empreses Institut Quimic de Sarria. NR 68 TC 17 Z9 18 U1 1 U2 11 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 JUL 3 PY 2015 VL 290 IS 27 BP 16744 EP 16758 DI 10.1074/jbc.M114.628313 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CM3HN UT WOS:000357572800022 PM 25953900 ER PT J AU Price, S Ferisin, S Sharifi, M Steinberg, D Bennett, G Wolin, KY Horan, C Koziol, R Marshall, R Taveras, EM AF Price, Sarah Ferisin, Stephanie Sharifi, Mona Steinberg, David Bennett, Gary Wolin, Kathleen Y. Horan, Christine Koziol, Renata Marshall, Richard Taveras, Elsie M. TI Development and Implementation of an Interactive Text Messaging Campaign to Support Behavior Change in a Childhood Obesity Randomized Controlled Trial SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID PROMOTE HEALTHY BEHAVIORS; WEIGHT-LOSS; MOBILE PHONE; PEDIATRIC OBESITY; PHYSICAL-ACTIVITY; YOUNG-PEOPLE; SWEET TALK; INTERVENTIONS; ADOLESCENTS; TECHNOLOGY AB Text messaging is a promising means of intervening on an array of health issues among varied populations, but little has been published about the development of such interventions. The authors describe the development and implementation of an interactive text messaging campaign for parents to support behavior change among children in a childhood obesity randomized controlled trial. The authors invited 160 parents to participate in a text messaging intervention that provided behavior change support in conjunction with health coaching phone calls and mailed materials on behavioral goals. Throughout the 1-year intervention, the authors sent 1-2 text messages per week. The first asked how the child did with a target behavior the day before; parents who replied received an immediate feedback message tailored to their response. The second included a tip about how to work toward a behavioral goal. Baseline surveys indicate that text messaging is a common means of communication for parents, and many are willing to use text messaging to support behavior change for their child. Results at 1 year indicate a high level of engagement with the text messaging intervention, with nearly two thirds responding to 75% or more of the questions they were sent by text. C1 [Price, Sarah; Sharifi, Mona; Horan, Christine; Taveras, Elsie M.] Massachusetts Gen Hosp, Div Gen Pediat, Dept Pediat, Boston, MA 02114 USA. [Ferisin, Stephanie] Stephanie Ferisin Hlth & Wellness, Boston, MA USA. [Steinberg, David] Steinberg Comp, Carrboro, NC USA. [Bennett, Gary] Duke Univ, Duke Obes Prevent Program, Durham, NC USA. [Wolin, Kathleen Y.] Coeus Hlth, Chicago, IL USA. [Koziol, Renata] Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA USA. [Koziol, Renata] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Marshall, Richard] Harvard Vanguard Med Associates, Dept Pediat, Boston, MA USA. RP Taveras, EM (reprint author), Massachusetts Gen Hosp, Div Gen Pediat, Dept Pediat, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM etaveras@partners.org RI Emchi, Karma/Q-1952-2016; OI Sharifi, Mona/0000-0002-1632-7038 FU American Recovery and Reinvestment Act [R18 AE000026] FX This study was supported by Award #R18 AE000026 from the American Recovery and Reinvestment Act to Dr. Elsie M. Taveras. NR 31 TC 1 Z9 1 U1 6 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD JUL 3 PY 2015 VL 20 IS 7 BP 843 EP 850 DI 10.1080/10810730.2015.1018582 PG 8 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CL6QS UT WOS:000357092700013 PM 25996181 ER PT J AU Hoover, EL Caplan, D Waters, G Budson, A AF Hoover, Elizabeth Louise Caplan, David Waters, Gloria Budson, Andrew TI Effects of impairment-based individual and socially oriented group therapies on verb production in aphasia SO APHASIOLOGY LA English DT Article DE impairment-based treatment; verb production; treatment; socially oriented treatment; aphasia ID SPONTANEOUS-RECOVERY; LANGUAGE; ADULTS; REHABILITATION; METAANALYSIS; NETWORKS; EFFICACY; SPEECH; STROKE; DAMAGE AB Purpose: Two philosophies of intervention exist in aphasia rehabilitation: impairment-based approaches and socially oriented approaches. Both approaches have been shown to improve communication in persons with aphasia, but no studies have directly compared the effects of each approach or a combined approach on a targeted linguistic skill. This article explores the effects of individual and group therapies used both in isolation and in combination on verb production in aphasia. Methods: Twelve individuals with chronic aphasia were trained on transitive verbs under three conditions-individual, group and combined-over a 6-week interval. Treatment was counterbalanced across subject and training groups. A delayed-treatment, within-participant design was used. Verb probe data were collected at 10 points throughout the study. Language measures were taken at two intervals pre- and two intervals post-treatment. Functional, narrative and quality-of-life measures were taken once pre- and once post-treatment. Results: Significant change was observed on linguistic, functional communication and quality-of-life measures. There was no significant effect of treatment condition. Conclusions: The results provide evidence of linguistic and psychosocial change in individuals with chronic aphasia following this treatment. Results failed to find that one treatment condition was superior to others. C1 [Hoover, Elizabeth Louise; Waters, Gloria] Boston Univ, Speech Language & Hearing Sci, Boston, MA 02215 USA. [Caplan, David] Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. [Budson, Andrew] VA Boston Healthcare Syst, Cognit & Behav Neurol, Jamaica Plain, MA 02130 USA. RP Hoover, EL (reprint author), Boston Univ, Speech Language & Hearing Sci, Boston, MA 02215 USA. EM ehoover@bu.edu NR 39 TC 2 Z9 2 U1 5 U2 18 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0268-7038 EI 1464-5041 J9 APHASIOLOGY JI Aphasiology PD JUL 3 PY 2015 VL 29 IS 7 BP 781 EP 798 DI 10.1080/02687038.2014.989953 PG 18 WC Clinical Neurology SC Neurosciences & Neurology GA CG2PN UT WOS:000353117000002 ER PT J AU Holtzman, CW Shea, JA Glanz, K Jacobs, LM Gross, R Hines, J Mounzer, K Samuel, R Metlay, JP Yehia, BR AF Holtzman, Carol W. Shea, Judy A. Glanz, Karen Jacobs, Lisa M. Gross, Robert Hines, Janet Mounzer, Karam Samuel, Rafik Metlay, Joshua P. Yehia, Baligh R. TI Mapping patient-identified barriers and facilitators to retention in HIV care and antiretroviral therapy adherence to Andersen's Behavioral Model SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE retention in care; barriers; antiretroviral therapy; Andersen's Behavioral Model; adherence ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; VIRAL SUPPRESSION; INFECTED PATIENTS; MEDICAL-CARE; WOMEN; ACCESS; ADULTS; INTERVENTIONS; ENGAGEMENT AB Andersen's Behavioral Model (ABM) provides a framework for understanding how patient and environmental factors impact health behaviors and outcomes. We compared patient-identified barriers/facilitators to retention in care and antiretroviral therapy (ART) adherence and evaluated how they mapped to ABM. Qualitative semi-structured interviews with 51 HIV-infected adults at HIV clinics in Philadelphia, PA, in 2013 were used to explore patients' experiences with HIV care and treatment. Interview data were analyzed for themes using a grounded theory approach. Among those interviewed, 53% were male and 88% were nonwhite; 49% were retained in care, 96% were on ART, and 57% were virally suppressed. Patients discussed 18 barriers/facilitators to retention in care and ART adherence: 11 common to both behaviors (stigma, mental illness, substance abuse, social support, reminder strategies, housing, insurance, symptoms, competing life activities, colocation of services, provider factors), 3 distinct to retention (transportation, clinic experiences, appointment scheduling), and 4 distinct to adherence (medication characteristics, pharmacy services, health literacy, health beliefs). Identified barriers/facilitators mapped to all ABM domains. These data support the use of ABM as a framework for classifying factors influencing HIV-specific health behaviors and have the potential to inform the design of interventions to improve retention in care and ART adherence. C1 [Holtzman, Carol W.] Temple Univ, Sch Pharm, Dept Pharm Practice, Philadelphia, PA 19122 USA. [Shea, Judy A.; Gross, Robert; Hines, Janet; Mounzer, Karam; Yehia, Baligh R.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Glanz, Karen; Gross, Robert] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Sch Nursing, Dept Biobehav Hlth Sci, Philadelphia, PA 19104 USA. [Jacobs, Lisa M.] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gross, Robert] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA USA. [Mounzer, Karam] Philadelphia FIGHT, Jonathan Lax Ctr, Philadelphia, PA USA. [Samuel, Rafik] Temple Univ, Sch Med, Dept Med, Philadelphia, PA 19122 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Holtzman, CW (reprint author), Temple Univ, Sch Pharm, Dept Pharm Practice, Philadelphia, PA 19122 USA. EM carolholtzman@gmail.com FU National Institutes of Health [K23-MH097647, P30-AI045008] FX This work was supported by the National Institutes of Health [grant number K23-MH097647], [grant number P30-AI045008]. NR 40 TC 8 Z9 8 U1 6 U2 37 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD JUL 3 PY 2015 VL 27 IS 7 BP 817 EP 828 DI 10.1080/09540121.2015.1009362 PG 12 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA CG7KP UT WOS:000353482500002 PM 25671515 ER PT J AU Xiang, M Kuperberg, G AF Xiang, Ming Kuperberg, Gina TI Reversing expectations during discourse comprehension SO LANGUAGE COGNITION AND NEUROSCIENCE LA English DT Article DE concessive connectives; ERP; discourse processing; P600; prediction; N400; late negativity; event structures ID EVENT-RELATED POTENTIALS; SPOKEN LANGUAGE COMPREHENSION; PROPOSITIONAL TRUTH-VALUE; LATENT SEMANTIC ANALYSIS; BRAIN POTENTIALS; SENTENCE COMPREHENSION; EYE-MOVEMENTS; COUNTERFACTUAL WORLDS; CONTINUOUS SPEECH; WORD RECOGNITION AB In two event-related potential experiments, we asked whether comprehenders used the concessive connective, even so, to predict upcoming events. Participants read coherent and incoherent scenarios, with and without even so, e.g. 'Elizabeth had a history exam on Monday. She took the test and aced/failed it. (Even so), she went home and celebrated wildly', as they rated coherence (Experiment 1) or simply answered intermittent comprehension questions (Experiment 2). The semantic function of even so was used to reverse real-world knowledge predictions, leading to an attenuated N400 to coherent versus incoherent target words ('celebrated'). Moreover, its pragmatic communicative function enhanced predictive processing, leading to more N400 attenuation to coherent targets in scenarios with than without even so. This benefit however, did not come for free: the detection of failed event predictions triggered a later posterior positivity and/or an anterior negativity effect, and costs of maintaining alternative likelihood relations manifest as a sustained negativity effect on sentence-final words. C1 [Xiang, Ming] Univ Chicago, Dept Linguist, Language & Proc Lab, Chicago, IL 60615 USA. [Kuperberg, Gina] Tufts Univ, Dept Psychol, Neurocognit Lab, Medford, MA 02155 USA. [Kuperberg, Gina] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. RP Xiang, M (reprint author), Univ Chicago, Dept Linguist, Language & Proc Lab, Chicago, IL 60615 USA. EM mxiang@uchicago.edu FU National Institute of Mental Health [R01MH071635] FX This work was funded by the National Institute of Mental Health (R01MH071635 to G.R.K.). NR 109 TC 6 Z9 6 U1 5 U2 30 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 2327-3798 EI 2327-3801 J9 LANG COGN NEUROSCI JI Lang. Cogn. Neurosci. PD JUL 3 PY 2015 VL 30 IS 6 BP 648 EP 672 DI 10.1080/23273798.2014.995679 PG 25 WC Audiology & Speech-Language Pathology; Behavioral Sciences; Linguistics; Psychology, Experimental SC Audiology & Speech-Language Pathology; Behavioral Sciences; Linguistics; Psychology GA CG6OE UT WOS:000353420700002 PM 25914891 ER PT J AU Williams, BR Wang, MQ Holt, CL Schulz, E Clark, EM AF Williams, Beverly Rosa Wang, Min Qi Holt, Cheryl L. Schulz, Emily Clark, Eddie M. TI Social Integration and Health Insurance Status Among African American Men and Women SO JOURNAL OF WOMEN & AGING LA English DT Article DE spiritual identity; health insurance; religiosity; African Americans; conjugal unit ID OLDER WOMEN; GENDER-DIFFERENCES; RACIAL INEQUITIES; PERCEIVED HEALTH; BLACK-WOMEN; LATE-LIFE; CARE; AGE; RETIREMENT; COMMUNITY AB Using 2010 national data, we investigate the relationship between social integration and health insurance for African American adults. During the previous year 21.6% of men and 19.8% of women lacked continuous health insurance. The effect of marital status, income, and employment on insurance coverage differed by age and gender. Additionally, frequency of church attendance was positively associated with continuous health insurance for women aged 51-64. Spiritual/religious identity was marginally associated with insurance status for men aged 36-50. As provisions of the Affordable Care Act take effect, implementation programs should expand enrollment efforts to include the conjugal unit and the church. C1 [Williams, Beverly Rosa] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Williams, Beverly Rosa] Univ Alabama Birmingham, Comprehens Ctr Hlth Aging, Birmingham, AL USA. [Wang, Min Qi; Holt, Cheryl L.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, College Pk, MD 20742 USA. [Schulz, Emily] AT Still Univ, Sch Hlth Sci, Dept Occupat Therapy, Mesa, AZ USA. [Clark, Eddie M.] St Louis Univ, Dept Psychol, St Louis, MO 63103 USA. RP Williams, BR (reprint author), 700 South 19th St,11-G, Birmingham, AL 35233 USA. EM bwilliams@aging.uab.edu FU Duke University Center for Spirituality, Theology, and Health through John Templeton Foundation [11993] FX This work was supported by a grant from the Duke University Center for Spirituality, Theology, and Health, through the John Templeton Foundation (#11993) and was approved by the University of Maryland Institutional Review Board (#08-0329). NR 93 TC 1 Z9 1 U1 6 U2 19 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0895-2841 EI 1540-7322 J9 J WOMEN AGING JI J. Women Aging PD JUL 3 PY 2015 VL 27 IS 3 BP 195 EP 215 DI 10.1080/08952841.2014.933635 PG 21 WC Gerontology; Women's Studies SC Geriatrics & Gerontology; Women's Studies GA CF9KB UT WOS:000352882500002 PM 25607717 ER PT J AU McNeish, J Gardner, JP Wainger, BJ Woolf, CJ Eggan, K AF McNeish, John Gardner, Jason P. Wainger, Brian J. Woolf, Clifford J. Eggan, Kevin TI From Dish to Bedside: Lessons Learned While Translating Findings from a Stem Cell Model of Disease to a Clinical Trial SO CELL STEM CELL LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; DRUG DISCOVERY; MOTOR-NEURONS; HYPEREXCITABILITY; PATIENT AB While iPSCs have created unprecedented opportunities for drug discovery, there remains uncertainty concerning the path to the clinic for candidate therapeutics discovered with their use. Here we share lessons that we learned, and believe are generalizable to similar efforts, while taking a discovery made using iPSCs into a clinical trial. C1 [McNeish, John; Gardner, Jason P.] GlaxoSmithKline, Regenerat Med Discovery Performance Unit, Cambridge, MA 02139 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Wainger, Brian J.; Woolf, Clifford J.; Eggan, Kevin] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Woolf, Clifford J.] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Woolf, Clifford J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Eggan, Kevin] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Eggan, Kevin] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Eggan, Kevin] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. RP McNeish, J (reprint author), GlaxoSmithKline, Regenerat Med Discovery Performance Unit, Cambridge, MA 02139 USA. EM john.d.mcneish@gsk.com; eggan@mcb.harvard.edu FU Howard Hughes Medical Institute; NINDS NIH HHS [R01 NS038253] NR 9 TC 11 Z9 11 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 2 PY 2015 VL 17 IS 1 BP 8 EP 10 DI 10.1016/j.stem.2015.06.013 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA CS2DI UT WOS:000361877600004 PM 26140603 ER PT J AU Trynka, G Westra, HJ Slowikowski, K Hu, XL Xu, H Stranger, BE Klein, RJ Han, B Raychaudhuri, S AF Trynka, Gosia Westra, Harm-Jan Slowikowski, Kamil Hu, Xinli Xu, Han Stranger, Barbara E. Klein, Robert J. Han, Buhm Raychaudhuri, Soumya TI Disentangling the Effects of Colocalizing Genomic Annotations to Functionally Prioritize Non-coding Variants within Complex-Trait Loci SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DISEASE ASSOCIATIONS; SUSCEPTIBILITY LOCI; CELL-TYPES; CHIP-SEQ; EXPRESSION; CANCER; RISK; DNA; IDENTIFICATION AB Identifying genomic annotations that differentiate causal from trait-associated variants is essential to fine mapping disease loci. Although many studies have identified non-coding functional annotations that overlap disease-associated variants, these annotations often colocalize, complicating the ability to use these annotations for fine mapping causal variation. We developed a statistical approach (Genomic Annotation Shifter [GoShifter]) to assess whether enriched annotations are able to prioritize causal variation. Go Shifter defines the null distribution of an annotation overlapping an allele by locally shifting annotations; this approach is less sensitive to biases arising from local genomic structure than commonly used enrichment methods that depend on SNP matching. Local shifting also allows Go Shifter to identify independent causal effects from colocalizing annotations. Using Go Shifter, we confirmed that variants in expression quantitative trail loci drive gene-expression changes though DNase-I hypersensitive sites (DHSs) near transcription start sites and independently through 3' UTR regulation. We also showed that (1) 15%-36% of trait-associated loci map to DHSs independently of other annotations; (2) loci associated with breast cancer and rheumatoid arthritis harbor potentially causal variants near the summits of histone marks rather than full peak bodies; (3) variants associated with height are highly enriched in embryonic stem cell DHSs; and (4) we can effectively prioritize causal variation at specific loci. C1 [Trynka, Gosia; Westra, Harm-Jan; Slowikowski, Kamil; Hu, Xinli; Han, Buhm; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02446 USA. [Trynka, Gosia; Westra, Harm-Jan; Slowikowski, Kamil; Hu, Xinli; Han, Buhm; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02446 USA. [Trynka, Gosia; Westra, Harm-Jan; Slowikowski, Kamil; Hu, Xinli; Han, Buhm; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Boston, MA 02446 USA. [Trynka, Gosia; Westra, Harm-Jan; Slowikowski, Kamil; Hu, Xinli; Han, Buhm; Raychaudhuri, Soumya] Partners Ctr Personalized Genet Med, Boston, MA 02446 USA. [Trynka, Gosia; Westra, Harm-Jan; Slowikowski, Kamil; Hu, Xinli; Han, Buhm; Raychaudhuri, Soumya] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Trynka, Gosia] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Slowikowski, Kamil] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA. [Hu, Xinli] Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [Xu, Han] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Xu, Han] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Stranger, Barbara E.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Stranger, Barbara E.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Klein, Robert J.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Han, Buhm] Asan Med Ctr, Asan Inst Life Sci, Seoul 138736, South Korea. [Han, Buhm] Univ Ulsan, Coll Med, Dept Med, Seoul 138736, South Korea. [Raychaudhuri, Soumya] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England. RP Raychaudhuri, S (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02446 USA. EM soumya@broadinstitute.org OI Stranger, Barbara/0000-0001-9021-7331 FU NIH [NIAMS-1R01AR063759, 1UH2AR067677-01, 1U19AI111224-01, NHGRI-1U01HG0070033]; Doris Duke Clinical Scientist Development Award; Rubicon grant from the Netherlands Organization for Scientific Research; Wellcome Trust Sanger Institute [WT098051] FX We acknowledge the GIANT consortium for providing us access to the height SNPs. We also acknowledge Joel Hirschhorn, X. Shirley Liu, Mark Daly, Tonu Esko, Dorothee Diogo, and Joshua Randall for helpful scientific discussions. This work was supported by funding from the NIH (NIAMS-1R01AR063759 [S.R.], 1UH2AR067677-01 [S.R.], 1U19AI111224-01 [S.R.], and NHGRI-1U01HG0070033 [R.J.K.]), a Doris Duke Clinical Scientist Development Award (S.R.), the Rubicon grant from the Netherlands Organization for Scientific Research (G.T.), and the Wellcome Trust Sanger Institute (WT098051 [G.T.]). NR 60 TC 19 Z9 20 U1 1 U2 4 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 JUL 2 PY 2015 VL 97 IS 1 BP 139 EP 152 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CN1OO UT WOS:000358189500012 PM 26140449 ER PT J AU Brand, H Collins, RL Hanscom, C Rosenfeld, JA Pillalamarri, V Stone, MR Kelley, F Mason, T Margolin, L Eggert, S Mitchell, E Hodge, JC Gusella, JF Sanders, SJ Talkowski, ME AF Brand, Harrison Collins, Ryan L. Hanscom, Carrie Rosenfeld, Jill A. Pillalamarri, Vamsee Stone, Matthew R. Kelley, Fontina Mason, Tamara Margolin, Lauren Eggert, Stacey Mitchell, Elyse Hodge, Jennelle C. Gusella, James F. Sanders, Stephan J. Talkowski, Michael E. TI Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COPY NUMBER VARIATION; AUTISM SPECTRUM DISORDERS; CHROMOSOMAL MICROARRAY; REVEALS; GENOME; REARRANGEMENTS; GENES; IDENTIFICATION; POPULATION; DISCOVERY AB Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome. One remarkably common class of complex rearrangement, which we term dupINVdup, involves two closely located duplications ("paired duplications") that flank the breakpoints of an inversion. This complex variant class is cryptic to CMA, but we observed it in 8.1% of all subjects. We also detected other paired-duplication signatures and duplication-mediated complex rearrangements in 15.8% of all ASD subjects. Breakpoint analysis showed that the predominant mechanism of formation of these complex duplication-associated variants was microhomology-mediated repair. On the basis of the striking prevalence of dupINVdups in this cohort, we explored the landscape of all inversion variation among the 235 highest-quality libraries and found abundant complexity among these variants: only 39.3% of inversions were canonical, or simple, inversions without additional rearrangement. Collectively, these findings indicate that dupINVdups, as well as other complex duplication-associated rearrangements, represent relatively common sources of genomic variation that is cryptic to population-based microarray and low-depth whole-genome sequencing. They also suggest that paired-duplication signatures detected by CMA warrant further scrutiny in genetic diagnostic testing given that they might mark complex rearrangements of potential clinical relevance. C1 [Brand, Harrison; Collins, Ryan L.; Hanscom, Carrie; Pillalamarri, Vamsee; Stone, Matthew R.; Eggert, Stacey; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Brand, Harrison; Collins, Ryan L.; Hanscom, Carrie; Pillalamarri, Vamsee; Stone, Matthew R.; Eggert, Stacey; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Brand, Harrison; Talkowski, Michael E.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Rosenfeld, Jill A.] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA. [Kelley, Fontina; Mason, Tamara; Margolin, Lauren; Gusella, James F.; Talkowski, Michael E.] Broad Inst Harvard & MIT, Program Med & Populat Genet & Genom Platform, Cambridge, MA 02141 USA. [Mitchell, Elyse; Hodge, Jennelle C.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Hodge, Jennelle C.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sanders, Stephan J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94103 USA. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. EM talkowski@chgr.mgh.harvard.edu OI Sanders, Stephan/0000-0001-9112-5148; Collins, Ryan/0000-0003-1268-9995 FU Simons Foundation for Autism Research [SFARI 238504]; Nancy Lurie Marks Family Foundation; March of Dimes; Charles Hood Foundation; Brain & Behavioral Research Foundation; National Institute of Mental Health [R00MH095867, GM061354]; National Institute of Child Health and Human Development [HD007396] FX We are grateful to all of the families at the participating Simons Simplex Collection sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Kiln, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We also thank Matthew State, Bernie Devlin, and Kathryn Roeder for contributing to the generation and analysis of the microarray copy-number-variant data and Patricia Greipp for coordinating efforts at the Mayo Clinic. We thank Dr. Lisa Shaffer, formerly of Signature Genomics, and Dr. Yiping Shen of Boston Children's Hospital for making the clinical diagnostic chromosomal-microarray data available to us. This work was supported by funding from the Simons Foundation for Autism Research (SFARI 238504), the Nancy Lurie Marks Family Foundation, the March of Dimes, the Charles Hood Foundation, the Brain & Behavioral Research Foundation, and the National Institute of Mental Health (R00MH095867 and GM061354) to M.E.T. H.B. is supported by a T32 fellowship from the National Institute of Child Health and Human Development (HD007396). NR 32 TC 6 Z9 6 U1 1 U2 8 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 JUL 2 PY 2015 VL 97 IS 1 BP 170 EP 176 DI 10.1016/j.ajhg.2015.05.012 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA CN1OO UT WOS:000358189500015 PM 26094575 ER PT J AU Prudente, S Jungtrakoon, P Marucci, A Ludovico, O Buranasupkajorn, P Mazza, T Hastings, T Milano, T Morini, E Mercuri, L Bailetti, D Mendonca, C Alberico, F Basile, G Romani, M Miccinilli, E Pizzuti, A Carella, M Barbetti, F Pascarella, S Marchetti, P Trischitta, V Di Paola, R Doria, A AF Prudente, Sabrina Jungtrakoon, Prapaporn Marucci, Antonella Ludovico, Ornella Buranasupkajorn, Patinut Mazza, Tommaso Hastings, Timothy Milano, Teresa Morini, Eleonora Mercuri, Luana Bailetti, Diego Mendonca, Christine Alberico, Federica Basile, Giorgio Romani, Marta Miccinilli, Elide Pizzuti, Antonio Carella, Massimo Barbetti, Fabrizio Pascarella, Stefano Marchetti, Piero Trischitta, Vincenzo Di Paola, Rosa Doria, Alessandro TI Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INSULIN-SECRETION; ENDOPLASMIC-RETICULUM; GLUCOSE-HOMEOSTASIS; MEMBRANE CURVATURE; GENE; INHIBITION; GENERATION; DOMAINS; DISEASE; YOUNG AB Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552*] and c.280G>A [p.Asp94Asnp]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552* alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3 beta phosphorylation that is observed after wild-type APPL1 transfection. These findings-linking APPL1 mutations to familial forms of diabetes-reaffirm the critical role of APPL1 in glucose homeostasis. C1 [Prudente, Sabrina; Mazza, Tommaso; Mercuri, Luana; Bailetti, Diego; Alberico, Federica; Basile, Giorgio; Romani, Marta; Miccinilli, Elide; Pizzuti, Antonio; Trischitta, Vincenzo] IRCCS Casa Sollievo Sofferenza, Mendel Lab, I-71013 San Giovanni Rotondo, Italy. [Jungtrakoon, Prapaporn; Buranasupkajorn, Patinut; Hastings, Timothy; Mendonca, Christine; Doria, Alessandro] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Jungtrakoon, Prapaporn; Buranasupkajorn, Patinut; Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Marucci, Antonella; Ludovico, Ornella; Morini, Eleonora; Trischitta, Vincenzo; Di Paola, Rosa] IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, I-71013 San Giovanni Rotondo, Italy. [Milano, Teresa; Pascarella, Stefano] Univ Roma La Sapienza, Dept Biochem Sci, I-00185 Rome, Italy. [Bailetti, Diego; Basile, Giorgio; Pizzuti, Antonio; Trischitta, Vincenzo] Univ Roma La Sapienza, Dept Expt Med, I-00161 Rome, Italy. [Carella, Massimo] IRCCS Casa Sollievo Sofferenza, Unit Med Genet, I-71013 San Giovanni Rotondo, Italy. [Barbetti, Fabrizio] Bambino Gesu Pediat Hosp, Lab Mendelian Diabet, I-00165 Rome, Italy. [Barbetti, Fabrizio] Univ Roma Tor Vergata, Dept Expt Med & Surg, I-00133 Rome, Italy. [Marchetti, Piero] Univ Pisa, Dept Clin & Expt Med, I-56127 Pisa, Italy. RP Prudente, S (reprint author), IRCCS Casa Sollievo Sofferenza, Mendel Lab, I-71013 San Giovanni Rotondo, Italy. EM s.prudente@css-mendel.it; alessandro.doria@joslin.harvard.edu RI Marchetti, Piero/J-7439-2013; Prudente, Sabrina/H-2886-2016; Di Paola, Rosa/G-7813-2011; Trischitta, Vincenzo/K-1487-2016; marucci, antonella/B-8722-2017; Mazza, Tommaso/H-6414-2016 OI Marchetti, Piero/0000-0003-4907-0635; Prudente, Sabrina/0000-0001-9220-8981; Di Paola, Rosa/0000-0001-5837-9111; Trischitta, Vincenzo/0000-0003-1174-127X; marucci, antonella/0000-0001-8131-8317; Mazza, Tommaso/0000-0003-0434-8533 FU Italian Society of Diabetology (SID) [FO.RI.SID 2011]; NIH [R01DK55523, P30 DK036836]; Italian Ministry of Health FX We wish to thank the subjects and families involved in the study. This work was supported by the Italian Society of Diabetology (SID) (grant FO.RI.SID 2011 to S. Prudente), NIH (grant R01DK55523 to A.D. and P30 DK036836 to the Joslin Diabetes Research Center [Advanced Genomics and Genetics Core]), and the Italian Ministry of Health (Ricerca Corrente 2014 and 2015 to S. Prudente, R.D.P., and V.T.). NR 35 TC 12 Z9 13 U1 1 U2 14 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 JUL 2 PY 2015 VL 97 IS 1 BP 177 EP 185 DI 10.1016/j.ajhg.2015.05.011 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA CN1OO UT WOS:000358189500016 PM 26073777 ER PT J AU Perotti, EA Georgopoulos, K Yoshida, T AF Perotti, Elizabeth A. Georgopoulos, Katia Yoshida, Toshimi TI An Ikaros Promoter Element with Dual Epigenetic and Transcriptional Activities SO PLOS ONE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHROMATIN REMODELER MI-2-BETA; DNA-BINDING PROTEINS; T-CELL DEVELOPMENT; LYMPHOCYTE DEVELOPMENT; GENE-EXPRESSION; LINEAGE COMMITMENT; GENOME-WIDE; COMPLEX; DIFFERENTIATION AB Ikaros DNA binding factor plays critical roles in lymphocyte development. Changes in Ikaros expression levels during lymphopoiesis are controlled by redundant but also unique regulatory elements of its locus that are critical for this developmental process. We have recently shown that Ikaros binds its own locus in thymocytes in vivo. Here, we evaluated the role of an Ikaros binding site within its major lympho-myeloid promoter. We identified an Ikaros/Ets binding site within a promoter sub-region that was highly conserved in mouse and human. Deletion of this binding site increased the percentage of the reporter-expressing mouse lines, indicating that its loss provided a more permissive chromatin environment. However, once transcription was established, the lack of this site decreased transcriptional activity. These findings implicate a dual role for Ikaros/Ets1 binding on Ikzf1 expression that is exerted at least through its promoter. C1 [Perotti, Elizabeth A.; Georgopoulos, Katia; Yoshida, Toshimi] Harvard Univ, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Sch Med, Charlestown, MA 02129 USA. RP Yoshida, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Sch Med, Charlestown, MA 02129 USA. EM toshimi.yoshida@cbrc2.mgh.harvard.edu FU National Institute of Health [537 R01 AI33062, 9R01CA162092-19, 5R01CA162092-22] FX Funding provided by the National Institute of Health, http://www.nih.gov/, 537 R01 AI33062 to KG, 9R01CA162092- 19 to KG, 5R01CA162092-22 to KG. NR 38 TC 1 Z9 1 U1 1 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 JUL 2 PY 2015 VL 10 IS 7 AR e0131568 DI 10.1371/journal.pone.0131568 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1CS UT WOS:000358154400056 PM 26135129 ER PT J AU Subbian, S Tsenova, L Kim, MJ Wainwright, HC Visser, A Bandyopadhyay, N Bader, JS Karakousis, PC Murrmann, GB Bekker, LG Russell, DG Kaplan, G AF Subbian, Selvakumar Tsenova, Liana Kim, Mi-Jeong Wainwright, Helen C. Visser, Annalie Bandyopadhyay, Nirmalya Bader, Joel S. Karakousis, Petros C. Murrmann, Gabriele B. Bekker, Linda-Gail Russell, David G. Kaplan, Gilla TI Lesion-Specific Immune Response in Granulomas of Patients with Pulmonary Tuberculosis: A Pilot Study SO PLOS ONE LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; ACTIVE TUBERCULOSIS; MATRIX METALLOPROTEINASES; TISSUE INHIBITORS; CAVITARY TUBERCULOSIS; T-CELLS; EXPRESSION; INFECTION; OSTEOPONTIN; DISEASE AB The formation and maintenance of granulomas is central to the host response to Mycobacterium tuberculosis (Mtb) infection. It is widely accepted that the lungs of patients with tuberculosis (TB) usually contain multiple infection foci, and that the granulomas evolve and differentiate independently, resulting in considerable heterogeneity. Although gene expression profiles of human blood cells have been proposed as biomarkers of Mtb infection and/or active disease, the immune profiles of discrete lesion types has not been studied extensively. Using histology, immunopathology and genome-wide transcriptome analysis, we explored the immunological profile of human lung TB granulomas. We show that although the different granulomas share core similarities in their immunological/inflammatory characteristics, they also exhibit significant divergence. Despite similar numbers of CD68(+) macrophages in the different lesions, the extent of immune reactivity, as determined by the density of CD3(+) T cells in the macrophage rich areas, and the extent of fibrosis, shows considerable variation. Both quantitative and qualitative differences among significantly differentially expressed genes (SDEG) were noted in each of the lesion types studied. Further, network/pathway analysis of SDEG revealed differential regulation of inflammatory response, immune cell trafficking, and cell mediated immune response in the different lesions. Our data highlight the formidable challenges facing ongoing efforts to identify peripheral blood biomarkers due to the diversity of lesion types and complexity of local immune responses in the lung. C1 [Subbian, Selvakumar; Tsenova, Liana] Rutgers State Univ, Rutgers Biomed & Hlth Sci, PHRI, Lab Mycobacterial Immun & Pathogenesis, Newark, NJ 07102 USA. [Tsenova, Liana] NYC Coll Technol, Dept Biol Sci, Brooklyn, NY USA. [Kim, Mi-Jeong] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Immunobiol, Boston, MA 02115 USA. [Wainwright, Helen C.; Visser, Annalie] Univ Cape Town, Fac Hlth Sci, Div Anat Pathol, ZA-7925 Cape Town, South Africa. [Bandyopadhyay, Nirmalya; Bader, Joel S.] Johns Hopkins Univ, High Throughput Biol Ctr, Dept Biomed Engn, Baltimore, MD USA. [Bandyopadhyay, Nirmalya; Bader, Joel S.] Johns Hopkins Univ, Inst Computat Med, Baltimore, MD USA. [Karakousis, Petros C.] Johns Hopkins Univ, Sch Med, Dept Med, Ctr TB Res, Baltimore, MD 21205 USA. [Karakousis, Petros C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Murrmann, Gabriele B.] Med Ctr Leeuwarden, Dept Gen & Thorac Surg, Leeuwarden, Netherlands. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [Russell, David G.] Cornell Univ, Coll Vet Med, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. [Kaplan, Gilla] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Subbian, S (reprint author), Rutgers State Univ, Rutgers Biomed & Hlth Sci, PHRI, Lab Mycobacterial Immun & Pathogenesis, Newark, NJ 07102 USA. EM subbiase@njms.rutgers.edu RI Russell, David/D-4533-2009 FU National Institute of Health [AI067027, HL055936, AI054338] FX This work was supported by grants from the National Institute of Health to DGR (AI067027 and HL055936) and GK (AI054338). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 12 Z9 12 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2015 VL 10 IS 7 AR e0132249 DI 10.1371/journal.pone.0132249 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CN1CS UT WOS:000358154400108 PM 26133981 ER PT J AU Steensma, DP Bejar, R Jaiswal, S Lindsley, RC Sekeres, MA Hasserjian, RP Ebert, BL AF Steensma, David P. Bejar, Rafael Jaiswal, Siddhartha Lindsley, R. Coleman Sekeres, Mikkael A. Hasserjian, Robert P. Ebert, Benjamin L. TI Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MINIMAL DIAGNOSTIC-CRITERIA; BONE-MARROW DYSPLASIA; B-CELL LYMPHOCYTOSIS; RING SIDEROBLASTS; CYTOGENETIC ABNORMALITIES; REFRACTORY-ANEMIA; STEM-CELL; UNDETERMINED SIGNIFICANCE; SIGNIFICANCE IDUS AB Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies. C1 [Steensma, David P.; Lindsley, R. Coleman] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02215 USA. [Steensma, David P.; Lindsley, R. Coleman] Brigham & Womens Hosp, Boston, MA 02215 USA. [Bejar, Rafael] Univ Calif San Diego, Div Hematol Oncol, Moores Canc Ctr, La Jolla, CA 92093 USA. [Jaiswal, Siddhartha; Ebert, Benjamin L.] Brigham & Womens Hosp, Div Hematol, Dept Med, Boston, MA 02215 USA. [Sekeres, Mikkael A.] Cleveland Clin, Taussig Canc Inst, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44106 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM david_steensma@dfci.harvard.edu FU Edward P. Evans Foundation FX D.P.S., B.L.E., M.A.S., R.C.L., and R.B. acknowledge support from the Edward P. Evans Foundation. NR 83 TC 96 Z9 100 U1 3 U2 17 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 JUL 2 PY 2015 VL 126 IS 1 BP 9 EP 16 DI 10.1182/blood-2015-03-631747 PG 8 WC Hematology SC Hematology GA CM4ZR UT WOS:000357696200006 PM 25931582 ER PT J AU Larkin, J Chiarion-Sileni, V Gonzalez, R Grob, JJ Cowey, CL Lao, CD Schadendorf, D Dummer, R Smylie, M Rutkowski, P Ferrucci, PF Hill, A Wagstaff, J Carlino, MS Haanen, JB Maio, M Marquez-Rodas, I McArthur, GA Ascierto, PA Long, GV Callahan, MK Postow, MA Grossmann, K Sznol, M Dreno, B Bastholt, L Yang, A Rollin, LM Horak, C Hodi, FS Wolchok, JD AF Larkin, J. Chiarion-Sileni, V. Gonzalez, R. Grob, J. J. Cowey, C. L. Lao, C. D. Schadendorf, D. Dummer, R. Smylie, M. Rutkowski, P. Ferrucci, P. F. Hill, A. Wagstaff, J. Carlino, M. S. Haanen, J. B. Maio, M. Marquez-Rodas, I. McArthur, G. A. Ascierto, P. A. Long, G. V. Callahan, M. K. Postow, M. A. Grossmann, K. Sznol, M. Dreno, B. Bastholt, L. Yang, A. Rollin, L. M. Horak, C. Hodi, F. S. Wolchok, J. D. TI Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PLUS DACARBAZINE; BRAF; SURVIVAL; VEMURAFENIB; MUTATION; TRIAL AB BACKGROUND Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.) C1 [Larkin, J.] Royal Marsden Hosp, Dept Med Oncol, London SW3 6JJ, England. [Wagstaff, J.] Singleton Hosp, South West Wales Canc Inst, Swansea SA2 8QA, W Glam, Wales. [Chiarion-Sileni, V.] Veneto Reg Oncol Res Inst, Melanoma Oncol Unit, Padua, Italy. [Ferrucci, P. F.] European Inst Oncol, Oncol Melanoma Unit, Milan, Italy. [Maio, M.] Univ Hosp Siena, Siena, Italy. [Ascierto, P. A.] Ist Nazl Tumori, Fdn Pascale, Naples, Italy. [Gonzalez, R.] Univ Colorado, Div Med Oncol, Denver, CO 80202 USA. [Grob, J. J.] Aix Marseille Univ, Hop La Timone, AP HM, Marseille, France. [Dreno, B.] Hop Hotel Dieu, Nantes, France. [Cowey, C. L.] Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Lao, C. D.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Lao, C. D.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Schadendorf, D.] Univ Essen Gesamthsch, Dept Dermatol, Essen, Germany. [Dummer, R.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Smylie, M.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. [Hill, A.] Tasman Oncol Res, Southport Gold Coast, Qld, Australia. [Carlino, M. S.] Univ Sydney, Westmead Hosp, Sydney, NSW 2006, Australia. [Carlino, M. S.] Univ Sydney, Blacktown Hosp, Sydney, NSW 2006, Australia. [Carlino, M. S.; Long, G. V.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Long, G. V.] Mater Hosp, Sydney, NSW, Australia. [McArthur, G. A.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [McArthur, G. A.] Univ Melbourne, Melbourne, Vic, Australia. [Haanen, J. B.] Netherlands Canc Inst, Div Med Oncol, Amsterdam, Netherlands. [Marquez-Rodas, I.] Hosp Gen Univ Gregorio Maranon, Med Oncol Serv, Madrid, Spain. [Callahan, M. K.; Postow, M. A.; Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr, New York, NY 10021 USA. [Callahan, M. K.; Postow, M. A.; Wolchok, J. D.] Weill Cornell Med Coll, New York, NY USA. [Grossmann, K.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Sznol, M.] Yale Univ, Sch Med, Yale New Haven Hosp, Yale Canc Ctr,Smilow Canc Hosp, New Haven, CT USA. [Bastholt, L.] Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark. [Yang, A.; Rollin, L. M.] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Horak, C.] Bristol Myers Squibb Co, Lawrenceville, NJ USA. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hodi, FS (reprint author), Royal Marsden Hosp, Dept Med Oncol, London SW3 6JJ, England. EM stephen_hodi@dfci.harvard.edu; wolchokj@mskcc.org OI coral, sandra/0000-0002-1308-3082; ferrucci, pier francesco/0000-0001-6255-5851; Rutkowski, Piotr/0000-0002-8920-5429 FU Bristol-Myers Squibb FX Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505. NR 17 TC 879 Z9 904 U1 29 U2 73 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 JUL 2 PY 2015 VL 373 IS 1 BP 23 EP 34 DI 10.1056/NEJMoa1504030 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CL8IS UT WOS:000357218700005 PM 26027431 ER PT J AU Blumenthal, DM Wasfy, JH AF Blumenthal, Daniel M. Wasfy, Jason H. TI Anatomical versus Functional Testing for Coronary Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Blumenthal, Daniel M.; Wasfy, Jason H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Blumenthal, DM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dblumenthal1@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 2 PY 2015 VL 373 IS 1 BP 90 EP 90 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CL8IS UT WOS:000357218700015 PM 26132950 ER PT J AU Douglas, PS Hoffmann, U AF Douglas, Pamela S. Hoffmann, Udo TI Anatomical versus Functional Testing for Coronary Artery Disease Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Douglas, Pamela S.] Duke Clin Res Inst, Durham, NC 27705 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Douglas, PS (reprint author), Duke Clin Res Inst, Durham, NC 27705 USA. EM pamela.douglas@duke.edu FU NHLBI NIH HHS [R01 HL098305] NR 1 TC 10 Z9 10 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 JUL 2 PY 2015 VL 373 IS 1 BP 91 EP 91 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CL8IS UT WOS:000357218700017 PM 26132947 ER PT J AU Winter, H Gunasekaran, T Tolia, V Gottrand, F Barker, PN Illueca, M AF Winter, Harland Gunasekaran, Thirumazhisai Tolia, Vasundhara Gottrand, Frederic Barker, Peter N. Illueca, Marta TI Esomeprazole for the Treatment of GERD in Infants Ages 1-11 Months SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE efficacy; gastroesophageal reflux; pediatrics; proton pump inhibitor; safety ID GASTROESOPHAGEAL-REFLUX DISEASE; NORTH-AMERICAN-SOCIETY; PEDIATRIC-GASTROENTEROLOGY; SYMPTOMS; RECOMMENDATIONS; QUESTIONNAIRE; LANSOPRAZOLE; PREVALENCE; GUIDELINES; NUTRITION AB Objectives: Gastroesophageal reflux disease (GERD) is present in pediatric patients when reflux of gastric contents causes troublesome symptoms and/or complications. The present study evaluates the efficacy and safety of esomeprazole in infants ages 1 to 11 months with GERD. Methods: In this multicenter randomized, double-blind, placebo-controlled, parallel-group, treatment-withdrawal study, infants received open-label, weight-adjusted doses of esomeprazole (2.5-10 mg) once daily for 2 weeks. Infants with symptom improvement were randomized to esomeprazole (weight-adjusted doses [2.5-10 mg]) or placebo for 4 weeks. The primary endpoint was time to discontinuation owing to symptom worsening based on global assessments by the parent/guardian and physician. Adverse events were recorded. Results: Of the 98 patients enrolled, 81 (82.7%) experienced symptom improvement determined by physician global assessment (PGA) during open-label esomeprazole treatment; 80 entered the double-blind phase. During this phase, discontinuation rates owing to symptom worsening were 48.8% (20/41) for placebo-treated versus 38.5% (15/39) for esomeprazole-treated patients (hazard ratio 0.69; P = 0.28). Posthoc analysis of infants with symptomatic GERD (ie, no diagnostic procedure performed) revealed that time to discontinuation was significantly longer with esomeprazole than placebo (hazard ratio 0.24; P = 0.01); the complementary subgroup difference was not significant (hazard ratio 1.39; P = 0.48). Esomeprazole was well tolerated. Conclusions: The discontinuation rate owing to symptom worsening did not differ significantly between infants receiving esomeprazole versus those receiving placebo. Improved diagnostic criteria in this age group are needed to identify infants with GERD who may benefit from acid suppression therapy. C1 [Winter, Harland] MassGen Hosp Children, Boston, MA USA. [Gunasekaran, Thirumazhisai] Advocate Lutheran Gen Childrens Hosp, Esophageal Ctr, Park Ridge, IL USA. [Gunasekaran, Thirumazhisai] Loyola Univ, Med Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. [Tolia, Vasundhara] Providence Hosp, Southfield, MI 48037 USA. [Gottrand, Frederic] Jeanne de Flandre Univ Hosp, Dept Pediat Gastroenterol Hepatol & Nutr, Lille, France. [Barker, Peter N.; Illueca, Marta] AstraZeneca LP, Wilmington, DE USA. RP Winter, H (reprint author), MassGen Hosp Children, Pediat GI Unit, CRPZ 5-560,175 Cambridge St, Boston, MA 02114 USA. EM hwinter@partners.org FU AstraZeneca LP; AstraZeneca; Johnson Johnson; Centocor; Proctor Gamble FX The present study was supported by AstraZeneca LP. Medical writing and editorial services were provided by Bret Fulton, freelance medical writer, and Stella Chow, Judy Fallon, Anny Wu, and Colleen Hedge from Scientific Connexions, Newtown, PA (all funded by AstraZeneca LP).; H.W. has been a consultant and investigator for AstraZeneca, Centocor, P & G, Takeda Pharmaceuticals, UCB, Salix, and Wyeth. T.G. has received grant/research support from and is a consultant for AstraZeneca. V.T. receives grant/research support from AstraZeneca, Johnson & Johnson, Centocor, and Proctor & Gamble. F.G. has no conflicts of interest. P.N.B. and M.I. are employees of and own stock in AstraZeneca. NR 23 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JUL PY 2015 VL 60 SU 1 BP S9 EP S15 DI 10.1097/MPG.0b013e3182496b35 PG 7 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA DK2TN UT WOS:000374767400003 PM 26121349 ER PT J AU Rojas, KD Montero, ML Yao, J Messing, E Fazili, A Joseph, J Ou, YM Rubens, DJ Parker, KJ Davatzikos, C Castaneda, B AF Diaz Rojas, Kristians Montero, Maria L. Yao, Jorge Messing, Edward Fazili, Anees Joseph, Jean Ou, Yangming Rubens, Deborah J. Parker, Kevin J. Davatzikos, Christos Castaneda, Benjamin TI Methodology to study the three-dimensional spatial distribution of prostate cancer and their dependence on clinical parameters SO JOURNAL OF MEDICAL IMAGING LA English DT Article DE prostate cancer; ultrasound; prostate specific antigen; image processing; registration; spatial distribution ID DIGITAL RECTAL EXAMINATION; SHAPE-BASED INTERPOLATION; BIOPSY; MODEL; OBJECTS; IMAGES AB A methodology to study the relationship between clinical variables [e.g., prostate specific antigen (PSA) or Gleason score] and cancer spatial distribution is described. Three-dimensional (3-D) models of 216 glands are reconstructed from digital images of whole mount histopathological slices. The models are deformed into one prostate model selected as an atlas using a combination of rigid, affine, and B-spline deformable registration techniques. Spatial cancer distribution is assessed by counting the number of tumor occurrences among all glands in a given position of the 3-D registered atlas. Finally, a difference between proportions is used to compare different spatial distributions. As a proof of concept, we compare spatial distributions from patients with PSA greater and less than 5 ng/ml and from patients older and younger than 60 years. Results suggest that prostate cancer has a significant difference in the right zone of the prostate between populations with PSA greater and less than 5 ng/ml. Age does not have any impact in the spatial distribution of the disease. The proposed methodology can help to comprehend prostate cancer by understanding its spatial distribution and how it changes according to clinical parameters. Finally, this methodology can be easily adapted to other organs and pathologies. (C) 2015 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Diaz Rojas, Kristians; Castaneda, Benjamin] Pontificia Univ Catolica Peru, Dept Engn, Sect Elect & Elect, Lab Med Images, San Miguel Lima 32, Peru. [Montero, Maria L.] Pontificia Univ Catolica Peru, Dept Sci, Sect Math, Stat Lab, San Miguel Lima 32, Peru. [Yao, Jorge] Univ Rochester, Med Ctr, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Messing, Edward; Fazili, Anees; Joseph, Jean] Univ Rochester, Med Ctr, Dept Urol, Rochester, NY 14642 USA. [Ou, Yangming] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Rubens, Deborah J.] Univ Rochester, Med Ctr, Dept Imaging Sci, Rochester, NY 14642 USA. [Parker, Kevin J.] Univ Rochester, Dept Elect & Comp Engn, Hopeman Engn Bldg 203,Box 270126, Rochester, NY 14627 USA. [Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Davatzikos, Christos] Univ Penn, Dept Elect & Comp Engn, Philadelphia, PA 19104 USA. RP Parker, KJ (reprint author), Univ Rochester, Dept Elect & Comp Engn, Hopeman Engn Bldg 203,Box 270126, Rochester, NY 14627 USA. EM kevin.parker@rochester.edu OI Ou, Yangming/0000-0002-7726-6208 FU NCI NIH HHS [R01 CA104976]; NIA NIH HHS [R01 AG029804] NR 40 TC 1 Z9 1 U1 0 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-4302 EI 2329-4310 J9 J MED IMAGING JI J. Med. Imaging PD JUL-SEP PY 2015 VL 2 IS 3 AR 037502 DI 10.1117/1.JMI.2.3.037502 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DJ5GM UT WOS:000374234800015 PM 26236756 ER PT J AU Thomson, AP Foust-Wright, CE Batalden, RP Berkowitz, LR AF Thomson, Alexcis P. Foust-Wright, Caroline Elizabeth Batalden, Rebecca P. Berkowitz, Lori R. TI Levatorplasty for Symptomatic Posterior Prolapse due to Recurrent Malignant Ascites SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE malignant ascites; levatorplasty; prolapse ID ENTEROCELE AB Background Although infrequently described, massive ascites due to malignancy contributes to symptomatic pelvic organ prolapse. Case A 73-year-old woman with recurrent ovarian cancer and massive ascites underwent a levatorplasty for repair of posterior prolapse after failing conservative management. Conclusions Management of patient with cancer with prolapse is complex. Patients with cancer with ascites also have pelvic organ prolapse, in addition to other, better described sequelae of increased intra-abdominal pressure. These patients should be treated specifically for prolapse, with therapy, including type of surgery, chosen with special consideration of their underlying disease. C1 [Thomson, Alexcis P.; Foust-Wright, Caroline Elizabeth; Batalden, Rebecca P.; Berkowitz, Lori R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St,Founders 4, Boston, MA USA. RP Foust-Wright, CE (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St,Founders 4, Boston, MA USA. EM c.foustwright@gmail.com 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 2151-8378 EI 2154-4212 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD JUL-AUG PY 2015 VL 21 IS 4 BP e41 EP e43 DI 10.1097/SPV.0000000000000174 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DI4CY UT WOS:000373449100003 PM 25730437 ER PT J AU Kuczmarski, TM Raja, AS Pallin, DJ AF Kuczmarski, Thomas M. Raja, Ali S. Pallin, Daniel J. TI How do Medical Societies Select Science for Conference Presentation? How Should They? SO WESTERN JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE abstract scoring; abstract scoring criteria; reviewer bias; abstract selection; medical society abstract ID STRUCTURED METHOD; ABSTRACTS; AGREEMENT; REVIEWER AB Introduction: Nothing has been published to describe the practices of medical societies in choosing abstracts for presentations at their annual meetings. We surveyed medical societies to determine their practices, and also present a theoretical analysis of the topic. Methods: We contacted a convenience sample of large U.S. medical conferences, and determined their approach to choosing abstracts. We obtained information from web sites, telephone, and email. Our theoretical analysis compares values-based and empirical approaches for scoring system development. Results: We contacted 32 societies and obtained data on 28 (response rate 88%). We excluded one upon learning that research was not presented at its annual meeting, leaving 27 for analysis. Only 2 (7%) made their abstract scoring process available to submitters. Reviews were blinded in most societies (21;78%), and all but one asked reviewers to recuse themselves for conflict of interest (96%). All required reviewers. Of the 24 providing information on how scores were generated, 21 (88%) reported using a single gestalt score, and three used a combined score created from pooled domain-specific sub-scores. We present a framework for societies to use in choosing abstracts, and demonstrate its application in the development of a new scoring system. Conclusions: Most medical societies use subjective, gestalt methods to select research for presentation at their annual meetings and do not disclose to submitters the details of how abstracts are chosen. We present a new scoring system that is transparent to submitters and reviewers alike with an accompanying statement of values and ground rules. We discuss the challenges faced in selecting abstracts fora large scientific meeting and share the values and practical considerations that undergird the new system. C1 [Kuczmarski, Thomas M.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Pallin, Daniel J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. RP Pallin, DJ (reprint author), Brigham & Womens Hosp, Emergency Dept, 75 Francis St, Boston, MA 02115 USA. EM dpallin@partners.org OI Pallin, Daniel/0000-0002-8517-9702 NR 11 TC 1 Z9 1 U1 0 U2 0 PU WESTJEM PI ORANGE PA C/O SHAHRAM LOTFIPOUR, MD, MPH, 333 CITY BLVD W STE 640, RT 128-01, ORANGE, CA 92868 USA SN 1936-900X EI 1936-9018 J9 WEST J EMERG MED JI West. J. Emerg. Med. PD JUL PY 2015 VL 16 IS 4 BP 543 EP 550 DI 10.5811/westjem.2015.5.25518 PG 8 WC Emergency Medicine SC Emergency Medicine GA DH9LG UT WOS:000373117000008 PM 26265966 ER PT J AU Saini, N Saini, V Kumar, V Bhatia, A Qazi, S AF Saini, N. Saini, V Kumar, V Bhatia, A. Qazi, S. TI 18F-FDG positron emission tomography scan findings in a case of rituximab-CHOP-induced pneumonitis SO INDIAN JOURNAL OF CANCER LA English DT Letter ID LYMPHOMA C1 [Saini, N.; Qazi, S.] North Shore Med Ctr, Dept Internal Med, Salem, OR USA. [Saini, V] Massachusetts Gen Hosp, Simches Res Ctr, Boston, MA 02114 USA. [Kumar, V] Pravara Inst Med Sci, Dept Internal Med, Ahmednagar, Maharashtra, India. [Bhatia, A.] Kimmel Canc Ctr, Dept Med Oncol, Philadelphia, PA USA. RP Saini, N (reprint author), North Shore Med Ctr, Dept Internal Med, Salem, OR USA. EM lymphomalogy@gmail.com NR 3 TC 0 Z9 0 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0019-509X EI 1998-4774 J9 INDIAN J CANCER JI Indian J. Cancer PD JUL-SEP PY 2015 VL 52 IS 3 BP 437 EP 438 DI 10.4103/0019-509X.176738 PG 2 WC Oncology SC Oncology GA DF8TH UT WOS:000371631600061 PM 26905161 ER PT J AU Kottakis, F Nicolay, BN Julia, NM Liesa, M Sirihai, OS Dyson, NJ Bardeesy, N AF Kottakis, Filippos Nicolay, Brandon N. Julia, Nagle M. Liesa, Marc Sirihai, Orian S. Dyson, Nicholas J. Bardeesy, Nabeel TI Metabolic changes, associated with loss of the tumor suppressor LKB1, promote tumorigenesis SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Kottakis, Filippos; Nicolay, Brandon N.; Julia, Nagle M.; Dyson, Nicholas J.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Liesa, Marc; Sirihai, Orian S.] Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA B42 DI 10.1158/1538-7445.PANCA2014-B42 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900123 ER PT J AU Kugel, S Sebastian, C Perera, RM Bardeesy, N Mostoslavsky, R AF Kugel, Sita Sebastian, Carlos Perera, Rushika M. Bardeesy, Nabeel Mostoslavsky, Raul TI The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Kugel, Sita; Sebastian, Carlos; Perera, Rushika M.; Bardeesy, Nabeel; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA B44 DI 10.1158/1538-7445.PANCA2014-B44 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900124 ER PT J AU Liss, AS Nahar, S Mertz, JA Bryant, B Sims, RJ Fernandez-del Castillo, C Lillemoe, KD Warshaw, AL Thayer, SP AF Liss, Andrew S. Nahar, Sabikun Mertz, Jennifer A. Bryant, Barbara Sims, Robert J., III Fernandez-del Castillo, Carlos Lillemoe, Keith D. Warshaw, Andrew L. Thayer, Sarah P. TI BET proteins are key mediators of pancreatic cancer cell growth and its tumor microenvironment SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Liss, Andrew S.; Nahar, Sabikun; Fernandez-del Castillo, Carlos; Lillemoe, Keith D.; Warshaw, Andrew L.; Thayer, Sarah P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mertz, Jennifer A.; Bryant, Barbara; Sims, Robert J., III] Constellat Pharmaceut, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA B107 DI 10.1158/1538-7445.PANCA2014-B107 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900095 ER PT J AU Lyssiotis, CA Son, J Mancias, JD Ying, HQ Cantley, LC Kimmelman, AC AF Lyssiotis, Costas A. Son, Jaekyoung Mancias, Joesph D. Ying, Haoqiang Cantley, Lewis C. Kimmelman, Alec C. TI Pancreatic cancers depend on a non-canonical glutamine metabolism pathway SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Lyssiotis, Costas A.; Cantley, Lewis C.] Weill Cornell Med Coll, New York, NY USA. [Son, Jaekyoung; Mancias, Joesph D.; Kimmelman, Alec C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ying, Haoqiang] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA B45 DI 10.1158/1538-7445.PANCA2014-B45 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900125 ER PT J AU Viale, A Pettazzoni, P Lyssiotis, C Ying, HQ Sanchez, N Marchesini, M Carugo, A Green, T Seth, S Giuliani, V Heffernan, T Kimmelman, A Wang, H Fleming, J Cantley, L DePinho, R Draetta, G AF Viale, Andrea Pettazzoni, Piergiorgio Lyssiotis, Costas Ying, Haoqiang Sanchez, Nora Marchesini, Matteo Carugo, Alessandro Green, Tessa Seth, Sahil Giuliani, Virginia Heffernan, Timothy Kimmelman, Alec Wang, Huamin Fleming, Jason Cantley, Lewis DePinho, Ronald Draetta, Giulio TI Pancreatic tumor stem cells resistant to inhibition of oncogenic signaling are dependent on mitochondrial function SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Viale, Andrea; Pettazzoni, Piergiorgio; Ying, Haoqiang; Sanchez, Nora; Marchesini, Matteo; Carugo, Alessandro; Green, Tessa; Wang, Huamin; Fleming, Jason; DePinho, Ronald; Draetta, Giulio] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lyssiotis, Costas; Cantley, Lewis] Weill Cornell Med Coll, New York, NY USA. [Seth, Sahil; Giuliani, Virginia; Heffernan, Timothy] MDACC, Inst Appl Canc Sci, Houston, TX USA. [Kimmelman, Alec] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA PR13 DI 10.1158/1538-7445.PANCA2014-PR13 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900189 ER PT J AU Viale, A Pettazzoni, P Lyssiotis, C Ying, HQ Sanchez, N Marchesini, M Carugo, A Green, T Seth, S Giuliani, V Heffernan, T Kimmelman, A Wang, HM Fleming, J Cantley, L DePinho, R Draetta, G AF Viale, Andrea Pettazzoni, Piergiorgio Lyssiotis, Costas Ying, Haoqiang Sanchez, Nora Marchesini, Matteo Carugo, Alessandro Green, Tessa Seth, Sahil Giuliani, Virginia Heffernan, Timothy Kimmelman, Alec Wang, Huamin Fleming, Jason Cantley, Lewis DePinho, Ronald Draetta, Giulio TI Pancreatic tumor stem cells resistant to inhibition of oncogenic signaling are dependent on mitochondrial function SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Viale, Andrea; Pettazzoni, Piergiorgio; Ying, Haoqiang; Sanchez, Nora; Marchesini, Matteo; Carugo, Alessandro; Green, Tessa; Wang, Huamin; Fleming, Jason; DePinho, Ronald; Draetta, Giulio] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lyssiotis, Costas; Cantley, Lewis] Weill Cornell Med Coll, New York, NY USA. [Seth, Sahil; Giuliani, Virginia; Heffernan, Timothy] MDACC, Inst Appl Canc Sci, Houston, TX USA. [Kimmelman, Alec] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA A87 DI 10.1158/1538-7445.PANCA2014-A87 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900077 ER PT J AU Wolpin, BM AF Wolpin, Brian M. TI Pancreatic adenocarcinoma and altered whole-body metabolism SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment CY MAY 18-21, 2014-2015 CL New Orleans, LA SP Amer Assoc Canc Res C1 [Wolpin, Brian M.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2015 VL 75 SU 13 MA IA26 DI 10.1158/1538-7445.PANCA2014-IA26 PG 1 WC Oncology SC Oncology GA DF3RL UT WOS:000371263900172 ER PT J AU Mueser, KT Penn, DL Addington, J Brunette, MF Gingerich, S Glynn, SM Lynde, DW Gottlieb, JD Meyer-Kalos, P McGurk, SR Cather, C Saade, S Robinson, DG Schooler, NR Rosenheck, RA Kane, JM AF Mueser, Kim T. Penn, David L. Addington, Jean Brunette, Mary F. Gingerich, Susan Glynn, Shirley M. Lynde, David W. Gottlieb, Jennifer D. Meyer-Kalos, Piper McGurk, Susan R. Cather, Corinne Saade, Sylvia Robinson, Delbert G. Schooler, Nina R. Rosenheck, Robert A. Kane, John M. TI The NAVIGATE Program for First-Episode Psychosis: Rationale, Overview, and Description of Psychosocial Components SO PSYCHIATRIC SERVICES LA English DT Article ID 1ST EPISODE PSYCHOSIS; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED MULTICENTER TRIAL; LOVING-KINDNESS MEDITATION; RECENT-ONSET SCHIZOPHRENIA; 5-YEAR FOLLOW-UP; EARLY INTERVENTION; POSITIVE PSYCHOTHERAPY; INDIVIDUAL PLACEMENT; STANDARD TREATMENT AB Comprehensive coordinated specialty care programs for first-episode psychosis have been widely implemented in other countries but not in the United States. The National Institute of Mental Health's Recovery After an Initial Schizophrenia Episode (RAISE) initiative focused on the development and evaluation of first-episode treatment programs designed for the U.S. health care system. This article describes the background, rationale, and nature of the intervention developed by the RAISE Early Treatment Program project-known as the NAVIGATE program-with a particular focus on its psychosocial components. NAVIGATE is a team-based, multicomponent treatment program designed to be implemented in routine mental health treatment settings and aimed at guiding people with a first episode of psychosis (and their families) toward psychological and functional health. The core services provided in the NAVIGATE program include the family education program (FEP), individual resiliency training (IRT), supported employment and education (SEE), and individualized medication treatment. NAVIGATE embraces a shared decision-making approach with a focus on strengths and resiliency and on collaboration with clients and family members in treatment planning and reviews. The NAVIGATE program has the potential to fill an important gap in the U.S. health care system by providing a comprehensive intervention specially designed to meet the unique treatment needs of persons recovering from a first episode of psychosis. A clusterrandomized controlled trial comparing NAVIGATE with usual community care has recently been completed. C1 [Mueser, Kim T.; Gottlieb, Jennifer D.; McGurk, Susan R.] Boston Univ, Sargent Coll, Ctr Psychiat Rehabil, Boston, MA 02215 USA. [Mueser, Kim T.; Gottlieb, Jennifer D.; McGurk, Susan R.] Boston Univ, Sargent Coll, Dept Occupat Therapy, Boston, MA 02215 USA. [Penn, David L.; Saade, Sylvia] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Penn, David L.] Australian Catholic Univ, Sch Psychol, Melbourne, Vic, Australia. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Brunette, Mary F.] Geisel Sch Med, Dept Psychiat, Lebanon, NH USA. [Glynn, Shirley M.] Dept Vet Affairs VA Greater Los Angeles Healthcar, MIRECC, Los Angeles, CA USA. [Meyer-Kalos, Piper] Minnesota Ctr Chem & Mental Hlth, Dept Social Work, St Paul, MN USA. [Cather, Corinne] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Robinson, Delbert G.; Kane, John M.] Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. [Schooler, Nina R.] Suny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Rosenheck, Robert A.] VA New England Healthcare Syst, MIRECC, West Haven, CT USA. RP Mueser, KT (reprint author), Boston Univ, Sargent Coll, Ctr Psychiat Rehabil, Boston, MA 02215 USA. EM mueser@bu.edu FU National Institute of Mental Health (NIMH) [HHSN-271-2009-00019C]; NIMH [HHSN271200900019C]; Advanced Center for Intervention and Services Research [P30MH090590]; American Recovery and Reinvestment Act; Alkermes; Bristol-Myers Squibb Foundation; Asubio; Bristol-Meyers Squibb; Janssen Pharmaceuticals; Otsuka; Shire FX Funding for this study was supported by contract HHSN-271-2009-00019C from the National Institute of Mental Health (NIMH). Additional NIMH funding was provided by contract HHSN271200900019C and award P30MH090590 from the Advanced Center for Intervention and Services Research. This project also received funding from the American Recovery and Reinvestment Act. The authors express their appreciation to the following people for contributions to this project: Sue T. Azrin, Ph.D., Christoph U. Correll, M.D., Lisa Dixon, M.D., Susan Essock, Ph.D., Sue Estroff, Ph.D., Amy B. Goldstein, Ph.D., Christina Gomez, B. A., C.C.R.P., Robert K. Heinssen, Ph.D., Colin Iwanski, B.S., Paul Julian, Eoin Killackey, Ph.D., David G. Kingdon, M.D., Kelsey Ludwig, B.S., Patricia Marcy, B.S.N., Priya Matneja, B.S., William R. McFarlane, M.D., Charles Olbert, B.S., Sandra Reese, M.A., James A. Robinson, M.Ed., Richard M. Ryan, Ph.D., Joanne Severe, M.S., and Karen Sullivan, B.A.; Dr. Brunette has received research grants from Alkermes and Bristol-Myers Squibb Foundation. Dr. Robinson has served as a consultant to or received grants from Asubio, Bristol-Meyers Squibb, Janssen Pharmaceuticals, Otsuka, and Shire. Dr. Schooler has received research grants from, served on the advisory boards for, or served as a consultant to Alkermes, Forum (formerly EnVivo), Genentech, Neurocrine, Otsuka, Roche, and Sunovion. Dr. Kane has served as a consultant or advisor to or has received honoraria from Alkermes, Amgen, Bristol-Myers Squibb, Eli Lilly, Esai, Forest Laboratories, Genentech, Gerson Lehman Group, IntraCellular Therapies, Janssen Pharmaceuticals, Jazz, Johnson & Johnson, Lundbeck, MedAvante, Merck, Novartis, Otsuka, Pfizer, Pierre Fabre, Proteus, Reviva, Roche, Sunovion, Takeda, Targacept, and Vanda. He is a shareholder of MedAvante. The other authors report no financial relationships with commercial interests. NR 70 TC 14 Z9 14 U1 6 U2 16 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 JUL PY 2015 VL 66 IS 7 BP 680 EP 690 DI 10.1176/appi.ps.201400413 PG 11 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DE5RO UT WOS:000370689600006 PM 25772766 ER PT J AU Stirman, SW Matza, A Gamarra, J Toder, K Xhezo, R Evans, AC Hurford, M Beck, AT Crits-Christoph, P Creed, T AF Stirman, Shannon Wiltsey Matza, Alexis Gamarra, Jennifer Toder, Katherine Xhezo, Regina Evans, Arthur C. Hurford, Matthew Beck, Aaron T. Crits-Christoph, Paul Creed, Torrey TI System-Level Influences on the Sustainability of a Cognitive Therapy Program in a Community Behavioral Health Network SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CHILDRENS MENTAL-HEALTH; IMPLEMENTATION; CARE; DISSEMINATION; FRAMEWORK AB Objective: The purpose of this study was to examine influences on the sustainability of a program to implement an evidence-based psychotherapy in a mental health system. Methods: Interviews with program administrators, training consultants, agency administrators, and supervisors (N = 24), along with summaries of program evaluation data and program documentation, were analyzed with a directed content-analytic approach. Results: Findings suggested a number of interconnected and interacting influences on sustainability, including alignment with emerging sociopolitical influences and system and organizational priorities; program-level adaptation and evolution; intervention flexibility; strong communication, collaboration, planning, and support; and perceived benefit. These individual factors appeared to mutually influence one another and contribute to the degree of program sustainability achieved at the system level. Although most influences were positive, financial planning and support emerged as potentially both facilitator and barrier, and evaluation of benefits at the patient level remained a challenge. Conclusions: Several factors appeared to contribute to the sustainability of a psychosocial intervention in a large urban mental health system and warrant further investigation. Understanding interconnections between multiple individual facilitators and barriers appears critical to advancing understanding of sustainability in dynamic systems and adds to emerging recommendations for other implementation efforts. In particular, implications of the findings include the importance of implementation strategies, such as long-term planning, coalition building, clarifying roles and expectations, planned adaptation, evaluation, diversification of financing strategies, and incentivizing implementation. C1 [Stirman, Shannon Wiltsey; Gamarra, Jennifer] US Dept Vet Affairs VA, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Stirman, Shannon Wiltsey] Boston Univ, Dept Psychiat, Boston, MA 02215 USA. [Matza, Alexis] US Dept Vet Affairs, Lesbian Gay Bisexual & Transgender Program, Off Patient Care Serv, Cent Off, Washington, DC USA. [Toder, Katherine; Beck, Aaron T.; Crits-Christoph, Paul; Creed, Torrey] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Xhezo, Regina; Evans, Arthur C.; Hurford, Matthew] Philadelphia Dept Behav Hlth & Intellectual DisAb, Philadelphia, PA USA. RP Stirman, SW (reprint author), US Dept Vet Affairs VA, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. EM sws@bu.edu FU National Institute of Mental Health (NIMH) [K99/R00 MH 080100]; Alkermes, Inc. FX Funding for this research was provided by grant K99/R00 MH 080100 from the National Institute of Mental Health (NIMH). When the research was conducted, Dr. Stirman was a fellow at NIMH and the Implementation Research Institute (R25 MH080916). The authors gratefully acknowledge the agencies, clinicians, and consumers who have participated in the Beck Initiative for their contributions to this project. Opinions expressed in this article do not necessarily reflect the viewpoints of the Veterans Health Administration or the National Institutes of Health.; Dr. Crits-Christoph has received research funding from Alkermes, Inc., to conduct analyses of a naturalistic database of treatments for substance abuse in Missouri. The other authors report no financial relationships with commercial interests. NR 24 TC 5 Z9 5 U1 0 U2 5 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 JUL PY 2015 VL 66 IS 7 BP 734 EP 742 DI 10.1176/appi.ps.201400147 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DE5RO UT WOS:000370689600013 PM 25828878 ER PT J AU Addington, J Heinssen, RK Robinson, DG Schooler, NR Marcy, P Brunette, MF Correll, CU Estroff, S Mueser, KT Penn, D Robinson, JA Rosenheck, RA Azrin, ST Goldstein, AB Severe, J Kane, JM AF Addington, Jean Heinssen, Robert K. Robinson, Delbert G. Schooler, Nina R. Marcy, Patricia Brunette, Mary F. Correll, Christoph U. Estroff, Sue Mueser, Kim T. Penn, David Robinson, James A. Rosenheck, Robert A. Azrin, Susan T. Goldstein, Amy B. Severe, Joanne Kane, John M. TI Duration of Untreated Psychosis in Community Treatment Settings in the United States SO PSYCHIATRIC SERVICES LA English DT Article ID 1ST-EPISODE SCHIZOPHRENIA; METAANALYSIS; EPISODE AB Objective: This study is the first to examine duration of untreated psychosis (DUP) among persons receiving care in community mental health centers in the United States. Methods: Participants were 404 individuals (ages 15-40) who presented for treatment for first-episode psychosis at 34 nonacademic clinics in 21 states. DUP and individual- and site-level variables were measured. Results: Median DUP was 74 weeks (mean=193.5 +/- 262.2 weeks; 68% of participants had DUP of greater than six months). Correlates of longer DUP included earlier age at first psychotic symptoms, substance use disorder, positive and general symptom severity, poorer functioning, and referral from outpatient treatment settings. Conclusions: This study reported longer DUP than studies conducted in academic settings but found similar correlates of DUP. Reducing DUP in the United States will require examination of factors in treatment delay in local service settings and targeted strategies for closing gaps in pathways to specialty FEP care. C1 [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Heinssen, Robert K.; Azrin, Susan T.; Goldstein, Amy B.; Severe, Joanne] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Robinson, Delbert G.; Correll, Christoph U.; Kane, John M.] Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. [Marcy, Patricia] Zucker Hillside Hosp, Glen Oaks, NY USA. [Marcy, Patricia] Feinstein Inst Med Res, Manhasset, NY USA. [Schooler, Nina R.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Brunette, Mary F.] Geisel Sch Med, Dept Psychiat, Lebanon, NH USA. [Estroff, Sue] Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. [Penn, David] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Penn, David] Australian Catholic Univ, Melbourne, Vic, Australia. [Mueser, Kim T.] Boston Univ, Ctr Psychiat Rehabil, Boston, MA 02215 USA. [Robinson, James A.] Nathan S Kline Inst Psychiat Res, Informat Sci Div, Orangeburg, NY USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. [Rosenheck, Robert A.] US Dept Vet Affairs, Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. RP Addington, J (reprint author), Univ Calgary, Dept Psychiat, Calgary, AB, Canada. EM jmadding@ucalgary.ca FU American Recovery and Reinvestment Act; National Institute of Mental Health (NIMH) [HHSN271200900019C]; Asubio; Bristol-Myers Squibb; Janssen; Otsuka; Shire; Genentech; Neurocrine; Roche; Sunovion; Alkermes; Bristol-Myers Squibb Foundation; Janssen/JJ FX This work has been funded in whole or in part with funds from the American Recovery and Reinvestment Act and the National Institute of Mental Health (NIMH) under contract HHSN271200900019C. The authors thank RAISE-ETP participants, their families, and clinical and research staff at our 34 sites. The contents are solely the responsibility of the authors and do not necessarily represent the views of NIMH or the U.S. Department of Health and Human Services.; Dr. Delbert G. Robinson has been a consultant to or has received grants from Asubio, Bristol-Myers Squibb, Janssen, Otsuka, and Shire. Dr. Schooler has received research grants from, served on the advisory boards for, or served as a consultant to Forum (formerly EnVivo), Genentech, Neurocrine, Otsuka, Roche, and Sunovion. Ms. Marcy reports owning shares of Pfizer stock. Dr. Brunette has received research grants from Alkermes and Bristol-Myers Squibb Foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from Actelion, Alexza, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, GersonLehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Merck, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda. He also received grant or material support in the form of free medications from Bristol-Myers Squibb, Janssen/J&J, and Otsuka. Dr. Kane has been a consultant or advisor to or has received honoraria from Alkermes, Amgen, Bristol-Myers Squibb, Eli Lilly, Esai, Forrest Labs, Genentech, Gerson Lehman Group, IntraCellular Therapies, Janssen, Jazz, J&J, Lundbeck, MedAvante, Merck, Novartis, Otsuka, Pierre Fabre, Proteus, Pfizer, Roche, Reviva, Sunovion, Takeda, Targacept, and Vanda, and he is a shareholder of MedAvante. The other authors report no financial relationships with commercial interests. NR 15 TC 9 Z9 9 U1 5 U2 9 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 JUL PY 2015 VL 66 IS 7 BP 753 EP 756 DI 10.1176/appi.ps.201400124 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DE5RO UT WOS:000370689600016 PM 25588418 ER PT J AU Andrabi, Y Patino, M Das, CJ Eisner, B Sahani, DV Kambadakone, A AF Andrabi, Yasir Patino, Manuel Das, Chandan J. Eisner, Brian Sahani, Dushyant V. Kambadakone, Avinash TI Advances in CT imaging for urolithiasis SO INDIAN JOURNAL OF UROLOGY LA English DT Review DE Advances; computed tomography; urolithiasis ID DUAL-ENERGY CT; SHOCK-WAVE LITHOTRIPSY; UNENHANCED HELICAL CT; SPIRAL COMPUTERIZED-TOMOGRAPHY; RADIATION-DOSE REDUCTION; URINARY STONE DISEASE; ACUTE FLANK PAIN; STATISTICAL ITERATIVE RECONSTRUCTION; TUBE CURRENT MODULATION; KIDNEY-STONES AB Urolithiasis is a common disease with increasing prevalence worldwide and a lifetime-estimated recurrence risk of over 50%. Imaging plays a critical role in the initial diagnosis, follow-up and urological management of urinary tract stone disease. Unenhanced helical computed tomography (CT) is highly sensitive (> 95%) and specific (> 96%) in the diagnosis of urolithiasis and is the imaging investigation of choice for the initial assessment of patients with suspected urolithiasis. The emergence of multi-detector CT (MDCT) and technological innovations in CT such as dual-energy CT (DECT) has widened the scope of MDCT in the stone disease management from initial diagnosis to encompass treatment planning and monitoring of treatment success. DECT has been shown to enhance pre-treatment characterization of stone composition in comparison with conventional MDCT and is being increasingly used. Although CT-related radiation dose exposure remains a valid concern, the use of low-dose MDCT protocols and integration of newer iterative reconstruction algorithms into routine CT practice has resulted in a substantial decrease in ionizing radiation exposure. In this review article, our intent is to discuss the role of MDCT in the diagnosis and post-treatment evaluation of urolithiasis and review the impact of emerging CT technologies such as dual energy in clinical practice. C1 [Andrabi, Yasir; Patino, Manuel; Sahani, Dushyant V.; Kambadakone, Avinash] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. [Das, Chandan J.] All India Inst Med Sci, Dept Radiol, New Delhi, India. [Eisner, Brian] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Kambadakone, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol,Dept Rad, White 270,55 Fruit St, Boston, MA 02114 USA. EM akambadakone@mgh.harvard.edu NR 82 TC 1 Z9 1 U1 0 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0970-1591 EI 1998-3824 J9 INDIAN J UROL JI Indian J. Urol. PD JUL-SEP PY 2015 VL 31 IS 3 BP 185 EP 193 DI 10.4103/0970-1591.156924 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DE1AV UT WOS:000370359100006 PM 26166961 ER PT J AU Gerits, A Vancraeyenest, P Vreysen, S Laramee, ME Michiels, A Gijsbers, R Van den Haute, C Moons, L Debyser, Z Baekelandt, V Arckens, L Vanduffel, W AF Gerits, Annelies Vancraeyenest, Pascaline Vreysen, Samme Laramee, Marie-Eve Michiels, Annelies Gijsbers, Rik Van den Haute, Chris Moons, Lieve Debyser, Zeger Baekelandt, Veerle Arckens, Lutgarde Vanduffel, Wim TI Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex SO NEUROPHOTONICS LA English DT Article DE promoters; histology; monkey; optogenetics; gene transfer; cell-specific expression ID CENTRAL-NERVOUS-SYSTEM; NONHUMAN PRIMATE BRAIN; VIRUS AAV; LENTIVIRAL VECTORS; GENE-EXPRESSION; PROTEIN-KINASE; IN-VIVO; NEUROLOGICAL DISORDERS; TRANSGENE EXPRESSION; PARKINSONS-DISEASE AB Viral vector-mediated expression of genes (e. g., coding for opsins and designer receptors) has grown increasingly popular. Cell-type specific expression is achieved by altering viral vector tropism through cross-packaging or by cell-specific promoters driving gene expression. Detailed information about transduction properties of most recombinant adeno-associated viral vector (rAAV) serotypes in macaque cortex is gradually becoming available. Here, we compare transduction efficiencies and expression patterns of reporter genes in two macaque neocortical areas employing different rAAV serotypes and promoters. A short version of the calmodulin-kinase-II (CaMKIIa0.4) promoter resulted in reporter gene expression in cortical neurons for all tested rAAVs, albeit with different efficiencies for spread: rAAV2/5>>rAAV2/7>rAAV2/8>rAAV2/9>>rAAV2/1 and proportion of transduced cells: rAAV2/1>rAAV2/5>rAAV2/7= rAAV2/9>rAAV2/8. In contrast to rodent studies, the cytomegalovirus (CMV) promoter appeared least efficient in macaque cortex. The human synapsin-1 promoter preceded by the CMV enhancer (enhSyn1) produced homogeneous reporter gene expression across all layers, while two variants of the CaMKIIa promoter resulted in different laminar transduction patterns and cell specificities. Finally, differences in expression patterns were observed when the same viral vector was injected in two neocortical areas. Our results corroborate previous findings that reporter-gene expression patterns and efficiency of rAAV transduction depend on serotype, promoter, cortical layer, and area. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. C1 [Gerits, Annelies; Vancraeyenest, Pascaline; Vanduffel, Wim] Katholieke Univ Leuven, Lab Neuro & Psychophysiol, Dept Neurosci, O&N2 Herestr 49 Bus 10-21, B-3000 Leuven, Belgium. [Vreysen, Samme; Laramee, Marie-Eve; Arckens, Lutgarde] Katholieke Univ Leuven, Lab Neuroplast & Neuroprote, Fac Sci, B-3000 Leuven, Belgium. [Michiels, Annelies; Van den Haute, Chris; Baekelandt, Veerle] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Dept Neurosci, B-3000 Leuven, Belgium. [Michiels, Annelies; Gijsbers, Rik; Van den Haute, Chris] Katholieke Univ Leuven, Leuven Viral Vector Core, B-3000 Leuven, Belgium. [Gijsbers, Rik; Debyser, Zeger] Katholieke Univ Leuven, Lab Mol Virol & Gene Therapy, Dept Neurosci, B-3000 Flanders, Belgium. [Moons, Lieve] Katholieke Univ Leuven, Lab Neural Circuit Dev & Regenerat, Fac Sci, B-3000 Leuven, Belgium. [Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. RP Vanduffel, W (reprint author), Katholieke Univ Leuven, Lab Neuro & Psychophysiol, Dept Neurosci, O&N2 Herestr 49 Bus 10-21, B-3000 Leuven, Belgium. EM wim@nmr.mgh.harvard.edu OI Laramee, Marie-Eve/0000-0003-0896-6224 NR 81 TC 3 Z9 3 U1 2 U2 4 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2015 VL 2 IS 3 AR 031209 DI 10.1117/1.NPh.2.3.031209 PG 17 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA DE3OR UT WOS:000370540100009 PM 26839901 ER PT J AU Yucel, MA Selb, J Aasted, CM Petkov, MP Becerra, L Borsook, D Boas, DA AF Yuecel, Meryem A. Selb, Juliette Aasted, Christopher M. Petkov, Mike P. Becerra, Lino Borsook, David Boas, David A. TI Short separation regression improves statistical significance and better localizes the hemodynamic response obtained by near-infrared spectroscopy for tasks with differing autonomic responses SO NEUROPHOTONICS LA English DT Article DE functional near-infrared spectroscopy; autonomic nervous system; electrical stimulus; pain; finger tapping; systemic physiology ID STIMULUS-INTENSITY; CEREBRAL HEMODYNAMICS; HUMAN ADULTS; BRAIN; CORTEX; CONNECTIVITY; ACTIVATION; INFANTS; SYSTEM; TISSUE AB Autonomic nervous system response is known to be highly task-dependent. The sensitivity of nearinfrared spectroscopy (NIRS) measurements to superficial layers, particularly to the scalp, makes it highly susceptible to systemic physiological changes. Thus, one critical step in NIRS data processing is to remove the contribution of superficial layers to the NIRS signal and to obtain the actual brain response. This can be achieved using short separation channels that are sensitive only to the hemodynamics in the scalp. We investigated the contribution of hemodynamic fluctuations due to autonomous nervous system activation during various tasks. Our results provide clear demonstrations of the critical role of using short separation channels in NIRS measurements to disentangle differing autonomic responses from the brain activation signal of interest. (C) 2015 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Yuecel, Meryem A.; Selb, Juliette; Becerra, Lino; Borsook, David; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Sch Med,Dept Radiol, 149 13th St, Charlestown, MA 02129 USA. [Aasted, Christopher M.; Petkov, Mike P.; Becerra, Lino; Borsook, David] Boston Childrens Hosp, Ctr Pain & Brain, Dept Anaesthesia, Boston, MA 02115 USA. [Aasted, Christopher M.; Petkov, Mike P.; Becerra, Lino; Borsook, David] Boston Childrens Hosp, Ctr Pain & Brain, Dept Radiol, Boston, MA 02115 USA. [Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Yucel, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Sch Med,Dept Radiol, 149 13th St, Charlestown, MA 02129 USA. EM mayucel@nmr.mgh.harvard.edu FU NIBIB NIH HHS [R01 EB006385, P41 EB015896]; NIGMS NIH HHS [R01 GM104986] NR 46 TC 4 Z9 4 U1 1 U2 2 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2015 VL 2 IS 3 AR 035005 DI 10.1117/1.NPh.2.3.035005 PG 10 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA DE3OR UT WOS:000370540100014 PM 26835480 ER PT J AU Chew, KW Bhattacharya, D McGinnis, KA Horwich, TB Tseng, CH Currier, JS Butt, AA AF Chew, Kara W. Bhattacharya, Debika McGinnis, Kathleen A. Horwich, Tamara B. Tseng, Chi-hong Currier, Judith S. Butt, Adeel A. CA ERCHIVES Elect Retrieved Cohort HC TI Short Communication: Coronary Heart Disease Risk by Framingham Risk Score in Hepatitis C and HIV/Hepatitis C-Coinfected Persons SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HIV-INFECTED PATIENTS; COMBINATION ANTIRETROVIRAL THERAPY; CHRONIC HCV INFECTION; INSULIN-RESISTANCE; CARDIOVASCULAR RISK; VIRUS-INFECTION; LIVER-DISEASE; ASSOCIATION; ATHEROSCLEROSIS; STEATOSIS AB We compared the Framingham risk score (FRS) for 10-year coronary heart disease (CHD) risk in age- and race-matched hepatitis C virus (HCV)-infected and HCV-uninfected persons: 114,073 HCV-infected (111,436 HCV-monoinfected and 2,637 HIV/HCV-coinfected) and 122,996 HCV-uninfected (121,380 HIV and HCV-uninfected and 1,616 HIV-monoinfected) males without cardiovascular disease, diabetes, or hepatitis B. In unadjusted analyses, FRS was similar between the HCV-infected and HCV-uninfected groups [median (interquartile range, IQR) risk points 13 (10-14) vs. 13 (10-14), p = 0.192]. Cholesterol levels were lower and current smoking more prevalent in the HCV groups (both HCV and HIV/HCV) compared with the uninfected groups (p < 0.001 for both). Prevalence of non-FRS CHD risk factors, such as substance abuse and chronic kidney disease, in the cohort was high, and differed by HCV and HIV status. Adjusting for age, race/ethnicity, body mass index, chronic kidney disease, drug and alcohol use, and HIV status, HCV infection was associated with minimally lower FRS (beta = -0.095 risk points, p < 0.001), suggesting a small but significant difference in 10-year CHD risk estimation in HCV-infected as compared to HCV-uninfected persons when measuring risk by FRS. Given the complex relationship between HCV, HIV, and CHD risk factors, some of which are not captured by the FRS, the FRS may underestimate CHD risk in HCV-monoinfected and HIV/HCV-coinfected persons. HCV-and HIV/HCV-specific risk scores may be needed to optimize CHD risk stratification. C1 [Chew, Kara W.; Bhattacharya, Debika; Horwich, Tamara B.; Tseng, Chi-hong; Currier, Judith S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90025 USA. [McGinnis, Kathleen A.; Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. RP Chew, KW (reprint author), Univ Calif Los Angeles, Ctr Clin AIDS Res & Educ, 11075 Santa Monica Blvd,Suite 100, Los Angeles, CA 90025 USA. EM kchew@mednet.ucla.edu OI Butt, Adeel/0000-0002-1118-1826 FU UCLA AIDS Institute and Center for AIDS Research [NIH P30AI028697] FX This project was supported by the UCLA AIDS Institute and Center for AIDS Research (NIH P30AI028697). This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System and the central data repositories maintained by the VA Information Resource Center, including the National Patient Care Database, Decisions Support System Database, and Pharmacy Benefits Management Database. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 38 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUL PY 2015 VL 31 IS 7 BP 718 EP 722 DI 10.1089/aid.2014.0284 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DD4IJ UT WOS:000369885400009 PM 25858663 ER PT J AU Zenteno, AC Carnes, T Levi, R Daily, BJ Price, D Moss, SC Dunn, PF AF Zenteno, Ana C. Carnes, Tim Levi, Retsef Daily, Bethany J. Price, Devon Moss, Susan C. Dunn, Peter F. TI Pooled Open Blocks Shorten Wait Times for Nonelective Surgical Cases SO ANNALS OF SURGERY LA English DT Article DE open blocks; operations research; OR scheduling; patient flow; pooling ID OPERATING-ROOM; EFFICIENCY; SURGERY; DEMAND AB Objective: Assess the impact of the implementation of a data-driven scheduling strategy that aimed to improve the access to care of nonelective surgical patients at Massachusetts General Hospital (MGH). Background: Between July 2009 and June 2010, MGH experienced increasing throughput challenges in its perioperative environment: approximately 30% of the nonelective patients were waiting more than the prescribed amount of time to get to surgery, hampering access to care and aggravating the lack of inpatient beds. Methods: This work describes the design and implementation of an "open block" strategy: operating room (OR) blocks were reserved for nonelective patients during regular working hours (prime time) and their management centralized. Discrete event simulation showed that 5 rooms would decrease the percentage of delayed patients from 30% to 2%, assuming that OR availability was the only reason for preoperative delay. Results: Implementation began in January 2012. We compare metrics for June through December of 2012 against the same months of 2011. The average preoperative wait time of all nonelective surgical patients decreased by 25.5% (P < 0.001), even with a volume increase of 9%. The number of bed-days occupied by nonurgent patients before surgery declined by 13.3% whereas the volume increased by 4.5%. Conclusions: The large-scale application of an open-block strategy significantly improved the flow of nonelective patients at MGH when OR availability was a major reason for delay. Rigorous metrics were developed to evaluate its performance. Strong managerial leadership was crucial to enact the new practices and turn them into organizational change. C1 [Zenteno, Ana C.; Levi, Retsef] MIT, Sloan Sch Management, Operat Management, Cambridge, MA 02139 USA. [Carnes, Tim] KPMG LLP, Amsterdam, Netherlands. [Daily, Bethany J.; Dunn, Peter F.] Massachusetts Gen Hosp, Perioperat Adm, Boston, MA 02114 USA. [Price, Devon] Stanford Hosp & Clin, Stanford, CA USA. [Moss, Susan C.] Partners Healthcare, Business Planning Dept, Boston, MA USA. RP Dunn, PF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM pdunn@mgh.harvard.edu FU NSF [DMS-0732175, CMMI-0846554]; AFOSR [FA9550-11-1-0150, FA9550-08-1-0369]; Massachusetts General Hospital; Massachusetts Institute of Technology Sloan School of Management FX Professor Levi is partially supported by NSF grants DMS-0732175 and CMMI-0846554 (CAREER Award) and AFOSR awards FA9550-11-1-0150 and FA9550-08-1-0369. This research project was conducted under protocols #2011P001124 (Massachusetts General Hospital) and #1201004856 (Massachusetts Institute of Technology). Support was provided by Massachusetts General Hospital and Massachusetts Institute of Technology Sloan School of Management. The views expressed herein do not represent the views of neither one of these institutions. The remaining authors have no conflicts of interest or financial disclosures to make. NR 21 TC 4 Z9 4 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 JUL PY 2015 VL 262 IS 1 BP 60 EP 67 DI 10.1097/SLA.0000000000001003 PG 8 WC Surgery SC Surgery GA DD0LV UT WOS:000369612400039 PM 26061212 ER PT J AU Loehrer, AP Song, ZR Auchincloss, HG Hutter, MM AF Loehrer, Andrew P. Song, Zirui Auchincloss, Hugh G. Hutter, Matthew M. TI Influence of Health Insurance Expansion on Disparities in the Treatment of Acute Cholecystitis SO ANNALS OF SURGERY LA English DT Article DE access to health care; acute cholecystitis; disparities; health care reform; health policy; racial disparities ID DELAYED LAPAROSCOPIC CHOLECYSTECTOMY; RACIAL DISPARITIES; PAYER STATUS; CARE REFORM; MASSACHUSETTS; MORTALITY; HOSPITALS; SURGERY; METAANALYSIS; TRIALS AB Objective: To evaluate the impact of the 2006 Massachusetts (MA) health reform on disparities in the management of acute cholecystitis (AC). Background: Immediate cholecystectomy has been shown to be the optimal treatment for AC, yet variation in care persists depending upon insurance status and patient race. How increased insurance coverage impacts these disparities in surgical care is not known. Methods: A cohort study of patients admitted with AC in MA and 3 control states from 2001 through 2009 was performed using the Hospital Cost andUtilization Project State Inpatient Databases. We examined all nonelderly white, black, or Latino patients by insurance type and patient race, evaluating changes in the probability of undergoing immediate cholecystectomy and disparities in receiving immediate cholecystectomy before and after Massachusetts health reform. Results: Data from 141,344 patients hospitalized for AC were analyzed. Before the 2006 reform, government-subsidized/self-pay (GS/SP) patients had a 6.6 to 9.9 percentage-point lower (P < 0.001) probability of immediate cholecystectomy in both MA control states. The MA insurance expansion was independently associated with a 2.5 percentage-point increased probability of immediate cholecystectomy for all GS/SP patients in MA (P = 0.049) and a 5.0 percentage-point increased probability (P = 0.011) for nonwhite, GS/SP patients compared to control states. Racial disparities in the probability of immediate cholecystectomy seen before health care reform were no longer statistically significant after reform in MA while persisting in control states. Conclusions: The MA health reform was associated with increased probability of undergoing immediate cholecystectomy for AC and reduced disparities in undergoing cholecystectomy by insurance status and patient race. C1 [Loehrer, Andrew P.; Auchincloss, Hugh G.; Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Song, Zirui] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Song, Zirui] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Loehrer, AP (reprint author), Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, 165 Cambridge St,Suite 403, Boston, MA 02114 USA. EM aloehrer@partners.org FU Department of Surgery, Massachusetts General Hospital, Boston, MA FX This study was supported by Department of Surgery, Massachusetts General Hospital, Boston, MA. There are no conflicts of interest to report. NR 38 TC 9 Z9 9 U1 2 U2 2 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 JUL PY 2015 VL 262 IS 1 BP 139 EP 145 DI 10.1097/SLA.0000000000000970 PG 7 WC Surgery SC Surgery GA DD0LV UT WOS:000369612400049 PM 25775059 ER PT J AU Kelly, KJ Yoon, SS Kuk, D Qin, LX Dukleska, K Chang, KK Chen, YL Delaney, TF Brennan, MF Singer, S AF Kelly, Kaitlyn J. Yoon, Sam S. Kuk, Deborah Qin, Li-Xuan Dukleska, Katerina Chang, Kevin K. Chen, Yen-Lin Delaney, Thomas F. Brennan, Murray F. Singer, Samuel TI Comparison of Perioperative Radiation Therapy and Surgery Versus Surgery Alone in 204 Patients With Primary Retroperitoneal Sarcoma A Retrospective 2-Institution Study SO ANNALS OF SURGERY LA English DT Article DE electron beam radiation therapy; intensity-modulated radiation therapy; neoadjuvant radiation therapy; proton beam radiation therapy; retropertioneal sarcoma ID SOFT-TISSUE SARCOMAS; ELECTRON-BEAM RADIOTHERAPY; RANDOMIZED-TRIAL; DOSE-ESCALATION; COMPETING RISK; LIPOSARCOMA; IRRADIATION; RECURRENCE; RESECTION; MARGIN AB Objective: To compare outcomes of patients with retroperitoneal or pelvic sarcoma treated with perioperative radiation therapy (RT) versus those treated without perioperative RT. Background: RT for retroperitoneal or pelvic sarcoma is controversial, and few studies have compared outcomes with and without RT. Methods: Prospectively maintained databases were reviewed to retrospectively compare patients with primary retroperitoneal or pelvic sarcoma treated during 2003-2011. Multivariate Cox regression models were used to assess associations with the primary endpoints: local recurrence-free survival (LRFS) and disease-specific survival. Results: At 1 institution, 172 patients were treated with surgery alone, whereas at another institution 32 patients were treated with surgery and perioperative proton beam RT or intensity-modulated RT with or without intra-operative RT. The groups were similar in age, tumor size, grade, and margin status (all P > 0.08). The RT group had a higher percentage of pelvic tumors (P = 0.03) and a different distribution of histologies (P = 0.04). Perioperative morbidity was higher in the RT group (44% vs 16% of patients; P = 0.004). After a median follow-up of 39 months, 5-year LRFS was 91% (95% confidence interval, 79%-100%) in the RT group and 65% (57%-74%) in the surgery-only group (P = 0.02). On multivariate analysis, RT was associated with better LRFS (hazard ratio, 0.26; P = 0.03). Five-year disease-specific survival was 93% (95% confidence interval, 82%-100%) in the RT group and 85% (78%-92%) in the surgery-only group (P = 0.3). Conclusions: The addition of advanced-modality RT to surgery for primary retroperitoneal or pelvic sarcoma was associated with improved LRFS, although this did not translate into significantly better disease-specific survival. This treatment strategy warrants further investigation in a randomized trial. C1 [Kelly, Kaitlyn J.; Yoon, Sam S.; Dukleska, Katerina; Brennan, Murray F.; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Dept Surg, Sarcoma Dis Management Program, New York, NY 10021 USA. [Yoon, Sam S.; Chang, Kevin K.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kuk, Deborah; Qin, Li-Xuan] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY USA. [Chen, Yen-Lin; Delaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Singer, S (reprint author), Mem Sloan Kettering Canc Ctr, Gastr & Mixed Tumor Serv, Dept Surg, Howard Bldg,H1205,1275 York Ave, New York, NY 10021 USA. EM singers@mskcc.org FU SPORE in Soft-Tissue Sarcoma [P50 CA140146]; NIH/NCI Cancer Center Support grant [P30 CA08748] FX Supported by the SPORE in Soft-Tissue Sarcoma (P50 CA140146; S.S., L.Q.) and by an NIH/NCI Cancer Center Support grant P30 CA08748. The authors declare no conflicts of interest. NR 30 TC 14 Z9 14 U1 0 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 JUL PY 2015 VL 262 IS 1 BP 156 EP 162 DI 10.1097/SLA.0000000000001063 PG 7 WC Surgery SC Surgery GA DD0LV UT WOS:000369612400051 PM 26061213 ER PT J AU Jonker, MA Heneghan, AF Fechner, JH Pierre, JF Sano, Y Lan, JG Kudsk, KA AF Jonker, Mark A. Heneghan, Aaron F. Fechner, John H. Pierre, Joseph F. Sano, Yoshifumi Lan, Jinggang Kudsk, Kenneth A. TI Gut Lymphocyte Phenotype Changes After Parenteral Nutrition and Neuropeptide Administration SO ANNALS OF SURGERY LA English DT Article DE bombesin; lymphocyte phenotype; mucosal immunity; parenteral nutrition; T regulatory cells ID UPPER RESPIRATORY-TRACT; B-CELL DIFFERENTIATION; MAJOR ABDOMINAL-TRAUMA; A IMMUNE-RESPONSE; MUCOSAL IMMUNITY; BACTERIAL PNEUMONIA; SEPTIC MORBIDITY; IN-VITRO; FED MICE; BOMBESIN AB Objective: To define gut-associated lymphoid tissue (GALT) phenotype changes with parenteral nutrition (PN) and PN with bombesin (BBS). Background: PN reduces respiratory tract (RT) and GALT Peyer patch and lamina propria lymphocytes, lowers gut and RT immunoglobulin A (IgA) levels, and destroys established RT antiviral and antibacterial immunity. BBS, an enteric nervous system neuropeptide, reverses PN-induced IgA and RT immune defects. Methods: Experiment 1: Intravenously cannulated ICR mice received chow, PN, or PN + BBS injections for 5 days. LSR-II flow cytometer analyzed Peyer patches and lamina propria isolated lymphocytes for homing phenotypes (L-selectin(+) and LPAM-1(+)) and state of activation (CD25(+), CD44(+)) in T (CD3(+))-cell subsets (CD4(+) and CD8(+)) along with homing phenotype (L-selectin(+) and LPAM-1(+)) in naive B (IgD(+)) and antigen-activated (Ig(-) Dor IgM(+)) B (CD45R/B220(+)) cells. Experiment 2: Following the initial experiment 1 protocol, lamina propria T regulatory cell phenotype was evaluated by Foxp3 expression. Results: Experiment 1: PN significantly reduced lamina propria (1) CD4(+) CD25(+) (activated) and (2) CD4(+) CD25(+) LPAM-1(+) (activated cells homed to the lamina propria) T cells, whereas PN-BBS assimilated chow levels. PN significantly reduced lamina propria (1) IgD+ (naive), (2) IgD-LPAM(+) (antigen-activated homed to the lamina propria) and CD44(+) memory B cells, whereas PN-BBS assimilated chow levels. Experiment 2: PN significantly reduced lamina propria CD4(+) CD25(+) Foxp3(+) T regulatory cells compared with chow-fed mice, whereas PN + BBS assimilated chow levels. Conclusions: PN reduces lamina propria activated and T regulatory cells and also naive and memory B cells. BBS addition to PN maintains these cell phenotypes, demonstrating the intimate involvement of the enteric nervous system in mucosal immunity. C1 [Jonker, Mark A.; Heneghan, Aaron F.; Fechner, John H.; Pierre, Joseph F.; Sano, Yoshifumi; Lan, Jinggang; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave,G5-341 CSC, Madison, WI 53792 USA. [Heneghan, Aaron F.; Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Kudsk, KA (reprint author), Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, 600 Highland Ave,G5-341 CSC, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu RI Fechner, John/C-5962-2016 OI Fechner, John/0000-0002-8220-7237 FU Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [I01BX001672]; National Institute of Health (NIH) [R01 GM53439] FX This research is supported by Award Number I01BX001672 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. This work is also supported by National Institute of Health (NIH) grant R01 GM53439. NR 50 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 JUL PY 2015 VL 262 IS 1 BP 194 EP 201 DI 10.1097/SLA.0000000000000878 PG 8 WC Surgery SC Surgery GA DD0LV UT WOS:000369612400057 PM 25563877 ER PT J AU Mishra, RK Yang, W Roy, J Anderson, AH Bansal, N Chen, J DeFilippi, C Delafontaine, P Feldman, HI Kallem, R Kusek, JW Lora, CM Rosas, SE Go, AS Shlipak, MG AF Mishra, Rakesh K. Yang, Wei Roy, Jason Anderson, Amanda H. Bansal, Nisha Chen, Jing DeFilippi, Christopher Delafontaine, Patrice Feldman, Harold I. Kallem, Radhakrishna Kusek, John W. Lora, Claudia M. Rosas, Sylvia E. Go, Alan S. Shlipak, Michael G. CA CRIC Study Investigators TI Kansas City Cardiomyopathy Questionnaire Score Is Associated With Incident Heart Failure Hospitalization in Patients With Chronic Kidney Disease Without Previously Diagnosed Heart Failure Chronic Renal Insufficiency Cohort Study SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; hospitalization; renal insufficiency, chronic ID QUALITY-OF-LIFE; ACUTE MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR STRUCTURE; HEALTH-STATUS; EJECTION FRACTION; NATRIURETIC PEPTIDE; DIASTOLIC FUNCTION; RISK; CKD; ECHOCARDIOGRAPHY AB Background-Chronic kidney disease is a risk factor for heart failure (HF). Patients with chronic kidney disease without diagnosed HF have an increased burden of symptoms characteristic of HF. It is not known whether these symptoms are associated with occurrence of new onset HF. Methods and Results-We studied the association of a modified Kansas City Cardiomyopathy Questionnaire with newly identified cases of hospitalized HF among 3093 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study who did not report HF at baseline. The annually updated Kansas City Cardiomyopathy Questionnaire score was categorized into quartiles (Q1-4) with the lower scores representing the worse symptoms. Multivariable-adjusted repeated measure logistic regression models were adjusted for demographic characteristics, clinical risk factors for HF, N-terminal probrain natriuretic peptide level and left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction. Over a mean (+/-SD) follow-up period of 4.3+/-1.6 years, there were 211 new cases of HF hospitalizations. The risk of HF hospitalization increased with increasing symptom quartiles; 2.62, 1.85, 1.14, and 0.74 events per 100 person-years, respectively. The median number of annual Kansas City Cardiomyopathy Questionnaire assessments per participant was 5 (interquartile range, 3-6). The annually updated Kansas City Cardiomyopathy Questionnaire score was independently associated with higher risk of incident HF hospitalization in multivariable-adjusted models (odds ratio, 3.30 [1.66-6.52]; P=0.001 for Q1 compared with Q4). Conclusions-Symptoms characteristic of HF are common in patients with chronic kidney disease and are associated with higher short-term risk for new hospitalization for HF, independent of level of kidney function, and other known HF risk factors. C1 [Mishra, Rakesh K.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yang, Wei; Roy, Jason; Anderson, Amanda H.; Feldman, Harold I.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kallem, Radhakrishna] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Bansal, Nisha] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Chen, Jing] Tulane Univ, Dept Hypertens & Nephrol, New Orleans, LA 70118 USA. [Delafontaine, Patrice] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [DeFilippi, Christopher] Univ Maryland, Dept Med, College Pk, MD 20742 USA. [Kusek, John W.] NIDDKD, NIH, Bethesda, MD USA. [Lora, Claudia M.] Univ Illinois, Div Nephrol, Champaign, IL 61820 USA. [Rosas, Sylvia E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Rosas, Sylvia E.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Go, Alan S.] Kaiser Permanente Div Res, Oakland, CA USA. [Mishra, Rakesh K.; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, 4150 Clement St 111A1, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu OI Delafontaine, Patrice/0000-0003-3744-3617 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland from the NCATS component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1TR000433]; University of Illinois at Chicago Clinical and Translational Science Award [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR [UCSF-CTSI UL1 RR-024131]; [R01 DK066488] FX This project was supported by R01 DK066488 award (principal investigator Dr Shlipak). Funding for the Chronic Renal Insufficiency Cohort (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 U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the NCATS component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago Clinical and Translational Science Award UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. NR 28 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2015 VL 8 IS 4 BP 702 EP U31 DI 10.1161/CIRCHEARTFAILURE.115.002097 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1XZ UT WOS:000369717800004 PM 25985796 ER PT J AU Badar, AA Perez-Moreno, AC Hawkins, NM Jhund, PS Brunton, APT Anand, IS McKelvie, RS Komajda, M Zile, MR Carson, PE Gardner, RS Petrie, MC McMurray, JJV AF Badar, Athar A. Perez-Moreno, Ana Cristina Hawkins, Nathaniel M. Jhund, Pardeep S. Brunton, Alan P. T. Anand, Inder S. McKelvie, Robert S. Komajda, Michel Zile, Michael R. Carson, Peter E. Gardner, Roy S. Petrie, Mark C. McMurray, John J. V. TI Clinical Characteristics and Outcomes of Patients With Coronary Artery Disease and Angina Analysis of the Irbesartan in Patients With Heart Failure and Preserved Systolic Function Trial SO CIRCULATION-HEART FAILURE LA English DT Article DE angina pectoris; coronary artery disease; heart failure; human; irbesartan ID SUDDEN CARDIAC DEATH; REDUCED EJECTION FRACTION; POPULATION; MODEL; RISK AB Background-The aim of our study was to investigate the relationship between coronary artery disease (CAD), angina, and clinical outcomes in patients with heart failure and preserved ejection fraction enrolled in the irbesartan in patients with heart failure and preserved systolic function (I-Preserve) trial. Methods and Results-The mean follow-up period for the 4128 patients enrolled in I-Preserve was 49.5 months. Patients were divided into 4 mutually exclusive groups according to history of CAD and angina: patients with no history of CAD or angina (n=2008), patients with no history of CAD but a history of angina (n=649), patients with a history of CAD but no angina (n=468), and patients with a history of CAD and angina (n=1003); patients with no known CAD or angina were the reference group. After adjustment for other prognostic variables using Cox proportional-hazard models, patients with CAD but no angina were found to be at higher risk of all-cause mortality (hazard ratio [HR], 1.58 [1.22-2.04]; P<0.01) and sudden death (HR, 2.12 [1.33-3.39]; P<0.01), compared with patients with no CAD or angina. Patients with CAD and angina were also at higher risk of all-cause mortality (HR, 1.29 [1.05-1.59]; P=0.02) and sudden death (HR, 1.83 [1.24-2.69]; P<0.01) compared with the same reference group and had the highest risk of unstable angina or myocardial infarction (HR, 5.84 [3.43-9.95]; P<0.01). Conclusions-Patients with heart failure and preserved ejection fraction and CAD are at higher risk of all-cause mortality and sudden death when compared with those without CAD. C1 [Badar, Athar A.; Perez-Moreno, Ana Cristina; Jhund, Pardeep S.; Brunton, Alan P. T.; Gardner, Roy S.; Petrie, Mark C.; McMurray, John J. V.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Badar, Athar A.; Gardner, Roy S.; Petrie, Mark C.] Golden Jubilee Natl Hosp, Scottish Natl Adv Heart Failure Serv, Glasgow, Lanark, Scotland. [Hawkins, Nathaniel M.] Univ British Columbia, Div Cardiol, Vancouver, BC V5Z 1M9, Canada. [Anand, Inder S.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA. [McKelvie, Robert S.] McMaster Univ, Hamilton Hlth Sci, Hamilton, ON, Canada. [Komajda, Michel] Hop La Pitie Salpetriere, Paris, France. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC USA. [Carson, Peter E.] Georgetown Univ, Washington, DC 20057 USA. [Carson, Peter E.] Washington DC Vet Affairs Med Ctr, Washington, DC USA. RP McMurray, JJV (reprint author), Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. EM john.mcmurray@glasgow.ac.uk OI Perez Moreno, Ana Cristina/0000-0001-9265-6880; mcmurray, john/0000-0002-6317-3975; Jhund, Pardeep/0000-0003-4306-5317 NR 18 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 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2015 VL 8 IS 4 BP 717 EP 724 DI 10.1161/CIRCHEARTFAILURE.114.002024 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1XZ UT WOS:000369717800006 PM 26067854 ER PT J AU Kheirbek, RE Fletcher, RD Bakitas, MA Fonarow, GC Parvataneni, S Bearden, D Bailey, FA Morgan, CJ Singh, S Blackman, MR Zile, MR Patel, K Ahmed, MB Tucker, RO Brown, CJ Love, TE Aronow, WS Roseman, JM Rich, MW Allman, RM Ahmed, A AF Kheirbek, Raya E. Fletcher, Ross D. Bakitas, Marie A. Fonarow, Gregg C. Parvataneni, Sridivya Bearden, Donna Bailey, Frank A. Morgan, Charity J. Singh, Steven Blackman, Marc R. Zile, Michael R. Patel, Kanan Ahmed, Momanna B. Tucker, Rodney O. Brown, Cynthia J. Love, Thomas E. Aronow, Wilbert S. Roseman, Jeffrey M. Rich, Michael W. Allman, Richard M. Ahmed, Ali TI Discharge Hospice Referral and Lower 30-Day All-Cause Readmission in Medicare Beneficiaries Hospitalized for Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE heart failure; hospice; Medicare; readmission ID RENIN-ANGIOTENSIN INHIBITION; PRESERVED EJECTION FRACTION; CHRONIC KIDNEY-DISEASE; LAST 6 MONTHS; PALLIATIVE CARE; PROPENSITY SCORE; OLDER PATIENTS; DIGOXIN; MORTALITY; OUTCOMES AB Background-Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown. Methods and Results-Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998-2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06-0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04-0.21) and 0.17 (0.08-0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients). Conclusions-A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral. C1 [Kheirbek, Raya E.; Fletcher, Ross D.; Bakitas, Marie A.; Singh, Steven; Ahmed, Ali] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Kheirbek, Raya E.; Bakitas, Marie A.] George Washington Univ, Dept Med, Washington, DC USA. [Fletcher, Ross D.; Singh, Steven; Blackman, Marc R.; Ahmed, Ali] Georgetown Univ, Dept Med, Washington, DC USA. [Bakitas, Marie A.] Univ Alabama Birmingham, Sch Nursing, Birmingham, AL USA. [Bakitas, Marie A.; Bearden, Donna; Ahmed, Momanna B.; Tucker, Rodney O.; Brown, Cynthia J.; Ahmed, Ali] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Roseman, Jeffrey M.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Parvataneni, Sridivya] E Tennessee State Univ, Dept Med, Johnson City, TN 37614 USA. [Bailey, Frank A.] Univ Colorado, Dept Med, Denver, CO 80202 USA. [Zile, Michael R.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Dept Med, Charleston, SC USA. [Patel, Kanan] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Brown, Cynthia J.] Vet Affairs Med Ctr, Dept Med, Birmingham, AL USA. [Love, Thomas E.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Aronow, Wilbert S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Rich, Michael W.] Washington Univ, Dept Med, St Louis, MO USA. [Allman, Richard M.] Dept Vet Affairs, Geriatr & Extended Care Serv, Washington, DC USA. RP Ahmed, A (reprint author), Washington DC Vet Affairs Med Ctr, Ctr Hlth & Aging, 50 Irving St NW, Washington, DC 20422 USA. EM aliahmedmdmph@gmail.com FU Veterans Affairs Capitol Healthcare Network [VISN 5]; National Institutes of Health from the National Heart, Lung, and Blood Institute [R01-HL085561, R01-HL085561-S, R01-HL097047]; National Palliative Care Research Center FX Dr Ahmed is supported by funds from the Veterans Affairs Capitol Healthcare Network (VISN 5) to the Center for Health and Aging and was also, in part, supported by the National Institutes of Health through grants (R01-HL085561, R01-HL085561-S, and R01-HL097047) from the National Heart, Lung, and Blood Institute. Dr Bakitas was, in part, supported by a pilot/exploratory grant from the National Palliative Care Research Center. NR 40 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2015 VL 8 IS 4 BP 733 EP 740 DI 10.1161/CIRCHEARTFAILURE.115.002153 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1XZ UT WOS:000369717800008 PM 26019151 ER PT J AU Vaduganathan, M Butler, J Pitt, B Gheorghiade, M AF Vaduganathan, Muthiah Butler, Javed Pitt, Bertram Gheorghiade, Mihai TI Contemporary Drug Development in Heart Failure Call for Hemodynamically Neutral Therapies SO CIRCULATION-HEART FAILURE LA English DT Article DE blood pressure; blood pressure measurement/monitoring; heart failure; hypotension; pharmacology ID VENTRICULAR EJECTION FRACTIONS; RANDOMIZED CONTROLLED TRIAL; SYSTOLIC BLOOD-PRESSURE; MORTALITY; ENALAPRIL; INSIGHTS; INHIBITION; SURVIVAL; OUTCOMES; MORBIDITY C1 [Vaduganathan, Muthiah] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY USA. [Pitt, Bertram] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 201 Huron,Galter 3-150, Chicago, IL 60601 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 201 Huron,Galter 3-150, Chicago, IL 60601 USA. EM m-gheorghiade@northwestern.edu FU National Institutes of Health; European Union; Health Resource Services Administration; Food and Drug Administration; AuraSense Therapeutics; DaVinci therapeutics; Relypsa; scPharmaceuticals; Tricida; Pfizer; Bayer; AstraZeneca; Merck; Stealth Peptides; Sarfez I; Forret Laboratories; Novartis; Johnson Johnson; Oxygen Biotherapeutics; Juventas Therapeutics; Abbott Laboratories; Astellas; Astra Zeneca; Bayer Schering Pharma AG; CorThera, Inc; Cytokinetics, Inc; DebioPharm SA; Errekappa Terapeutici (Milan, Italy); GlaxoSmithKline; Medtronic; Novartis Pharma AG; Otsuka Pharmaceuticals; Pericor Therapeutics; Protein Design Laboratories; Sanofi-Aventis; Sigma Tau; Solvay Pharmaceuticals FX Dr Butler reports receiving research support from the National Institutes of Health, European Union, Health Resource Services Administration, and Food and Drug Administration and serving as a consultant for Amgen, Bayer, Celladon, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono, Relypsa, and Trevena. Dr Pitt reports receiving consulting fees from and holding stock and stock options in AuraSense Therapeutics and DaVinci therapeutics, receiving consulting fees from and holding stock options in Relypsa, scPharmaceuticals, and Tricida, receiving consulting fees from Pfizer, Bayer, AstraZeneca, Merck, Stealth Peptides, Sarfez I, and Forret Laboratories, receiving fees for serving on data and safety monitoring boards from Novartis, Johnson & Johnson, and Oxygen Biotherapeutics, receiving fees for serving on a clinical-events committee from Juventas Therapeutics, and holding a pending patent related to site-specific delivery of eplerenone to the myocardium (14/175,733). Dr Gheorghiade reports receiving consultant fees from Abbott Laboratories (modest), Astellas (modest), Astra Zeneca (modest), Bayer Schering Pharma AG (significant), CorThera, Inc (modest), Cytokinetics, Inc (modest), DebioPharm SA (significant), Errekappa Terapeutici (Milan, Italy; modest), GlaxoSmithKline (modest), Johnson & Johnson (modest), Medtronic (significant), Merck (modest), Novartis Pharma AG (significant), Otsuka Pharmaceuticals (significant), Pericor Therapeutics (significant), Protein Design Laboratories (modest), Sanofi-Aventis (modest), Sigma Tau (significant), Solvay Pharmaceuticals (significant). Dr Vaduganathan reports no conflicts. NR 37 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2015 VL 8 IS 4 BP 826 EP 831 DI 10.1161/CIRCHEARTFAILURE.115.002271 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1XZ UT WOS:000369717800018 PM 26199309 ER PT J AU Borlaug, BA Chen, H Lin, G Redfield, MM Lewis, GD Semigran, MJ McNulty, SE LeWinter, M Deswal, A Margulies, KB AF Borlaug, Barry A. Chen, Horng Lin, Grace Redfield, Margaret M. Lewis, Gregory D. Semigran, Mare J. McNulty, Steven E. LeWinter, Martin Deswal, Anita Margulies, Kenneth B. TI Response to Letter Regarding Article, "Effects of Sildenafil on Ventricular and Vascular Function in Heart Failure With Preserved Ejection Fraction" SO CIRCULATION-HEART FAILURE LA English DT Letter C1 [Borlaug, Barry A.; Chen, Horng; Lin, Grace; Redfield, Margaret M.] Mayo Clin, Div Cardiol, Rochester, MN USA. [Lewis, Gregory D.; Semigran, Mare J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [McNulty, Steven E.] Duke Clin Res Inst, Durham, NC USA. [LeWinter, Martin] Univ Vermont, Coll Med, Cardiol Unit, Burlington, VT 05405 USA. [Deswal, Anita] Baylor Coll Med, Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Deswal, Anita] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Margulies, Kenneth B.] Univ Penn, Translat Res Ctr, Philadelphia, PA 19104 USA. RP Borlaug, BA (reprint author), Mayo Clin, Div Cardiol, Rochester, MN USA. FU NHLBI NIH HHS [U10 HL110262, U01 HL084907, U10 HL110338, R01 HL064112] 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 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2015 VL 8 IS 4 BP 840 EP 840 DI 10.1161/CIRCHEARTFAILURE.115.002372 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1XZ UT WOS:000369717800022 PM 26405727 ER PT J AU Rhee, EP AF Rhee, Eugene P. TI Metabolomics and renal disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE metabolite profiling; metabolomics; renal metabolism ID POLYCYSTIC KIDNEY-DISEASE; HEMODIALYSIS-PATIENTS; UREMIC SOLUTES; DIABETIC-NEPHROPATHY; GENERAL-POPULATION; INDOXYL SULFATE; INCIDENT CKD; PLASMA; METABOLITES; MARKERS AB Purpose of review This review summarizes recent metabolomics studies of renal disease, outlining some of the limitations of the literature to date. Recent findings The application of metabolomics in nephrology research has expanded from the initial analyses of uremia to include both cross-sectional and longitudinal studies of earlier stages of kidney disease. Although these studies have nominated several potential markers of incident chronic kidney disease (CKD) and CKD progression, a lack of overlap in metabolite coverage has limited the ability to synthesize results across groups. Furthermore, direct examination of renal metabolite handling has underscored the substantial impact kidney function has on these potential markers (and many other circulating metabolites). In experimental studies, metabolomics has been used to identify a signature of decreased mitochondrial function in diabetic nephropathy and a preference for aerobic glucose metabolism in polycystic kidney disease. In each case, these studies have outlined novel therapeutic opportunities. Finally, as a complement to the longstanding interest in renal metabolite clearance, the microbiome has been increasingly recognized as the source of many plasma metabolites, including some with potential functional relevance to CKD and its complications. Summary The high-throughput, high-resolution phenotyping enabled by metabolomics technologies has begun to provide insight on renal disease in clinical, physiologic, and experimental contexts. C1 [Rhee, Eugene P.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Rhee, Eugene P.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Rhee, EP (reprint author), Simches Res Bldg,Room 3212,185 Cambridge St, Boston, MA 02114 USA. EM eprhee@partners.org FU NIH [K08-DK-090142]; Extramural Grant Program of Satellite Healthcare FX This work was supported by NIH grant K08-DK-090142 and the Extramural Grant Program of Satellite Healthcare, a not-for-profit renal care provider. NR 60 TC 5 Z9 6 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2015 VL 24 IS 4 BP 371 EP 379 DI 10.1097/MNH.0000000000000136 PG 9 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA DD0MD UT WOS:000369613200013 PM 26050125 ER PT J AU Mundel, P Greka, A AF Mundel, Peter Greka, Anna TI Developing therapeutic 'arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE CD80/B7-1; integrin inactivation; nephrotic syndrome; precision medicine; proteinuria ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; MINIMAL-CHANGE DISEASE; URINARY CD80; ABATACEPT; PODOCYTES AB Purpose of review A core mission for modern medicine is the development of precision therapeutics. Cancer therapies have been at the leading edge of this effort, while nephrology has lagged on the path to precision medicine. Breaking the stalemate, recent work revealed CD80 (B7-1) as a candidate for targeted therapy in the treatment of resistant nephrotic syndrome. This review aims to summarize the current state of our understanding of podocyte CD80 biology, its therapeutic implications and the challenges that lie ahead in essential future validation studies. Recent findings The CD80 targeting agent abatacept (CTLA4-Ig), approved to treat rheumatoid arthritis, was shown to induce remission of nephrotic range proteinuria in four patients with recurrence of disease posttransplant and one patient with primary, treatment resistant nephrotic syndrome. The concept of 'CD80-positive' proteinuric kidney disease due to podocyte CD80 staining in patient kidney biopsies was introduced as a molecular biomarker to define disease and guide treatment. The mechanism of action of CTLA4-Ig in podocytes was shown to centre on beta 1 integrin activation in a T-cell independent fashion. Subsequent work revealed a putative role for podocyte CD80 in diabetic kidney disease. Summary These studies have direct implications for patient care, and intense interest has focused on validating these findings in upcoming clinical trials. C1 [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Mundel, Peter; Greka, Anna] Harvard Univ, Sch Med, Boston, MA USA. [Greka, Anna] Brigham & Womens Hosp, Glom NExT Ctr Glomerular Kidney Dis & Novel Expt, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Greka, A (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 4 Blackfan Circle, Boston, MA 02115 USA. EM agreka@rics.bwh.harvard.edu FU NIH [DK099465, DK103658, DK095045, DK057683, DK062472, DK091218] FX A.G. is supported by NIH grants DK099465, DK103658 and DK095045, and P.M. by NIH grants DK057683, DK062472 and DK091218. NR 18 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2015 VL 24 IS 4 BP 388 EP 392 DI 10.1097/MNH.0000000000000137 PG 5 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA DD0MD UT WOS:000369613200015 PM 26050127 ER PT J AU Johnson, SG Gruntowicz, D Chua, T Morlock, RJ AF Johnson, Samuel G. Gruntowicz, Don Chua, Theresa Morlock, Robert J. TI Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention SO JOURNAL OF MANAGED CARE & SPECIALTY PHARMACY LA English DT Article ID COST-EFFECTIVENESS; CLINICAL PHARMACOGENETICS; ATRIAL-FIBRILLATION; CLOPIDOGREL; OUTCOMES; IMPLEMENTATION; METAANALYSIS; PRASUGREL; WARFARIN; TRIAL AB BACKGROUND: Dual antiplatelet therapy is an established standard of care for patients with acute coronary syndrome (ACS) to reduce thrombotic risk. Raduced CYP2C19 activity impairs dopidogrel bio-activation and increases risk of adverse clinical outcomes. Patients with poor and intermediate CYP2C19 metabolizers treated with dopidogrel incur higher cardiovascular event rates, including myocardial infarction, stroke, and stent thrombosis, following ACS than patients with normal CYP2C19 function. Tests are available to identify the CYP2C19 genotype and can be used to support individualization of antiplatelet therapy. OBJECTIVE: To estimate the financial impact of CYP2C19 genotyping in a theoretical cohort of 1,000 patients with ACS, who received percutaneous coronary intervention and coronary stent implantation and were treated with dopidogrel, prasugrel, or ticagrelor in a managed care setting. METHODS: Differences in overall and average cost per patient were estimated based on the rate of CYP2C19 genotyping in a theoretical cohort of 1,000 patients. Sensitivity analysis was carried out for varying costs, adherence, and the percentage of patients treated according to genotyping results. All clinical event costs were reported in terms of 2012 U.S. dollars. The budget impact analysis used published event rates from primary literature to estimate costs of events analysis for 3 different scenarios: Scenario A, no CYP2C19 genotyping; Scenario B, 50% of patients received CYP2C19 genotyping with appropriate treatment based on genotype; and Scenario C, 100% of patients received CYP2C19 genotyping with appropriate treatment based on genotype. RESULTS: According to this model, there was no change in the market share for the 3 antiplatelet agents in Scenario A Initial market share for dopidogrel, prasugrel, and ticagrelor was 93%, 5%, and 2%, respectively; however, use of CYP2C19 genotyping is expected to shift market share from dopidogrel to either prasugrel or ticagrelor. In Scenario B, where 50% of the patients received genotyping, dopidogrel market share was reduced to 83%, while prasugrel increased to 12.1% and ticagrelor increased to 4.9%. In Scenario C; where all patients received genotyping, dopidogrel market share was reduced to 73%, prasugrel increased to 19.3%, and ticagrelor increased to 7.7%. Total estimated cost differences when all possible patients were genotyped included annual savings of roughly $444,852. CONCLUSIONS: Important financial benefits may be realized through use of genotype-guided antiplatelet therapy to reserve prasugrel or ticagrelor use for patients with reduced CYP2C19 activity to avoid costs associated with adverse cardiac events. Copyright (C) 2015, Academy of Managed Care Pharmacy. Al rights reserved. C1 [Johnson, Samuel G.; Chua, Theresa] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Denver, CO 80202 USA. [Johnson, Samuel G.] Kaiser Permanente Colorado, Clin Pharm Serv, Appl Pharmacogen, Aurora, CO USA. [Gruntowicz, Don] Genelex Corp, Seattle, WA USA. [Gruntowicz, Don] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Gruntowicz, Don] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Morlock, Robert J.] YourCareChoice, Ann Arbor, MI USA. RP Johnson, SG (reprint author), Kaiser Permanente Colorado, 16601 E Centretech Pkwy, Aurora, CO 80011 USA. EM samuel.gjohnson@kp.org FU Genelex; Institute of Medicine Anniversary Fellowship FX Morlock and Gruntowicz received funding for this research from Genelex. Johnson received an Institute of Medicine Anniversary Fellowship Grant to support this project. The authors declare no other potential conflicts of interest, financial or otherwise. NR 25 TC 5 Z9 5 U1 1 U2 1 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 2376-0540 EI 2376-1032 J9 J MANAG CARE SPEC PH JI J. Manag. Care Spec. Pharm. PD JUL PY 2015 VL 21 IS 7 BP 552 EP 557 PG 6 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA DC4KV UT WOS:000369190700003 PM 26108379 ER PT J AU Hasegawa, K Tsugawa, Y Cohen, A Camargo, CA AF Hasegawa, Kohei Tsugawa, Yusuke Cohen, Ari Camargo, Carlos A. TI Infectious Disease-related Emergency Department Visits Among Children in the US SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE infectious disease; respiratory infection; bronchiolitis; emergency department; hospitalization ID HEALTH-CARE UTILIZATION; UNITED-STATES; SOCIOECONOMIC-FACTORS; HOSPITALIZATIONS; ROTAVIRUS; DIARRHEA; VACCINE; INFANTS; TRENDS; RISK AB Background: Although most research on infectious diseases (IDs) has focused on hospitalizations, this provides an incomplete picture of healthcare utilization. We describe the burden and epidemiologic features of ID-related emergency department (ED) visits among U.S. children. Methods: We conducted a cross-sectional analysis of the Nationwide Emergency Department Sample, a nationally representative sample of ED patients. We identified children who presented to the ED with a primary diagnosis of ID. Outcome measures were ID-related ED visits, hospitalizations through the ED and ED charges. Results: During 2011, we identified 1,914,509 ID-related ED visits among U.S. children, corresponding to a weighted estimate of 8,524,357 ED visits. This accounted for 28% of all ED visits by children. The frequency of ID-related ED visits was 10,290 visits per 100,000 children. The most common diagnoses were upper respiratory infection (41%), otitis media (18%) and lower respiratory infection (14%). Overall, 62% of ID-related ED visits were made by children with Medicaid; 35% were by those in the lowest income quartile. Among the ID-related ED visits, 424,725 (5%) resulted in hospitalization, with 513 hospitalizations per 100,000 children. The most common reason for hospitalization was lower respiratory infection, which accounted for 40% of all ID-related hospitalizations from the ED. Median charge per ED visit was $ 718, with total annual charges of $ 9.6 billion. Conclusions: The public health burden of IDs, as measured by ED visits, subsequent hospitalizations and associated charges, was substantial. We also found that children with markers of lower socioeconomic status comprised a disproportionately high proportion of ID-related ED visits. C1 [Hasegawa, Kohei; Cohen, Ari; Camargo, Carlos A.] Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. [Hasegawa, Kohei; Cohen, Ari; Camargo, Carlos A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tsugawa, Yusuke] Harvard Interfac Initiat Hlth Policy, Cambridge, MA USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM khasegawa1@partners.org FU NIH (Bethesda, MD) [U01 AI-87881] FX C.A.C. was supported, in part, by NIH U01 AI-87881 (Bethesda, MD). The funding organizations had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data and preparation, review or approval of the manuscript. All of the authors have no conflicts of interest relevant to this article to disclose. NR 27 TC 4 Z9 4 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2015 VL 34 IS 7 BP 681 EP 685 DI 10.1097/INF.0000000000000704 PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DD0CC UT WOS:000369586900004 PM 25860534 ER PT J AU Burton, JR O'Leary, JG Helmke, S Trotter, JF Denning, J Pang, P McHutchison, J Curry, MP Everson, GT AF Burton, James R. O'Leary, Jacquelyn G. Helmke, Steve Trotter, James F. Denning, Jill Pang, Phillip McHutchison, John Curry, Michael P. Everson, Gregory T. TI HepQuant (R) (HQ)-SHUNT Improves in Liver Recipients with Allograft Fibrosis or Cirrhosis During Ledipasvir/Sofosbuvir/Ribavirin Treatment for HCV SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Burton, James R.; Helmke, Steve; Everson, Gregory T.] UC Denver, Hepatol, Aurora, CO USA. [O'Leary, Jacquelyn G.; Trotter, James F.] BUMC, Hepatol, Dallas, TX USA. [Denning, Jill; Pang, Phillip; McHutchison, John] Gilead Sci Inc, Foster City, CA 94404 USA. [Curry, Michael P.] BIDMC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA O-57 BP 103 EP 103 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500058 ER PT J AU Serper, M Kaplan, DE AF Serper, Marina Kaplan, David E. TI The Burden of Immunosuppression Non-Adherence and Post-Transplant Complications among US Veterans SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Serper, Marina; Kaplan, David E.] Univ Penn, Sect Gastroenterol & Hepatol, Philadelphia VA Med Ctr, Philadelphia, PA 19104 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA O-80 BP 110 EP 110 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500081 ER PT J AU Ramaswami, B Yoshida, O Ippolito, R Marrari, M Bentlejewski, C Metes, D Zeevi, A Thomson, A Mazariegos, G Chalasani, G AF Ramaswami, Balathiripurasundari Yoshida, Osamu Ippolito, Renee Marrari, Marilyn Bentlejewski, Carol Metes, Diana Zeevi, Adriana Thomson, Angus Mazariegos, George Chalasani, Geetha TI Pediatric Liver Transplant Recipients With Operational Tolerance Exhibit Features of Immune Activation and Exhaustion SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Ramaswami, Balathiripurasundari; Yoshida, Osamu; Ippolito, Renee; Marrari, Marilyn; Bentlejewski, Carol; Metes, Diana; Zeevi, Adriana; Thomson, Angus; Mazariegos, George; Chalasani, Geetha] Univ Pittsburgh, Starzl Transplantat Inst, Hiilman Ctr Pediat Transplantat, Surg,Pathol,Renal Electrolyte,Childrens Hosp, Pittsburgh, PA USA. [Chalasani, Geetha] VA Pittsburgh Healthcare Syst, VA, Pittsburgh, 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA O-95 BP 115 EP 116 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500096 ER PT J AU Shah, JA Navarro-Alvarez, N Yeh, H Elias, N Ligocka, J Markmann, JF Hertl, M Sachs, DH Vagefi, PA AF Shah, Jigesh A. Navarro-Alvarez, Nalu Yeh, Heidi Elias, Nahel Ligocka, Joanna Markmann, James F. Hertl, Martin Sachs, David H. Vagefi, Parsia A. TI Infusion of Human Factor 7a Restores Circulating Platelets and Prevents TMA in Pig-to-Baboon Liver Xenotransplantation SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Shah, Jigesh A.; Navarro-Alvarez, Nalu; Yeh, Heidi; Elias, Nahel; Ligocka, Joanna; Markmann, James F.; Hertl, Martin; Sachs, David H.; Vagefi, Parsia A.] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA O-94 BP 115 EP 115 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500095 ER PT J AU Basu, PP Shah, NJ Perez, A John, N Gress, F AF Basu, P. Patrick Shah, Niraj James Perez, Audrik John, Nimy Gress, Frank TI Novel Colonoscopy Preparation of Organic Coconut Water With Miralax and Dulcolax in Split Doses for Decompensated Cirrhotics. A Randomized Double Blinded Open Labelled Clinical Pilot Single Centered Observational Study. COSMIC Study SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Basu, P. Patrick; Gress, Frank] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Basu, P. Patrick; Perez, Audrik; John, Nimy] Kings Cty Hosp, Med Ctr, Brooklyn, NY USA. [Shah, Niraj James] Icahn Sch Med Mt Sinai, James J Peters VA Med Ctr, New York, NY 10029 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA P-115 BP 166 EP 166 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500267 ER PT J AU Dima, S Duda, D Cucu, D Eftimie, M Tica, V Bacalbasa, N Croitoru, A Herlea, V Tanase, C Popescu, I AF Dima, Simona Duda, Dan Cucu, Dana Eftimie, Mihai Tica, Valeria Bacalbasa, Nicolae Croitoru, Adina Herlea, Vlad Tanase, Cristiana Popescu, Irinel TI Angiogenic Markers in Patients With Liver Transplantation for Hepatocellular Carcinoma SO TRANSPLANTATION LA English DT Meeting Abstract CT 21st Annual International Congress of the International-Liver-Transplant-Society (ILTS) CY JUL 08-11, 2015 CL Chicago, IL SP Int Liver Transplant Soc C1 [Dima, Simona; Cucu, Dana; Eftimie, Mihai; Tica, Valeria; Bacalbasa, Nicolae; Croitoru, Adina; Herlea, Vlad; Popescu, Irinel] Fundeni Clin Inst, Gen Surg & Liver Transplantat, Bucharest, Bucuresti Ilfov, Romania. [Duda, Dan] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Duda, Dan] Harvard Univ, Sch Med, Boston, MA USA. [Tanase, Cristiana] Maiorescu Univ, Bucharest, Ilfov, Romania. RI Bacalbasa, Nicolae/A-4222-2017; Tanase, Cristiana/C-2473-2011 NR 0 TC 0 Z9 0 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 SU 1 MA P-502 BP 283 EP 283 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DB6LM UT WOS:000368626500678 ER PT J AU Sheu, EG Rattner, DW AF Sheu, Eric G. Rattner, David W. TI Evaluation of the LINX antireflux procedure SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE gastroesophageal reflux disease; LINX device; magnetic sphincter augmentation ID GASTROESOPHAGEAL-REFLUX DISEASE; MAGNETIC SPHINCTER AUGMENTATION; NISSEN FUNDOPLICATION; ANGELCHIK PROSTHESIS; TERM OUTCOMES; DEVICE; FEASIBILITY; SAFETY; TRIAL; GERD AB Purpose of review To evaluate the current data on the safety, efficacy, and indications for magnetic sphincter augmentation (MSA) using the LINX device to treat gastroesophageal reflux disease (GERD). Recent findings The LINX device has demonstrated excellent safety and GERD efficacy in several recent nonblinded, single arm studies with strict inclusion criteria and up to 3 years follow-up. Dysphagia has been the most common adverse effect occurring after LINX. Other gastrointestinal side-effects seen after laparoscopic fundoplication (bloating, gas, and inability to belch) may be less common after LINX. Summary The LINX device is a safe, well tolerated, and effective therapy for GERD in the short term. MSA should be considered for selected GERD patients without significant anatomic or motility defects. However, the long-term safety and efficacy of LINX - both alone and in comparison to current GERD therapies - remains to be determined. C1 [Sheu, Eric G.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Sheu, Eric G.; Rattner, David W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Rattner, David W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Rattner, DW (reprint author), Massachusetts Gen Hosp, 15 Parkman St, Boston, MA 02114 USA. EM drattner@partners.org NR 15 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 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD JUL PY 2015 VL 31 IS 4 BP 334 EP 338 DI 10.1097/MOG.0000000000000189 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DD0EH UT WOS:000369592700011 PM 26039726 ER PT J AU Lee, J Dykstra, B Sackstein, R Rossi, DJ AF Lee, Jungmin Dykstra, Brad Sackstein, Robert Rossi, Derrick J. TI Progress and obstacles towards generating hematopoietic stem cells from pluripotent stem cells SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE cell migration; directed differentiation; hematopoietic stem cell; homing; pluripotency; pluripotent stem cell ID HUMAN CD34(+) CELLS; PROGENITOR CELLS; BONE-MARROW; STROMAL CELLS; IN-VIVO; STEM/PROGENITOR CELLS; FORCED EXPRESSION; HUMAN FIBROBLASTS; DEFINED FACTORS; NOD/SCID MICE AB Purpose of review Human pluripotent stem cells (PSCs) have the potential to provide an inexhaustible source of hematopoietic stem cells (HSCs) that could be used in disease modeling and in clinical applications such as transplantation. Although the goal of deriving definitive HSCs from PSCs has not been achieved, recent studies indicate that progress is being made. This review will provide information on the current status of deriving HSCs from PSCs, and will highlight existing challenges and obstacles. Recent findings Recent strides in HSC generation from PSCs has included derivation of developmental intermediates, identification of transcription factors and small molecules that support hematopoietic derivation, and the development of strategies to recapitulate niche-like conditions. Summary Despite considerable progress in defining the molecular events driving derivation of hematopoietic progenitor cells from PSCs, the generation of robust transplantable HSCs from PSCs remains elusive. We propose that this goal can be facilitated by better understanding of the regulatory pathways governing HSC identity, development of HSC supportive conditions, and examining the marrow homing properties of PSC-derived HSCs. C1 [Lee, Jungmin; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lee, Jungmin; Rossi, Derrick J.] Boston Childrens Hosp, Program Cellular & Mol Med, Div Hematol Oncol, Boston, MA USA. [Dykstra, Brad; Sackstein, Robert; Rossi, Derrick J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA. [Dykstra, Brad; Sackstein, Robert; Rossi, Derrick J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Program Excellence Glycosci, Boston, MA USA. [Sackstein, Robert] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Hematol, Boston, MA USA. [Rossi, Derrick J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Rossi, Derrick J.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Rossi, DJ (reprint author), 200 Longwood Ave,Warren Alpert Bldg Room 149e, Boston, MA 02115 USA. EM derrick.rossi@childrens.harvard.edu FU NIH (NHLBI Program of Excellence in Glycosciences) [PO1 HL107146, R01HL107630, U01DK072473]; Leona M. and Harry B. Helmsley Charitable Trust; Harvard Stem Cell Institute; New York Stem Cell Foundation FX The study was supported in part by NIH grants PO1 HL107146 (NHLBI Program of Excellence in Glycosciences) (R.S.), R01HL107630 (D.J.R.), and U01DK072473 (D.J.R.), the Leona M. and Harry B. Helmsley Charitable Trust (D.J.R.), the Harvard Stem Cell Institute (D.J.R.), and the New York Stem Cell Foundation. NR 76 TC 2 Z9 2 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2015 VL 22 IS 4 BP 317 EP 323 DI 10.1097/MOH.0000000000000147 PG 7 WC Hematology SC Hematology GA DD0QQ UT WOS:000369624900007 PM 26049752 ER PT J AU Kinsella, SD Chauvin, NA Diaz, T Morey, JM Wells, L AF Kinsella, Stuart D. Chauvin, Nancy A. Diaz, Tomas Morey, Jose M. Wells, Lawrence TI Traumatic Shoulder Dislocation Among Adolescents: Hill-Sachs Lesion Volume and Recurrent Instability SO JOURNAL OF PEDIATRIC ORTHOPAEDICS LA English DT Article DE shoulder dislocation; magnetic resonance arthrography; adolescent; Hill-Sachs ID ARTHROSCOPIC BANKART REPAIR; GLENOHUMERAL INSTABILITY; BONE DEFECTS; REMPLISSAGE; OUTCOMES; MOTION; RANGE; JOINT AB Background: Accurate assessment of Hill-Sachs lesions (HSLs) and their relationship to the glenoid track is essential to optimizing management following traumatic shoulder dislocation. The purpose of this study was to measure the size of HSLs by a novel method with magnetic resonance (MR) arthrography and to investigate the relationship between lesion size and instability history in adolescents (below 19 y of age) with a history of traumatic dislocation. Methods: All shoulder MR arthrograms queried to identify HSLs over a 4-year period were retrospectively reviewed and independently evaluated by 2 blinded musculoskeletal radiologists. HSLs were evaluated on axial T1-weighted fat-saturated images. For each consecutive image slice in which the HSL was identified, a freehand region of interest was constructed along the compression fracture cavity. Region of interest sum was multiplied by image slice thickness (and gap between slices if present) to generate a total HSL volume (mm(3)). Subject chart review was then performed to acquire demographic data, including shoulder dislocation history. Results: A total of 30 patients met inclusion criteria and included 22 boys (mean age, 16.3 y) and 8 girls (mean age, 16.4 y). Four patients had a history of 1 traumatic dislocation, 12 had a history of 2, and 14 had a history of >= 3. The average size of the HSL for all patients was 3.8mm(3) (range, 0.52 to 11mm(3)). There was no significant difference in HSL volume between the 21 skeletally immature (3.7mm(3)) and 9 skeletally mature (4.2mm(3)) patients (P=0.67). Patients with a history of 1, 2, or 3+ dislocations had an average HSL volume of 1.3, 3.7, and 4.7mm(3), respectively. The measurement method revealed excellent inter-reader reliability (P=0.00). There was a statistically significant difference between dislocation history group mean HSL volumes (P=0.019), as well as a statistically significant difference between the number of dislocations and lesion volume (P=0.011). Conclusions: HSLs can be effectively measured in adolescent patients using MR arthrography and patients with larger HSLs have more recurrent instability episodes, potentially meriting greater and earlier attention to the defect. Level of Evidence: Prognostic/diagnostic study level IV. C1 [Kinsella, Stuart D.] Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. [Chauvin, Nancy A.; Wells, Lawrence] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Chauvin, Nancy A.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wells, Lawrence] Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Morey, Jose M.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Kinsella, SD (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM skinsella@partners.org 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 0271-6798 EI 1539-2570 J9 J PEDIATR ORTHOPED JI J. Pediatr. Orthop. PD JUL-AUG PY 2015 VL 35 IS 5 BP 455 EP 461 PG 7 WC Orthopedics; Pediatrics SC Orthopedics; Pediatrics GA DD0BE UT WOS:000369584500007 PM 25264552 ER PT J AU Busic, M Spasovski, G Zota, V Codreanu, I Sarajlic, L Simeonova, M Milojicic, N Nikolov, I Ashkenazi, T Durro, V Delmonico, FL AF Busic, Mirela Spasovski, Goce Zota, Victor Codreanu, Igor Sarajlic, Lada Simeonova, Maryana Milojicic, Nenad Nikolov, Igor Ashkenazi, Tamar Durro, Vjollca Delmonico, Francis L. TI South East European Health Network Initiative for Organ Donation and Transplantation SO TRANSPLANTATION LA English DT Editorial Material C1 [Busic, Mirela] Minist Hlth, Inst Transplantat & Biomed, Zagreb, Croatia. [Spasovski, Goce] Univ Skopje, Dept Nephrol, Skopje, Macedonia. [Zota, Victor] Natl Transplant Agcy, Bucharest, Romania. [Codreanu, Igor] Transplant Agcy, Kishinev, Moldova. [Sarajlic, Lada] Fed Minist Hlth, Ctr Transplantat Med, Sarajevo, Bosnia & Herceg. [Simeonova, Maryana] Bulgarian Execut Agcy Transplantat, Sofia, Bulgaria. [Milojicic, Nenad] Minist Hlth, Direct Biomed, Belgrade, Serbia. [Nikolov, Igor] Univ Clin Nephrol, Skopje, Macedonia. [Ashkenazi, Tamar] Minist Hlth, Israel Transplant Ctr, Tel Aviv, Israel. [Durro, Vjollca] Minist Hlth, Hosp Dept, Tirana, Albania. [Delmonico, Francis L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Busic, M (reprint author), Minist Hlth, Inst Transplantat & Biomed, Zagreb, Croatia. EM Mirela.Busic@miz.hr NR 2 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 IS 7 BP 1302 EP 1304 DI 10.1097/TP.0000000000000726 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DC2XX UT WOS:000369083200005 PM 26147131 ER PT J AU Madariaga, MLL Michel, SG La Muraglia, GM Sihag, S Leonard, DA Farkash, EA Colvin, RB Cetrulo, CL Huang, CA Sachs, DH Madsen, JC Allan, JS AF Madariaga, Maria Lucia L. Michel, Sebastian G. La Muraglia, Glenn M., II Sihag, Smita Leonard, David A. Farkash, Evan A. Colvin, Robert B. Cetrulo, Curtis L., Jr. Huang, Christene A. Sachs, David H. Madsen, Joren C. Allan, James S. TI Recipient-matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine SO TRANSPLANTATION LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; HUMAN RENAL-ALLOGRAFTS; RAT-LIVER ALLOGRAFTS; PERIPHERAL-BLOOD; CELL-MIGRATION; TRANSPLANTATION; REJECTION; CHIMERISM; MICROCHIMERISM; ANTIBODIES AB Background. Allograft rejection continues to be a vexing problem in clinical lung transplantation, and the role played by passenger leukocytes in the rejection or acceptance of an organ is unclear. We tested whether recipient-matching of donor graft passenger leukocytes would impact graft survival in a preclinical model of orthotopic left lung transplantation. Methods. In the experimental group (group 1), donor lungs were obtained from chimeric swine, in which the passenger leukocytes (but not the parenchyma) were major histocompatibility complex-matched to the recipients (n = 3). In the control group (group 2), both the donor parenchyma and the passenger leukocytes were major histocompatibility complex-mismatched to the recipients (n = 3). Results. Lungs harvested from swine previously rendered chimeric by hematopoietic stem cell transplantation using recipient-type cells showed a high degree of passenger leukocyte chimerism by immunohistochemistry and flow cytometry. The chimeric lungs containing passenger leukocytes matched to the lung recipient (group 1) survived on average 107 days (range, 80-156). Control lung allografts (group 2) survived on average 45 days (range, 29-64; P < 0.05). Conclusions. Our data indicate that recipient-matching of passenger leukocytes significantly prolongs lung allograft survival. C1 [Madariaga, Maria Lucia L.; Michel, Sebastian G.; La Muraglia, Glenn M., II; Sihag, Smita; Leonard, David A.; Farkash, Evan A.; Colvin, Robert B.; Cetrulo, Curtis L., Jr.; Huang, Christene A.; Sachs, David H.; Madsen, Joren C.; Allan, James S.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Dept Surg, Boston, MA 02114 USA. RP Allan, JS (reprint author), Massachusetts Gen Hosp, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM jallan@partners.org FU NCRR NIH HHS [C06 RR020135, C06RR020135-01]; NHLBI NIH HHS [F32 HL117540, P01 HL018646, F32HL117540, P01HL18646]; NIAID NIH HHS [R01AI84657, R01 AI084657, K23 AI108951] NR 42 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 IS 7 BP 1372 EP 1378 DI 10.1097/TP.0000000000000676 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DC2XX UT WOS:000369083200018 PM 25757217 ER PT J AU Martin, DE Nakagawa, TA Siebelink, MJ Bramstedt, KA Brierley, J Dobbels, F Rodrigue, JR Sarwal, M Shapiro, R Dominguez-, B Danovitch, G Sweet, SC Trompeter, RS Moazam, F Bos, MA Delmonico, FL AF Martin, Dominique E. Nakagawa, Thomas A. Siebelink, Marion J. Bramstedt, Katrina A. Brierley, Joe Dobbels, Fabienne Rodrigue, James R. Sarwal, Minnie Shapiro, Ron Dominguez-Gil, Beatriz Danovitch, Gabriel Sweet, Stuart C. Trompeter, Richard S. Moazam, Farhat Bos, Michael A. Delmonico, Francis L. TI Pediatric Deceased Donation-A Report of the Transplantation Society Meeting in Geneva SO TRANSPLANTATION LA English DT Article ID ORGAN DONATION; CARDIAC DEATH; CIRCULATORY DETERMINATION; ALLOCATION POLICY; DONOR HOSPITALS; BRAIN-DEATH; CHILDREN; RECOMMENDATIONS; IMPACT; MANAGEMENT AB The Ethics Committee of The Transplantation Society convened a meeting on pediatric deceased donation of organs in Geneva, Switzerland, on March 21 to 22, 2014. Thirty-four participants from Africa, Asia, the Middle East, Oceania, Europe, and North and South America explored the practical and ethical issues pertaining to pediatric deceased donation and developed recommendations for policy and practice. Their expertise was inclusive of pediatric intensive care, internal medicine, and surgery, nursing, ethics, organ donation and procurement, psychology, law, and sociology. The report of the meeting advocates the routine provision of opportunities for deceased donation by pediatric patients and conveys an international call for the development of evidence-based resources needed to inform provision of best practice care in deceased donation for neonates and children. C1 [Martin, Dominique E.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Hlth Equ, Melbourne, Vic, Australia. [Nakagawa, Thomas A.] Wake Forest Sch Med, Dept Anesthesiol & Pediat, Winston Salem, NC USA. [Siebelink, Marion J.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Bramstedt, Katrina A.] Bond Univ, Fac Hlth Sci & Med, Robina, Qld, Australia. [Brierley, Joe] Great Ormond St Hosp Sick Children, London, England. [Dobbels, Fabienne] Univ Leuven KU Leuven, Dept Publ Hlth & Primary Care, Leuven, Belgium. [Rodrigue, James R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Sarwal, Minnie] Univ Calif San Francisco, Div Transplant Surg, San Francisco, CA 94143 USA. [Shapiro, Ron] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. [Dominguez-Gil, Beatriz] Org Nacl Trasplantes, Madrid, Spain. [Danovitch, Gabriel] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Sweet, Stuart C.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Trompeter, Richard S.] UCL Ctr Nephrol, Royal Free Campus, London, England. [Moazam, Farhat] SIUT, Ctr Biomed Eth & Culture, Karachi, Pakistan. [Bos, Michael A.] Eth Comm, Transplantat Soc, Montreal, PQ, Canada. [Delmonico, Francis L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Martin, DE (reprint author), Univ Melbourne, Level 4,207 Bouverie St, Melbourne, Vic 3010, Australia. EM dominique.martin@unimelb.edu.au NR 52 TC 4 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 IS 7 BP 1403 EP 1409 DI 10.1097/TP.0000000000000758 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DC2XX UT WOS:000369083200022 PM 25996634 ER PT J AU Gabardi, S Asipenko, N Fleming, J Lor, K McDevitt-Potter, L Mohammed, A Rogers, C Tichy, EM Weng, R Lee, RA AF Gabardi, Steven Asipenko, Natalya Fleming, James Lor, Kevin McDevitt-Potter, Lisa Mohammed, Anisa Rogers, Christin Tichy, Eric M. Weng, Renee Lee, Ruth-Ann TI Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients SO TRANSPLANTATION LA English DT Article ID SOLID-ORGAN TRANSPLANTATION; KIDNEY-TRANSPLANTATION; ORAL GANCICLOVIR; 450 MG; PROPHYLAXIS; EFFICACY; SAFETY; IMPACT AB Background. Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). Methods. Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. Results. Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. Conclusions. Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir may provide a significant cost avoidance benefit. C1 [Gabardi, Steven] Brigham & Womens Hosp, Dept Transplant Surg, 75 Francis St, Boston, MA 02115 USA. [Gabardi, Steven; Mohammed, Anisa] Brigham & Womens Hosp, Dept Pharm Serv, 75 Francis St, Boston, MA 02115 USA. [Gabardi, Steven] Brigham & Womens Hosp, Div Renal, 75 Francis St, Boston, MA 02115 USA. [Gabardi, Steven; Rogers, Christin] Harvard Univ, Sch Med, Boston, MA USA. [Asipenko, Natalya] Beth Israel Deaconess Med Ctr, Dept Pharm Serv, Boston, MA 02215 USA. [Fleming, James] Henry Ford Hosp, Dept Pharm Serv, Detroit, MI 48202 USA. [Lor, Kevin] Univ Calif San Diego, Med Ctr, Dept Pharm Serv, 225 Dickinson St, San Diego, CA 92103 USA. [McDevitt-Potter, Lisa] Tufts Med Ctr, Dept Transplant Surg & Pharm Serv, Boston, MA USA. [Tichy, Eric M.] Yale New Haven Med Ctr, Dept Pharm Serv, 20 York St, New Haven, CT 06504 USA. [Weng, Renee] Univ Calif Irvine, Med Ctr, Dept Pharm Serv, Orange, CA USA. [Lee, Ruth-Ann] Massachusetts Gen Hosp, Dept Pharm Serv, Boston, MA 02114 USA. RP Gabardi, S (reprint author), Brigham & Womens Hosp, Dept Transplant Surg, 75 Francis St, Boston, MA 02115 USA.; Gabardi, S (reprint author), Brigham & Womens Hosp, Div Renal, 75 Francis St, Boston, MA 02115 USA. EM sgabardi@partners.org OI Gabardi, Steven/0000-0001-8022-2751 NR 29 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL PY 2015 VL 99 IS 7 BP 1499 EP 1505 DI 10.1097/TP.0000000000000570 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DC2XX UT WOS:000369083200036 PM 25643140 ER PT J AU Kertesz, SG Austin, EL Holmes, SK Pollio, DE Lukas, CV AF Kertesz, Stefan G. Austin, Erika Laine Holmes, Sally K. Pollio, David E. Lukas, Carol VanDeusen TI Housing First and the Risk of Failure A Comment on Westermeyer and Lee (2013) SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Editorial Material DE Homelessness; housing first; substance use treatment; veterans ID CASE-MANAGEMENT PROGRAM; ILL HOMELESS ADULTS; ENDING HOMELESSNESS; TREATMENT OUTCOMES; RANDOMIZED-TRIAL; MENTAL-ILLNESS; DRUG-USE; INTERVENTION; VETERANS; ALCOHOL AB Over the last 5 years, community policies in response to homelessness have shifted toward offering permanent housing accompanied by treatment supports, without requiring treatment success as a precondition. The US Department of Veterans Affairs (VA) has embraced this "Housing First" approach. A 2013 report sounds a contrarian note. In a 16-person quasi-experimental study, 8 veterans who entered VA's permanent supportive housing did poorly, whereas 8 veterans who remained inmore traditional treatment did well. In this commentary, we suggest that the report was problematic in the conceptualization of the matters it sought to address and in its science. Nonetheless, it highlights challenges that must not be ignored. From this report and other research, we now know that even more attention is required to support clinical recovery for Housing First clients. Successful implementation of Housing First requires guidance from agency leaders, and their support for clinical staff when individual clients fare poorly. C1 [Kertesz, Stefan G.; Austin, Erika Laine] Birmingham VA Med Ctr, Mail Stop 151,700 South 19th St, Birmingham, AL 35233 USA. [Kertesz, Stefan G.; Austin, Erika Laine; Pollio, David E.] Univ Alabama Birmingham, Birmingham, AL USA. [Holmes, Sally K.] Boston VA Med Ctr, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Lukas, Carol VanDeusen] Boston Univ, Boston, MA 02215 USA. RP Kertesz, SG (reprint author), Birmingham VA Med Ctr, Mail Stop 151,700 South 19th St, Birmingham, AL 35233 USA. EM skertesz@uabmc.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health [SDR-11233] FX Supported by grant SDR-11233 from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health. NR 36 TC 0 Z9 0 U1 3 U2 6 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 JUL PY 2015 VL 203 IS 7 BP 559 EP 562 DI 10.1097/NMD.0000000000000328 PG 4 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DC2VL UT WOS:000369076000013 PM 26121153 ER PT J AU Zera, CA Bates, DW Stuebe, AM Ecker, JL Seely, EW AF Zera, Chloe A. Bates, David W. Stuebe, Alison M. Ecker, Jeffrey L. Seely, Ellen W. TI Diabetes Screening Reminder for Women With Prior Gestational Diabetes A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MELLITUS; HISTORY AB OBJECTIVE: To evaluate whether an electronic health record (EHR) reminder improves rates of screening for type 2 diabetes in women with prior gestational diabetes. METHODS: We randomly allocated primary care providers (by clinic site) to a reminder for type 2 diabetes screening within the EHR or to usual care. Women with previous gestational diabetes mellitus were identified through an automated search of laboratory results and the problem list. We compared rates of screening during the study period (2010-2012) in women at intervention sites with those at control sites. With a sample size of 850 participants, we had 80% power to detect a 15% difference in screening rates. RESULTS: We included 847 individuals seen at a participating clinic during the study period, of whom 471 were at a reminder clinic and 376 were at a control clinic. A similar proportion of women were screened for type 2 diabetes in both groups (n=265, 56.3% of the reminder group compared with n=206, 54.8% of the control group, P=.67; adjusted odds ratio [OR] 1.04, 95% confidence interval [CI] 0.79-1.38). Patient characteristics associated with risk for diabetes including body mass index (adjusted OR per kg/m(2) 1.05, 95% CI 1.01-1.08) and race (adjusted OR for nonwhite race 2.14, 95% CI 1.57-2.92) were significantly associated with screening. CONCLUSION: A simple EHR reminder did not increase the rate of diabetes screening in women with prior gestational diabetes mellitus. C1 Brigham & Womens Hosp, Div Maternal Fetal Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gen Internal Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Maternal Fetal Med, Dept Obstet & Gynecol, Boston, MA 02114 USA. Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Sch Med, Chapel Hill, NC 27599 USA. RP Zera, CA (reprint author), Brigham & Womens Hosp, Div Maternal Fetal Med, 75 Francis St, Boston, MA 02115 USA. EM czera@partners.org FU Partners Information Services Research Council; National Institutes of Health [K24 HL096141] FX Supported by the Partners Information Services Research Council. Dr. Seely is supported in part by the National Institutes of Health (K24 HL096141). NR 16 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2015 VL 126 IS 1 BP 109 EP 114 DI 10.1097/AOG.0000000000000883 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC2WS UT WOS:000369080100018 PM 26241263 ER PT J AU Barth, WH AF Barth, William H., Jr. TI Persistent Occiput Posterior Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Barth, William H., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Barth, WH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 3 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2015 VL 126 IS 1 BP 213 EP 214 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC2WS UT WOS:000369080100035 PM 26241278 ER PT J AU Phillips, GA Fenton, N Cohen, S Javalkar, K Ferris, M AF Phillips, G. Alexandra Fenton, Nicole Cohen, Sarah Javalkar, Karina Ferris, Maria TI Self-Management and Health Care Use in an Adolescent and Young Adult Medicaid Population With Differing Chronic Illnesses SO PREVENTING CHRONIC DISEASE LA English DT Article ID CHRONIC DISEASE; PROGRAM; SUPPORT; OUTCOMES; INTERVENTIONS; CHILDREN; TOOL AB Introduction Few studies of adults question the validity of the claim that self-management reduces the use of health care services and, as a result, health care costs. The aim of our study was to determine the relationship between self-management and health care use in a population of adolescent and young adult recipients of North Carolina Medicaid with chronic health conditions, who received care in either the pediatric or adult clinic. Our secondary objective was to characterize the patterns of health care use among this same population. Methods One hundred and fifty adolescents or young adults aged 14 to 29 were recruited for this study. Participants completed a demographics questionnaire and the self-management subdomain of the University of North Carolina TRxANSITION Scale. Information on each participant's emergency department and inpatient use was obtained by using the North Carolina Medicaid Provider Portal. Results This cohort had a high level of emergency health care use; average lifetime use was 3.18 (standard deviation [SD], 5.58) emergency department visits, 2.02 (SD, 3.42) inpatient visits, and 12.5 (SD, 23.9) days as an inpatient. Age group (pediatric or adult), diagnosis, race/ethnicity, and sex were controlled for in all analyses. Results indicate that patients with a high rate of disease self-management had more emergency department visits and hospitalizations and a longer length of stay in the hospital than did those with a low rate. Conclusion In a group of North Carolina Medicaid recipients with chronic conditions, better self-management is associated with more health care use. This is likely the result of many factors, including more interactions with health care professionals, greater ability to recognize the need for emergency medical attention, and the use of the emergency department for primary health care. C1 [Phillips, G. Alexandra; Cohen, Sarah; Javalkar, Karina; Ferris, Maria] Univ N Carolina, Chapel Hill, NC 27514 USA. [Fenton, Nicole] Boston Children Canc Ctr, Dana Farber, Boston, MA USA. [Fenton, Nicole] Boston Blood Disorders Ctr, Dana Farber, Boston, MA USA. RP Ferris, M (reprint author), Univ N Carolina, Kidney Ctr, 7021 Burnett Womack,CB 7155, Chapel Hill, NC 27514 USA. EM maria_ferris@med.unc.edu FU University of North Carolina Kidney Center; Renal Research Institute FX This investigation was partially funded by the University of North Carolina Kidney Center and the Renal Research Institute. We thank Dr. William Primack and Dr. Keisha Gibson for their assistance in recruiting participants for this study. NR 17 TC 0 Z9 0 U1 1 U2 5 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2015 VL 12 AR E103 DI 10.5888/pcd12.150023 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DB6ZL UT WOS:000368664100002 PM 26133646 ER PT J AU Girgis, F Walcott, BP Kwon, CS Sheth, SA Asaad, W Nahed, BV Eskandar, EN Coumans, JV AF Girgis, Fady Walcott, Brian P. Kwon, Churl-Su Sheth, Sameer A. Asaad, Wael Nahed, Brian V. Eskandar, Emad N. Coumans, Jean-Valery TI The Absence of Fever or Leukocytosis Does Not Exclude Infection Following Cranioplasty SO CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES LA English DT Article DE cranioplasty; trauma; infections of the nervous system; complication; craniofacial surgery ID SURGICAL SITE INFECTION; BONE FLAPS; CASE SERIES; GRAFT INFECTION; CRANIECTOMY; ABSCESS; PRESERVATION; DIAGNOSIS; PATIENT AB Background: Cranioplasty encompasses various cranial reconstruction techniques that are used following craniectomy due to stroke or trauma. Despite classical infectious signs, symptoms, and radiologic findings, however, the diagnosis of infection following cranioplasty can be elusive, with the potential to result in definitive treatment delay. We sought to determine if fever or leukocytosis at presentation were indicative of infection, as well as to identify any factors that may limit its applicability. Methods: Following institutional review board approval, a retrospective cohort of 239 patients who underwent cranioplasty following craniectomy for stroke or trauma was established from 2001-2011 at a single center (Massachusetts General Hospital). Analysis was then focused on those who developed a surgical site infection, as defined by either frank intra-operative purulence or positive intra-operative cultures, and subsequently underwent operative management. Results: In 27 total cases of surgical site infection, only two had a fever and four had leukocytosis at presentation. This yielded a false-negative rate for fever of 92.6% and for leukocytosis of 85.2%. In regard to infectious etiology, 22 (81.5%) cases generated positive intra-operative cultures, with Propionibacterium acnes being the most common organism isolated. Median interval to infection was 99 days from initial cranioplasty to time of infectious presentation, and average follow-up was 3.4 years. Conclusions: The utilization of fever and elevated white blood cell count in the diagnosis of post-cranioplasty infection is associated with a high false-negative rate, making the absence of these features insufficient to exclude the diagnosis of infection. C1 [Girgis, Fady] Univ Calgary, Foothills Hosp, Dept Neurosurg, Calgary, AB T2N 2T9, Canada. [Walcott, Brian P.; Kwon, Churl-Su; Sheth, Sameer A.; Nahed, Brian V.; Eskandar, Emad N.; Coumans, Jean-Valery] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Asaad, Wael] Brown Univ, Alpert Med Sch, Dept Neurosurg, Providence, RI 02912 USA. [Asaad, Wael] Brown Univ, Alpert Med Sch, Brown Inst Brain Sci, Providence, RI 02912 USA. Rhode Isl Hosp, Providence, RI USA. RP Girgis, F (reprint author), Univ Calgary, Dept Neurosurg, Foothills Med Ctr, 12th Floor,1403,29 St NW, Calgary, AB T2N 2T9, Canada. EM fadygirgis@yahoo.com NR 27 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0317-1671 EI 2057-0155 J9 CAN J NEUROL SCI JI Can. J. Neurol. Sci. PD JUL PY 2015 VL 42 IS 4 BP 255 EP 259 DI 10.1017/cjn.2015.46 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA DB5CC UT WOS:000368530000008 PM 26062405 ER PT J AU Flory, JD AF Flory, Janine D. TI Defining the Construct of Reactive Aggression in Borderline Personality Disorder: Commentary on "Aggression in Borderline Personality Disorder-A Multidimensional Model" SO PERSONALITY DISORDERS-THEORY RESEARCH AND TREATMENT LA English DT Editorial Material ID EMOTION DYSREGULATION; BIOMARKERS C1 [Flory, Janine D.] James J Peters Vet Affairs Med Ctr, 526 OOMll PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA. [Flory, Janine D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. RP Flory, JD (reprint author), James J Peters Vet Affairs Med Ctr, 526 OOMll PTSD 116-A,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM Janine.Flory@mssm.edu NR 11 TC 1 Z9 1 U1 1 U2 1 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1949-2715 EI 1949-2723 J9 PERSONAL DISORD JI Personal. Disord. PD JUL PY 2015 VL 6 IS 3 BP 294 EP 295 DI 10.1037/per0000134 PG 2 WC Psychology, Clinical SC Psychology GA DB6BQ UT WOS:000368598500010 PM 26191824 ER PT J AU Moy, AP Murali, M Kroshinsky, D Duncan, LM Nazarian, RM AF Moy, Andrea Primiani Murali, Mandakolathur Kroshinsky, Daniela Duncan, Lyn M. Nazarian, Rosalynn M. TI Immunologic Overlap of Helper T-Cell Subtypes 17 and 22 in Erythrodermic Psoriasis and Atopic Dermatitis SO JAMA DERMATOLOGY LA English DT Article ID SEVERE PLAQUE PSORIASIS; ADAPTIVE IMMUNITY; DOUBLE-BLIND; EXPRESSION; SKIN; TH17; INTERLEUKIN-17; SECUKINUMAB; DISTINCT; IL-17 AB IMPORTANCE Psoriasis and atopic dermatitis (AD) are inflammatory diseases thought to be mediated by helper T-cell subtypes 1 and 2 (T(H)1 and T(H)2), respectively. Although psoriasis and AD show histopathologic differences during chronic disease, they are difficult to distinguish histologically during erythrodermic exacerbations. OBJECTIVE To determine whether the immune phenotype of helper T cells can differentiate erythrodermic psoriasis and erythrodermic AD by studying skin biopsy specimens of patients with psoriasis and AD during erythrodermic and chronic disease phases. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective study using biopsy samples of psoriasis, AD, and erythroderma belonging to the surgical pathology files of the James HomerWright Pathology Laboratories, Massachusetts General Hospital, and collected from January 1, 2004, through December 31, 2011. Samples were obtained from patients with chronic psoriasis (n = 20), chronic AD (n = 20), erythroderma subsequently diagnosed as psoriasis (n = 7), and erythroderma subsequently diagnosed as AD (n = 5). We evaluated immunohistochemical stains for CD3 and dual stains for CD4 and T-bet, GATA binding protein 3 (GATA3), signal transducer and activator of transcription 3 (STAT3), or basonuclin 2 (BNC2), which are transcription factors reported to be specific and mutually exclusive for T(H)1, T(H)2, T(H)17, and T(H)22 cells, respectively. Two investigators independently counted CD3(+) cells and dual-labeled CD4(+)/T-bet(+), CD4(+)/GATA3(+), CD4(+)/STAT3(+), and CD4(+)/BNC2(+) cells in 5 consecutive high-power fields. MAIN OUTCOMES AND MEASURES We evaluated the percentage of T(H)1, T(H)2, T(H)17, and T(H)22 cells in CD3+ T cells and the T(H)1:T(H)2 ratio in chronic psoriasis, chronic AD, erythrodermic psoriasis, and erythrodermic AD. RESULTS We found a significant difference in the T(H)1:T(H)2 ratio between chronic psoriasis and chronic AD (0.26 and 0.09, respectively; P = .005). However, we detected no significant difference in the percentage of T(H)1 (6.5% and 4.8%), T(H)2 (55.2% and 64.6%), T(H)17 (14.7% and 30.4%), and T(H)22 (3.8% and 3.3%) cells of CD3(+) T cells or in the T(H)1:T(H)2 ratio (0.16 and 0.07) within biopsy specimens from patients with erythrodermic psoriasis and AD, respectively. CONCLUSIONS AND RELEVANCE This study confirms the T(H)1- and T(H)2-skewed phenotype of chronic psoriasis and chronic AD, respectively. However, the immune phenotype, as determined by immunohistochemical analysis, cannot discriminate between these inflammatory diseases in the erythrodermic phase. These findings advance our understanding of the pathophysiological characteristics of erythroderma, psoriasis, and AD and may influence therapeutic decisions. C1 [Moy, Andrea Primiani; Murali, Mandakolathur; Duncan, Lyn M.; Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dermatopathol Unit, Pathol Serv, Boston, MA 02114 USA. [Moy, Andrea Primiani; Murali, Mandakolathur; Kroshinsky, Daniela; Duncan, Lyn M.; Nazarian, Rosalynn M.] Harvard Univ, Sch Med, Boston, MA USA. [Murali, Mandakolathur] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Nazarian, RM (reprint author), Massachusetts Gen Hosp, Dermatopathol Unit, Pathol Serv, 55 Fruit St,Warren 829A, Boston, MA 02114 USA. EM rmnazarian@partners.org FU Harvard Medical School Eleanor; Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine FX This study was supported in part by the Harvard Medical School Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine. NR 38 TC 8 Z9 10 U1 2 U2 2 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 JUL PY 2015 VL 151 IS 7 BP 753 EP 760 DI 10.1001/jamadermatol.2015.2 PG 8 WC Dermatology SC Dermatology GA DA7OE UT WOS:000367992800014 PM 25760640 ER PT J AU Agerbo, E Sullivan, PF Vilhjalmsson, BJ Pedersen, CB Mors, O Borglum, AD Hougaard, DM Hollegaard, MV Meier, S Mattheisen, M Ripke, S Wray, NR Mortensen, PB AF Agerbo, Esben Sullivan, Patrick F. Vilhjalmsson, Bjarni J. Pedersen, Carsten B. Mors, Ole Borglum, Anders D. Hougaard, David M. Hollegaard, Mads V. Meier, Sandra Mattheisen, Manuel Ripke, Stephan Wray, Naomi R. Mortensen, Preben B. TI Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia A Danish Population-Based Study and Meta-analysis SO JAMA PSYCHIATRY LA English DT Article ID CAUSATION-SELECTION ISSUE; CENTRAL RESEARCH REGISTER; GENETIC-VARIANTS; ENVIRONMENT AB IMPORTANCE Schizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult. OBJECTIVE To estimate (1) how strongly the risk for schizophrenia relates to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed to these factors; (3) whether family background interacts with an individual's genetic liability so that specific subgroups are particularly risk prone; and (4) to what extent a proband's genetic makeup mediates the risk associated with familial background. DESIGN, SETTINGS, AND PARTICIPANTS We conducted a nested case-control study based on Danish population-based registers. The study consisted of 866 patients diagnosed as having schizophrenia between January 1, 1994, and December 31, 2006, and 871 matched control individuals. Genome-wide data and family psychiatric and socioeconomic background information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34 600 cases and 45 968 control individuals) were applied to calculate polygenic risk scores. EXPOSURES Polygenic risk scores, parental socioeconomic status, and family psychiatric history. MAIN OUTCOMES AND MEASURES Odds ratios (ORs), attributable risks, liability R-2 values, and proportions mediated. RESULTS Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95% CI, 4.53-14.16 for highest vs lowest decile), socioeconomic status (OR, 8.10; 95% CI, 3.24-20.3 for 6 vs no exposures), and a history of schizophrenia/psychoses (OR, 4.18; 95% CI, 2.57-6.79). The R-2 values were 3.4% (95% CI, 2.1-4.6) for the polygenic risk score, 3.1% (95% CI, 1.9-4.3) for parental socioeconomic status, and 3.4% (95% CI, 2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted for 45.8% (95% CI, 36.1-55.5) and 25.8% (95% CI, 21.2-30.5) of cases, respectively. There was an interaction between the polygenic risk score and family history (P =.03). A total of 17.4% (95% CI, 9.1-26.6) of the effect associated with family history of schizophrenia/psychoses was mediated through the polygenic risk score. CONCLUSIONS AND RELEVANCE Schizophrenia was associated with the polygenic risk score, family psychiatric history, and socioeconomic status. Our study demonstrated that family history of schizophrenia/psychoses is partly mediated through the individual's genetic liability. C1 [Agerbo, Esben; Pedersen, Carsten B.; Mors, Ole; Borglum, Anders D.; Meier, Sandra; Mattheisen, Manuel; Mortensen, Preben B.] Lundbeck Fdn, Initiat Integrat Psychiat Res, Aarhus, Denmark. [Agerbo, Esben; Pedersen, Carsten B.; Meier, Sandra; Mortensen, Preben B.] Aarhus Univ, Natl Ctr Register Based Res, DK-8210 Aarhus V, Denmark. [Agerbo, Esben; Pedersen, Carsten B.; Mortensen, Preben B.] Aarhus Univ, Ctr Integrated Register Based Res, DK-8210 Aarhus V, Denmark. [Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Vilhjalmsson, Bjarni J.] Aarhus Univ, Bioinformat Res Ctr, DK-8210 Aarhus V, Denmark. [Mors, Ole; Borglum, Anders D.] Aarhus Univ Hosp, Dept P, Risskov, Denmark. [Borglum, Anders D.] Aarhus Univ, Dept Biomed, DK-8210 Aarhus V, Denmark. [Borglum, Anders D.] Aarhus Univ, Ctr Integrat Sequencing, DK-8210 Aarhus V, Denmark. [Hougaard, David M.; Hollegaard, Mads V.] Statens Serum Inst, Danish Ctr Neonatal Screening, DK-2300 Copenhagen, Denmark. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Ripke, Stephan] Harvard Univ, Cambridge, MA 02138 USA. [Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia. RP Agerbo, E (reprint author), Aarhus Univ, Ctr Integrated Register Based Res, Fuglesangs Alle 4, DK-8210 Aarhus V, Denmark. EM ea@econ.au.dk RI Vilhjalmsson, Bjarni/K-3971-2014; Pedersen, Carsten Bocker/B-8441-2013; OI Vilhjalmsson, Bjarni/0000-0003-2277-9249; Pedersen, Carsten Bocker/0000-0003-2077-8533; Mortensen, Preben Bo/0000-0002-5230-9865 FU Danish Strategic Research Council; Faculty of Health Sciences at Aarhus University; Lundbeck Foundation; Stanley Medical Research Institute; European Research Council [GA 294838]; Australian National Health and Medical Research Council [613602, 1047956] FX This study was supported by grants from the Danish Strategic Research Council, the Faculty of Health Sciences at Aarhus University, the Lundbeck Foundation, the Stanley Medical Research Institute, and a European Research Council advanced grant (Dr Mortensen; GA 294838). Dr Wray acknowledges funding from the Australian National Health and Medical Research Council (grants 613602 and 1047956). NR 30 TC 25 Z9 25 U1 3 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2015 VL 72 IS 7 BP 635 EP 641 DI 10.1001/jamapsychiatry.2015.0346 PG 7 WC Psychiatry SC Psychiatry GA DA1PQ UT WOS:000367568100003 PM 25830477 ER PT J AU Tsai, AC Venkataramani, AS AF Tsai, Alexander C. Venkataramani, Atheendar S. TI A More Robust Test of the Penrose Hypothesis SO JAMA PSYCHIATRY LA English DT Letter C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Tsai, Alexander C.; Venkataramani, Atheendar S.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Venkataramani, Atheendar S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU US National Institutes of Health [K23MH096220]; Robert Wood Johnson Health and Society Scholars Program FX The authors received no specific funding for this study. Dr Tsai acknowledges salary support from the US National Institutes of Health (K23MH096220) and the Robert Wood Johnson Health and Society Scholars Program. NR 5 TC 1 Z9 1 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2015 VL 72 IS 7 BP 735 EP 736 DI 10.1001/jamapsychiatry.2015.0212 PG 3 WC Psychiatry SC Psychiatry GA DA1PQ UT WOS:000367568100017 PM 25945426 ER PT J AU Rosas, HD Doros, G Bhasin, S Thomas, B Gevorkian, S Malarick, K Matson, W Hersch, SM AF Rosas, Herminia D. Doros, Gheorghe Bhasin, Swati Thomas, Beena Gevorkian, Sona Malarick, Keith Matson, Wayne Hersch, Steven M. TI A systems-level "misunderstanding": the plasma metabolome in Huntington's disease SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID INDOLE-3-PROPIONIC ACID; HOMOVANILLIC-ACID; PARKINSON-DISEASE; KYNURENIC ACID; TRYPTOPHAN; MELATONIN; BIOMARKERS; PREDICTOR; URATE; SERUM AB Objective: Huntington's disease (HD) is a rare neurodegenerative disease caused by the expansion of an N-terminal repeat in the huntingtin protein. The protein is expressed in all cells in the body; hence, peripheral tissues, such as blood, may recapitulate processes in the brain. The plasma metabolome may provide a window into active processes that influence brain health and a unique opportunity to noninvasively identify processes that may contribute to neurodegeneration. Alterations in metabolic pathways in brain have been shown to profoundly impact HD. Therefore, identification and quantification of critical metabolomic perturbations could provide novel biomarkers for disease onset and disease progression. Methods: We analyzed the plasma metabolomic profiles from 52 premanifest (PHD), 102 early symptomatic HD, and 140 healthy controls (NC) using liquid chromatography coupled with a highly sensitive electrochemical detection platform. Results: Alterations in tryptophan, tyrosine, purine, and antioxidant pathways were identified, including many related to energetic and oxidative stress and derived from the gut microbiome. Multivariate statistical modeling demonstrated mutually distinct metabolomic profiles, suggesting that the processes that determine onset were likely distinct from those that determine progression. Gut microbiome-derived metabolites particularly differentiated the PHD metabolome, while the symptomatic HD metabolome was increasingly influenced by metabolites that may reflect mutant huntingtin toxicity and neurodegeneration. Interpretation: Understanding the complex changes in the delicate balance of the metabolome and the gut microbiome in HD, and how they relate to disease onset, progression, and phenotypic variability in HD are critical questions for future research. C1 [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith; Hersch, Steven M.] Dept Neurol, Boston, MA USA. [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith] Ctr Neuroimaging Aging & Neurodegenerat Dis, Boston, MA USA. [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Rosas, Herminia D.] Massachusetts Gen Hosp, Radiol, Boston, MA 02114 USA. [Rosas, Herminia D.] Harvard Univ, Sch Med, Boston, MA USA. [Doros, Gheorghe] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bhasin, Swati; Thomas, Beena; Matson, Wayne] Edith Nourse Rogers Mem Vet Hosp, Bedford, MA USA. [Hersch, Steven M.] Boston Univ, Lab Neurodegenerat & Neurotherapeut, MassGen Inst Neurodegenerat Dis, Boston, MA 02215 USA. RP Rosas, HD (reprint author), Ctr Neuroimaging Aging & Neurodegenerat Dis, 149 13th St Room 2275, Charlestown, MA 02129 USA. EM rosas@helix.mgh.harvard.edu FU FDA HHS [R01 FD003359]; NCCIH NIH HHS [R01 AT000613, U01 AT000613]; NINDS NIH HHS [R56 NS042861, P01 NS058793, R01 NS042861] NR 59 TC 5 Z9 5 U1 3 U2 6 PU WILEY-BLACKWELL 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 JUL PY 2015 VL 2 IS 7 BP 756 EP 768 DI 10.1002/acn3.214 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CZ6UC UT WOS:000367235500005 PM 26273688 ER PT J AU Liu, F Ferreira, E Porter, RM Glatt, V Schinhan, M Shen, Z Randolph, MA Kirker-Head, CA Wehling, C Vrahas, MS Evans, CH Wells, JW AF Liu, F. Ferreira, E. Porter, R. M. Glatt, V. Schinhan, M. Shen, Z. Randolph, M. A. Kirker-Head, C. A. Wehling, C. Vrahas, M. S. Evans, C. H. Wells, J. W. TI RAPID AND RELIABLE HEALING OF CRITICAL SIZE BONE DEFECTS WITH GENETICALLY MODIFIED SHEEP MUSCLE SO EUROPEAN CELLS & MATERIALS LA English DT Article DE Bone healing; gene therapy; muscle; adenovirus; bone morphogenetic protein; sheep; rat; immunosuppression ID PERCUTANEOUS GENE DELIVERY; MORPHOGENETIC PROTEIN-2; RAT; THERAPY; CELLS; MODEL; FK506; IMMUNOSUPPRESSION; REGENERATION; EXPRESSION AB Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials. C1 [Liu, F.; Ferreira, E.; Porter, R. M.; Glatt, V.; Schinhan, M.; Shen, Z.; Wehling, C.; Evans, C. H.; Wells, J. W.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA USA. [Liu, F.; Ferreira, E.; Porter, R. M.; Glatt, V.; Shen, Z.; Vrahas, M. S.; Evans, C. H.; Wells, J. W.] AO Fdn, Collaborat Res Ctr, Davos, Switzerland. [Schinhan, M.] Univ Vienna, Sch Med, Dept Orthoped Surg, Vienna, Austria. [Randolph, M. A.; Vrahas, M. S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthoped Surg, Boston, MA USA. [Kirker-Head, C. A.] Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA 01536 USA. [Wehling, C.] Univ Munich, Sch Med, Munich, Germany. RP Evans, CH (reprint author), Mayo Clin, Rehabil Med Res Ctr, 200 First St SW, Rochester, MN 55905 USA. EM evans.christopher@mayo.edu RI Randolph, Mark/A-4406-2009 FU NIAMS [RO1 AR050243]; AO Foundation (GENDEF) FX The authors thank Prof. Angus Thompson of the University of Pittsburgh School of Medicine for advice concerning immunosuppression with FK506 and SEW2871. This work was funded by NIAMS grant number RO1 AR050243 and the AO Foundation (GENDEF). We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. NR 40 TC 3 Z9 3 U1 0 U2 1 PU AO RESEARCH INSTITUTE DAVOS-ARI PI DAVOS PA CLAVADELERSTRASSE 8, DAVOS, CH 7270, SWITZERLAND SN 1473-2262 J9 EUR CELLS MATER JI Eur. Cells Mater. PD JUL-DEC PY 2015 VL 30 BP 118 EP 131 PG 14 WC Cell & Tissue Engineering; Engineering, Biomedical; Materials Science, Biomaterials SC Cell Biology; Engineering; Materials Science GA CY1BM UT WOS:000366141600009 PM 26388615 ER PT J AU Dusetzina, SB Ellis, S Freedman, RA Conti, RM Winn, AN Chambers, JD Alexander, GC Huskamp, HA Keating, NL AF Dusetzina, Stacie B. Ellis, Shellie Freedman, Rachel A. Conti, Rena M. Winn, Aaron N. Chambers, James D. Alexander, G. Caleb Huskamp, Haiden A. Keating, Nancy L. TI How Do Payers Respond to Regulatory Actions? The Case of Bevacizumab SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID METASTATIC BREAST-CANCER; HEALTH-CARE UTILIZATION; CELL LUNG-CANCER; 1ST-LINE TREATMENT; LOCAL COVERAGE; IMPACT; PACLITAXEL AB Purpose: In February 2008, the US Food and Drug Administration (FDA) granted accelerated approval for bevacizumab for metastatic breast cancer. After public hearings in July 2010, and June 2011, the FDA revoked this approved indication in November 2011, on the basis of additional evidence regarding its risk/benefit profile. The Centers for Medicare and Medicaid Services, local Medicare contractors, and commercial payers varied in their stated intentions to cover bevacizumab after FDA's regulatory actions. We examined payer-specific trends in bevacizumab use after the FDA's regulatory actions. Methods: We used outpatient medical claims compiled by IMS Health to evaluate trends in bevacizumab use for breast cancer for Medicare-insured and commercially insured patients (N = 102,906) using segmented regression. Given that Medicare coverage policies may vary across regional contractors, we estimated trends in bevacizumab use across 10 local coverage areas. In a sensitivity analysis, we estimated trends in bevacizumab use for breast cancer compared with trends in use for lung cancer using difference-in-differences models. Results: Among chemotherapy infusions for breast cancer, bevacizumab use decreased from 31% in July 2010, to 4% in September 2012. Use decreased by 11% among commercially insured and 13% among Medicare-insured patients after July 2010 (interaction P = .68) and continued to decline by 9% per month (interaction P = .61). We observed no contractor-level variation in bevacizumab use among Medicare beneficiaries. During the same period, bevacizumab use for lung cancer was stable. Conclusion: Although insurers varied in public statements regarding coverage intentions, bevacizumab use declined similarly among all payers, suggesting that provider decision making, rather than payer-specific coverage policies, drove reductions. C1 UNC Eshelman Sch Pharm, Chapel Hill, NC USA. Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. Univ Kansas, Sch Med, Kansas City, KS USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Chicago, Chicago, IL 60637 USA. Mem Sloan Kettering Canc Ctr, Ctr Hlth Policy & Outcomes, New York, NY 10021 USA. Johns Hopkins Med, Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Drug Safety & Effectiveness, Baltimore, MD USA. RP Dusetzina, SB (reprint author), Univ N Carolina, Div Pharmaceut Outcomes & Policy, UNC Eshelman Sch Pharm, Dept Hlth Policy & Management,Gillings Sch Global, Kerr Hall,Room 2203, Chapel Hill, NC 27599 USA. EM Dusetzina@unc.edu FU AHRQ HHS [R01 HS0189960]; NCATS NIH HHS [UL1 TR001111]; NCI NIH HHS [K07 CA138906, K24 CA181510] NR 33 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 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD JUL PY 2015 VL 11 IS 4 BP 313 EP + DI 10.1200/JOP.2015.004218 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CY1PQ UT WOS:000366180100018 PM 26060224 ER PT J AU Reddy, P Blouin, GC Yeh, YC Burstein, HJ AF Reddy, Prabashni Blouin, Gayle C. Yeh, Yu-Chen Burstein, Harold J. TI Choosing Treatments on the Basis of Cost: Can Clinicians Opt for Less Expensive Treatments? SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Editorial Material ID ADVANCED BREAST-CANCER; ZOLEDRONIC ACID; BONE METASTASES; DENOSUMAB; OUTCOMES C1 Partners Healthcare, Ctr Drug Policy, Needham, MA 02494 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Reddy, P (reprint author), Partners Healthcare, 115 4th Ave, Needham, MA 02494 USA. EM preddy2@partners.org NR 21 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD JUL PY 2015 VL 11 IS 4 BP 322 EP + DI 10.1200/JOP.2014.003152 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CY1PQ UT WOS:000366180100020 PM 25967907 ER PT J AU Gottlieb, E Mostoslaysky, R AF Gottlieb, Eyal Mostoslaysky, Raul TI Cancer and metabolism: Why should we care? SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material ID MAMMALIAN PROTEIN C1 [Gottlieb, Eyal] Beatson Inst, Canc Res UK, Glasgow G61 1BD, Lanark, Scotland. [Mostoslaysky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Gottlieb, E (reprint author), Beatson Inst, Canc Res UK, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland. EM e.gottlieb@beatson.gla.ac.uk; rmostoslavsky@mgh.harvard.edu RI Gottlieb, Eyal/G-6450-2010 OI Gottlieb, Eyal/0000-0002-9770-0956 NR 10 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUL PY 2015 VL 43 BP 1 EP 2 DI 10.1016/j.semcdb.2015.10.007 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CW3IZ UT WOS:000364887100001 PM 26611348 ER PT J AU Sebastian, C Mostoslavsky, R AF Sebastian, Carlos Mostoslavsky, Raul TI The role of mammalian sirtuins in cancer metabolism SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Sirtuins; Cancer metabolism; NAD deacylases; Aging ID HISTONE DEACETYLASE SIRT6; CELL LUNG-CANCER; PYRUVATE-DEHYDROGENASE ACTIVITY; STRESS-RESPONSIVE DEACETYLASE; INDUCIBLE FACTOR 1-ALPHA; PHOSPHATE SYNTHETASE 1; GLUTAMINE-METABOLISM; CALORIE RESTRICTION; TUMOR-GROWTH; LIFE-SPAN AB Metabolic reprogramming has recently emerged as a key feature of cancer cells, which need to rewire their cellular metabolism in order to sustain their faster proliferation and growth. New insight into the molecular mechanisms governing this metabolic reprogramming has implicated mammalian sirtuins as important regulators of cancer metabolism. Sirtuins are NAD(+)-dependent protein deacylases involved in a variety of biological functions, including life span and health span regulation, genomic stability, tumorigenesis, inflammation, and metabolism. Due to the requirement of HAD' for their function, sirtuins can act as sensors of the metabolic state of the cell and regulate core metabolic pathways in response to cellular stresses, thus being good candidates to control the reprogramming of cellular metabolism that occurs during tumorigenesis. Here, we summarize our current knowledge of the roles of mammalian sirtuins in cancer metabolism, and discuss their implication in controlling this metabolic shift during aging and aging-associated cancers. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Sebastian, Carlos; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu FU NIH [1R01CA175727-01A1, R21CA185416-01, 1R21ES025638-01]; Department of Defense FX Work in the Mostoslavsky's lab is supported in part by NIH grants 1R01CA175727-01A1, R21CA185416-01, and 1R21ES025638-01. R.M. is the Kristine and Bob Higgins MGH Research Scholar, the Warshaw Institute Fellow, and a Howard Goodman Awardee. C.S. is the recipient of a Visionary Postdoctoral Award from the Department of Defense. NR 159 TC 9 Z9 9 U1 2 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUL PY 2015 VL 43 BP 33 EP 42 DI 10.1016/j.semcdb.2015.07.008 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CW3IZ UT WOS:000364887100005 PM 26238985 ER PT J AU Israelsen, WJ Vander Heiden, MG AF Israelsen, William J. Vander Heiden, Matthew G. TI Pyruvate kinase: Function, regulation and role in cancer SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Cancer metabolism; Pyruvate kinase; PKM2 ID SUGAR PHOSPHOTRANSFERASE SYSTEM; STEADY-STATE TREATMENT; TUMOR-CELLS; PROTEIN-KINASE; M2 ISOFORM; KINETIC-PROPERTIES; FRUCTOSE 1,6-DIPHOSPHATE; ALLOSTERIC REGULATION; MULTIMOLECULAR FORMS; TISSUE DISTRIBUTION AB Pyruvate kinase is an enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism. There are four mammalian pyruvate kinase isoforms with unique tissue expression patterns and regulatory properties. The M2 isoform of pyruvate kinase (PKM2) supports anabolic metabolism and is expressed both in cancer and normal tissue. The enzymatic activity of PKM2 is allosterically regulated by both intracellular signaling pathways and metabolites; PKM2 thus integrates signaling and metabolic inputs to modulate glucose metabolism according to the needs of the cell. Recent advances have increased our understanding of metabolic regulation by pyruvate kinase, raised new questions, and suggested the possibility of non-canonical PKM2 functions to regulate gene expression and cell cycle progression via protein protein interactions and protein kinase activity. Here we review the structure, function, and regulation of pyruvate kinase and discuss how these properties enable regulation of PKM2 for cell proliferation and tumor growth. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Israelsen, William J.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, 77 Massachusetts Ave,Bldg 76-561, Cambridge, MA 02139 USA. EM william.israelsen@utsouthwestern.edu; mvh@mit.edu FU NIH [R01CA168653]; Burroughs Wellcome Fund; Sara and Frank McKnight Fund for Biochemical Research FX This work was supported by NIH R01CA168653 and the Burroughs Wellcome Fund. WJI additionally acknowledges support from the Sara and Frank McKnight Fund for Biochemical Research. We thank Aaron M. Hosios, Talya L. Dayton, Katherine R. Mattaini, Lucas B. Sullivan, and Andrea J. Howell for helpful discussion and feedback on the manuscript. NR 119 TC 22 Z9 22 U1 9 U2 24 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD JUL PY 2015 VL 43 BP 43 EP 51 DI 10.1016/j.semcdb.2015.08.004 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA CW3IZ UT WOS:000364887100006 PM 26277545 ER PT J AU Yehia, BR Mody, A Stewart, L Holtzman, CW Jacobs, LM Hines, J Mounzer, K Glanz, K Metlay, JP Shea, JA AF Yehia, Baligh R. Mody, Aaloke Stewart, Leslie Holtzman, Carol W. Jacobs, Lisa M. Hines, Janet Mounzer, Karam Glanz, Karen Metlay, Joshua P. Shea, Judy A. TI Impact of the Outpatient Clinic Experience on Retention in Care: Perspectives of HIV-Infected Patients and Their Providers SO AIDS PATIENT CARE AND STDS LA English DT Letter ID UNITED-STATES; BARRIERS C1 [Yehia, Baligh R.; Mody, Aaloke; Stewart, Leslie; Hines, Janet; Mounzer, Karam; Shea, Judy A.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Jacobs, Lisa M.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Holtzman, Carol W.] Columbia Univ, Mailman Sch Publ Hlth, ICAP, Maseru, Lesotho. [Mounzer, Karam] Philadelphia FIGHT, Jonathan Lax Ctr, Philadelphia, PA USA. [Glanz, Karen] Univ Penn, Sch Nursing, Dept Biobehav Hlth Sci, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Yehia, BR (reprint author), Univ Penn, Perelman Sch Med, Dept Med, 1021 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM byehia@upenn.edu FU Gilead Sciences FX BRY received investigator-initiated research support (to the University of Pennsylvania) and consulting fees from Gilead Sciences. NR 12 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 EI 1557-7449 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JUL 1 PY 2015 VL 29 IS 7 BP 365 EP 369 DI 10.1089/apc.2015.0049 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA CV1AL UT WOS:000363985100001 PM 26061902 ER PT J AU Losoi, H Silverberg, ND Waljas, M Turunen, S Rosti-Otajarvi, E Helminen, M Luoto, TMA Julkunen, J Ouml;hman, J Iverson, GL AF Losoi, Heidi Silverberg, Noah D. Waljas, Minna Turunen, Senni Rosti-Otajarvi, Eija Helminen, Mika Luoto, Teemu Miikka Artturi Julkunen, Juhani Oehman, Juha Iverson, Grant L. TI Resilience Is Associated with Outcome from Mild Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE head injury; patient outcome assessment; resilience; traumatic brain injury ID BNI FATIGUE SCALE; QUALITY-OF-LIFE; HEAD-INJURY; PSYCHOMETRIC PROPERTIES; ILLNESS PERCEPTIONS; RELIABILITY; SYMPTOMS; GUIDELINES; VALIDITY; VERSION AB Resilient individuals manifest adaptive behavior and are better able to recover from adversity. The association between resilience and outcome from mild traumatic brain injury (mTBI) is examined, and the reliability and validity of the Resilience Scale and its short form in mTBI research is evaluated. Patients with mTBI (n=74) and orthopedic controls (n=39) completed the Resilience Scale at one, six, and 12 months after injury. Additionally, self-reported post-concussion symptoms, fatigue, insomnia, pain, post-traumatic stress, and depression, as well as quality of life, were evaluated. The internal consistency of the Resilience Scale and the short form ranged from 0.91 to 0.93 for the mTBI group and from 0.86 to 0.95 for controls. The test-retest reliability ranged from 0.70 to 0.82. Patients with mTBI and moderate-to-high resilience reported significantly fewer post-concussion symptoms, less fatigue, insomnia, traumatic stress, and depressive symptoms, and better quality of life, than the patients with low resilience. No association between resilience and time to return to work was found. Resilience was associated with self-reported outcome from mTBI, and based on this preliminary study, can be reliably evaluated with Resilience Scale and its short form in those with mTBIs. C1 [Losoi, Heidi; Waljas, Minna; Turunen, Senni; Rosti-Otajarvi, Eija; Luoto, Teemu Miikka Artturi; Oehman, Juha] Tampere Univ Hosp, Dept Neurosci & Rehabil, FI-33521 Tampere, Finland. [Losoi, Heidi; Julkunen, Juhani] Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland. [Silverberg, Noah D.] Univ British Columbia, Div Phys Med & Rehabil, Vancouver, BC V5Z 1M9, Canada. [Silverberg, Noah D.] GF Strong Rehab Ctr, Vancouver, BC, Canada. [Helminen, Mika] Univ Tampere & Sci Ctr, Sch Hlth Sci, Tampere, Finland. [Iverson, Grant L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Charlestown, MA USA. [Iverson, Grant L.] MassGen Hosp Children, Sports Concuss Program, Boston, MA USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Losoi, H (reprint author), Tampere Univ Hosp, POB 2000, FI-33521 Tampere, Finland. EM heidi.losoi@gmail.com OI Ohman, Juha/0000-0002-6592-1367; Luoto, Teemu/0000-0002-7329-3284 FU INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium - Department of Defense Psychological Health/Traumatic Brain Injury Research Program [X81XWH-07-CC-CSDoD] FX The authors thank research assistants Anne sSimi and Marika Suopanki-Ervasti for their contribution in data collection. GLI notes that he was supported in part by the INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD). This study was done as part of the first author's PhD thesis research program. NR 47 TC 6 Z9 6 U1 3 U2 11 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 JUL 1 PY 2015 VL 32 IS 13 BP 942 EP 949 DI 10.1089/neu.2014.3799 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0SU UT WOS:000363964200002 PM 25764398 ER PT J AU Watts, LT Shen, Q Deng, SW Chemello, J Duong, TQ AF Watts, Lora Talley Shen, Qiang Deng, Shengwen Chemello, Jonathan Duong, Timothy Q. TI Manganese-Enhanced Magnetic Resonance Imaging of Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE calcium activity; controlled cortical impact; cortical spreading depolarization; gliosis; MEMRI; TBI ID REACTIVE GLIOSIS; MRI; CALCIUM; ACTIVATION; VISUALIZATION; CONNECTIVITY; PERFUSION; ISCHEMIA; MICE AB Calcium dysfunction is involved in secondary traumatic brain injury (TBI). Manganese-enhanced MRI (MEMRI), in which the manganese ion acts as a calcium analog and a MRI contrast agent, was used to study rats subjected to a controlled cortical impact. Comparisons were made with conventional T2 MRI, sensorimotor behavior, and immunohistology. The major findings were: (1) Low-dose manganese (29mg/kg) yielded excellent contrast with no negative effects on behavior scores relative to vehicle; (2) T1-weighted MEMRI was hyperintense in the impact area at 1-3h, hypointense on day 2, and markedly hypointense with a hyperintense area surrounding the core on days 7 and/or 14, in contrast to the vehicle group, which did not show a biphasic profile; (3) in the hyperacute phase, the area of hyperintense T1-weighted MEMRI was larger than that of T2 MRI; (4) glial fibrillary acidic protein staining revealed that the MEMRI signal void in the impact core and the hyperintense area surrounding the core on day 7 and/or 14 corresponded to tissue cavitation and reactive gliosis, respectively; (5) T2 MRI showed little contrast in the impact core at 2h, hyperintense on day 2 (indicative of vasogenic edema), hyperintense in some animals but pseudonormalized in others on day 7 and/or 14; (6) behavioral deficit peaked on day 2. We concluded that MEMRI detected early excitotoxic injury in the hyperacute phase, preceding vasogenic edema. In the subacute phase, MEMRI detected contrast consistent with tissue cavitation and reactive gliosis. MEMRI offers novel contrasts of biological processes that complement conventional MRI in TBI. C1 [Watts, Lora Talley; Shen, Qiang; Deng, Shengwen; Chemello, Jonathan; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Watts, Lora Talley] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Watts, Lora Talley] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Shen, Qiang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu NR 28 TC 4 Z9 5 U1 1 U2 4 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 JUL 1 PY 2015 VL 32 IS 13 BP 1001 EP 1010 DI 10.1089/neu.2014.3737 PG 10 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CV0SU UT WOS:000363964200009 ER PT J AU Mantz, J Rathmell, JP Eisenach, JC AF Mantz, Jean Rathmell, James P. Eisenach, James C. TI Science, Medicine, and the Anesthesiologist SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Mantz, Jean] Paris Val Seine Univ Hosp, AP HP, Dept Anesthesia & Crit Care, Paris, France. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol & Crit Care Med, Boston, MA USA. [Eisenach, James C.] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC USA. RP Mantz, J (reprint author), Paris Val Seine Univ Hosp, AP HP, Dept Anesthesia & Crit Care, Paris, France. EM jean.mantz@bjn.aphp.fr NR 0 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 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2015 VL 123 IS 1 BP 1 EP 4 DI 10.1097/ALN.0000000000000711 PG 4 WC Anesthesiology SC Anesthesiology GA CU4YB UT WOS:000363536300001 ER PT J AU Eikermann, M Kurth, T AF Eikermann, Matthias Kurth, Tobias TI Apply Protective Mechanical Ventilation in the Operating Room in an Individualized Approach to Perioperative Respiratory Care SO ANESTHESIOLOGY LA English DT Editorial Material ID ACUTE LUNG INJURY; TIDAL VOLUMES; SURGERY; DYSFUNCTION C1 [Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Eikermann, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Team Neuroepidemiol, Inserm Res Ctr Epidemiol & Biostat U897, Bordeaux, France. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM meikermann@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 NR 12 TC 3 Z9 3 U1 1 U2 2 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 JUL PY 2015 VL 123 IS 1 BP 12 EP 14 DI 10.1097/ALN.0000000000000707 PG 3 WC Anesthesiology SC Anesthesiology GA CU4YB UT WOS:000363536300005 PM 25978325 ER PT J AU Kurth, CD Cote, CJ AF Kurth, C. Dean Cote, Charles J. TI Postoperative Apnea in Former Preterm Infants General Anesthesia or Spinal Anesthesia-Do We Have an Answer? SO ANESTHESIOLOGY LA English DT Editorial Material ID PREMATURE-INFANTS; RISK C1 [Kurth, C. Dean] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Dept Anesthesia & Pediat, Cincinnati, OH 45220 USA. [Cote, Charles J.] Harvard Univ, Sch Med, MassGen Hosp Children, Div Pediat Anesthesia, Boston, MA USA. [Cote, Charles J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Kurth, CD (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Dept Anesthesia & Pediat, Cincinnati, OH 45220 USA. EM dean.kurth@cchmc.org NR 12 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 JUL PY 2015 VL 123 IS 1 BP 15 EP 17 DI 10.1097/ALN.0000000000000710 PG 3 WC Anesthesiology SC Anesthesiology GA CU4YB UT WOS:000363536300006 PM 26001034 ER PT J AU Ahmed, SU Zhang, Y Chen, L Cohen, A St Hillary, K Vo, T Houghton, M Mao, JR AF Ahmed, Shihab U. Zhang, Yi Chen, Lucy Cohen, Abigail St Hillary, Kristin Vo, Trang Houghton, Mary Mao, Jianren TI Effect of 1.5% Topical Diclofenac on Clinical Neuropathic Pain SO ANESTHESIOLOGY LA English DT Article ID GENERAL-POPULATION; OSTEOARTHRITIS; KNEE; TRIAL; PENNSAID(R); COMBINATION; MANAGEMENT; EFFICACY; THERAPY AB Background: Neuropathic pain is a condition resulting from injury to the peripheral and/or central nervous system. Despite extensive research over the last several decades, neuropathic pain remains difficult to manage. Methods: The authors conducted a randomized, placebo-controlled, double-blinded, and crossover clinical trial to examine the effect of 1.5% topical diclofenac (TD) on neuropathic pain. The authors hypothesized that 1.5% TD would reduce the visual pain score and improve both quantitative sensory testing and functional status in subjects with neuropathic pain. The authors recruited subjects with postherpetic neuralgia and complex regional pain syndrome. The primary outcome was subject's visual pain score. Results: Twenty-eight subjects completed the study (12 male and 16 female) with the mean age of 48.8 yr. After 2 weeks of topical application, subjects in 1.5% TD group showed lower overall visual pain score compared with placebo group (4.9 [1.9] vs. 5.6 [2.1], difference: 0.8; 95% CI, 0.1 to 1.3; P = 0.04) as well as decreased burning pain (2.9 [2.6] vs. 4.3 [2.8], difference, 1.4; 95% CI, 0.2 to 2.6; P = 0.01). There were no statistical differences in constant pain, shooting pain, or hypersensitivity over the painful area between the groups. This self-reported improvement of pain was corroborated by the decreased pain summation detected by quantitative sensory testing. There were no statistically significant changes in functional status in these subjects. There were no complications in both groups. Conclusion: The findings indicate that 1.5% TD may serve as an effective treatment option for patients with neuropathic pain from postherpetic neuralgia and complex regional pain syndrome. C1 [Ahmed, Shihab U.; Zhang, Yi; Chen, Lucy; Cohen, Abigail; St Hillary, Kristin; Vo, Trang; Houghton, Mary; Mao, Jianren] Harvard Univ, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Ctr Translat Pain Res,Sch Med, Boston, MA 02114 USA. RP Ahmed, SU (reprint author), Harvard Univ, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Ctr Translat Pain Res,Sch Med, 101 Merrimac St,Suite 610, Boston, MA 02114 USA. EM sahmed@partners.org FU Covidien, Minneapolis, Minnesota FX This work was supported by an investigator-initiated research proposal funded by Covidien, Minneapolis, Minnesota. NR 28 TC 2 Z9 2 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 JUL PY 2015 VL 123 IS 1 BP 191 EP 198 DI 10.1097/ALN.0000000000000693 PG 8 WC Anesthesiology SC Anesthesiology GA CU4YB UT WOS:000363536300022 PM 25955980 ER PT J AU Meyer, MJ Sasaki, N Eikermann, M AF Meyer, Matthew J. Sasaki, Nobuo Eikermann, Matthias TI Neostigmine: You Can't Have It Both Ways Reply SO ANESTHESIOLOGY LA English DT Letter ID POSTOPERATIVE RESPIRATORY COMPLICATIONS; NEUROMUSCULAR BLOCKING-AGENTS; REVERSAL; SCORE C1 [Meyer, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Meyer, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM matthewjmeyer@gmail.com 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 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2015 VL 123 IS 1 BP 233 EP 234 DI 10.1097/ALN.0000000000000679 PG 2 WC Anesthesiology SC Anesthesiology GA CU4YB UT WOS:000363536300032 PM 26510199 ER EF